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Ann Thorac Surg 2002;73:1049-1054
© 2002 The Society of Thoracic Surgeons

Original article: general thoracic

Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors

Akira Iyoda, MDa, Kenzo Hiroshima, MDb, Masayuki Baba, MDa, Yukio Saitoh, MDa, Hidemi Ohwada, MDb, Takehiko Fujisawa, MD*a

a Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
b Department of Basic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

Accepted for publication December 16, 2001.

* Address reprint requests to Dr Fujisawa, Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
e-mail: fujisawa{at}med.m.chiba-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. In 1999, the World Health Organization (WHO) categorized large cell carcinoma with neuroendocrine features as variants of large cell carcinoma and reclassified neuroendocrine lung tumors, especially typical and atypical carcinoid tumors. However, to date, the clinical relationship between these categories of neuroendocrine lung tumors has not been clearly defined.

Methods. We analyzed 133 cases of neuroendocrine tumors from primary lung carcinoma cases surgically resected. Using electron microscopy and immunohistochemical staining, we classified these cases as typical carcinoid (TC), atypical carcinoid (AC), large cell carcinoma with neuroendocrine features (LCNF), or small cell lung carcinoma (SCLC) based upon the WHO classification.

Results. TC and AC tumors were not related to smoking (p < 0.001) and, unlike LCNF, were found in younger patients (p < 0.001) without a male predominance (p < 0.001). Multivariate analysis revealed that LCNF predicted poorer overall and disease-free survivals comparable with SCLC (overall survival, p = 0.019, hazards ratio, 6.34; disease-free survival, p = 0.007, hazards ratio, 8.19).

Conclusions. The prognoses of LCNF are comparable with those of SCLC, and LCNF should be classified as high-grade neuroendocrine tumors.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Since atypical carcinoid was proposed [1], typical carcinoid (TC), atypical carcinoid (AC), and small cell lung carcinoma (SCLC) were classified together as pulmonary neuroendocrine tumors. In the 1980s and in 1991, a fourth high-grade neuroendocrine tumor of the lung was recognized, such as large cell neuroendocrine tumor [2], intermediate cell neuroendocrine carcinoma [3], or large cell neuroendocrine carcinoma [4]. This has been categorized as lying between AC and SCLC in terms of clinical aggressiveness [5, 6]. Subsequently, in 1998, the criteria established by Arrigoni and colleagues [1], were modified [7] such that a lower mitotic threshold for AC was set at two mitoses per 2 mm2, and TC with necrosis was reclassified as AC. In addition, TC was clearly classified as representing a low-grade neuroendocrine tumor, AC as an intermediate grade neuroendocrine tumor and large cell neuroendocrine carcinoma, and SCLC as high-grade neuroendocrine tumors in survival analysis. In 1999, the World Health Organization [8] adopted this classification for neuroendocrine tumors and reclassified large cell carcinomas into four types based upon neuroendocrine morphology determined by light microscopy and neuroendocrine differentiation demonstrable by immunohistochemistry or electron microscopy: (1) large cell neuroendocrine carcinoma (LCNEC) has both neuroendocrine morphology and evidence of neuroendocrine differentiation by immunohistochemistry and/or electron microscopy; (2) large cell carcinoma with neuroendocrine differentiation (LCCND) lacks neuroendocrine morphology but has neuroendocrine markers by immunohistochemistry or electron microscopy; (3) large cell carcinoma with neuroendocrine morphology (LCCNM) has neuroendocrine morphological features but lacks neuroendocrine markers by immunohistochemistry or electron microscopy; and (4) classic large cell carcinoma lacks neuroendocrine morphology or differentiation.

We found that large cell carcinoma with neuroendocrine features (LCNF), which combined LCNEC, LCCND, and LCCNM, appears to be a more clinically aggressive tumor than classic large cell carcinoma [9]. However, the clinical relationship between carcinoid, LCNF, and SCLC of the lung has not been defined to date. In this study, we have examined the clinical and biological behavior of these different tumor types based upon the WHO classification.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
We analyzed 133 cases diagnosed as TC, AC, LCNF, or SCLC of the lung out of primary lung carcinoma cases resected surgically at Chiba University Hospital between 1969 and 2000. We excluded so-called combined carcinomas with cytological features of mixed small cell carcinoma [8, 10]. We then reviewed these cases by light microscopical analysis retrospectively. We classified TC (Fig 1) as a tumor with carcinoid morphology, lacking necrosis with less than two mitoses per 2 mm2. Tumors with carcinoid morphology, areas of necrosis, and/or 2 to 10 mitoses per 2 mm2 were classified as AC (Fig 2).



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  		Fig 1. Histological features of typical carcinoid. Light microscopy (hematoxylin and eosin stain, x40). The tumor cells reveal growth patterns such as organoid, palisading, or rosette-like arrangements, which suggest neuroendocrine differentiation. These tumor cells have uniform cytologic features with eosinophilic, finely granular cytoplasm and nuclei with a finely granular chromatin pattern. Typical carcinoids have less than two mitoses per 2 mm2 and lack necrosis.

 


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  		Fig 2. Histological features of atypical carcinoid. Light microscopy (hematoxylin and eosin stain, x40). The tumor cells reveal growth patterns such as typical carcinoid. However, atypical carcinoids have 2 to 10 mitoses per 2 mm2 and/or necrosis.

 
In large cell carcinomas, tumors were classified as LCNEC (Figs 3, 4) or LCCNM if they had evidence of the following: (1) neuroendocrine morphology such as organoid nesting, palisading, rosettes, and trabeculae; (2) a high mitotic rate (> 10 mitoses per 2 mm2); (3) necrosis (often large zone); or (4) cytological features of a non-small cell carcinoma (ie, large cell size, low nuclear-to-cytoplasmic ratio, vesicular or fine chromatin, or frequent nucleoli).



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  		Fig 3. Histological features of large cell neuroendocrine carcinoma. Light microscopy (hemotoxylin and eosin stain, x40). The tumor cells have a neuroendocrine morphology with organoid nesting, palisading, and rosettes. Numerous mitoses, which are 11 or greater per 2 mm2, are seen. Cytologic features include large cell size, low nuclear-to-cytoplasmic ratio, fine chromatin, and nucleoli.

 


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  		Fig 4. Histological features of large cell neuroendocrine carcinoma. Immunohistochemistry (x40). The tumor cells stain positive with a polyclonal anti-chromogranin A antibody.

 
Immunohistochemical staining was performed on large cell carcinomas using both a polyclonal anti-chromogranin A antibody (Nichirei Corporation, Tokyo, Japan) and a monoclonal anti-synaptophysin antibody (Dako, Glostrup, Denmark). Formalin-fixed, paraffin-embedded 4-µm sections, treated with 3% hydrogen peroxide in phosphate-buffered solution (0.01 mol/L sodium phosphate buffer, pH 7.2, 0.15 mol/L NaCl) to block endogenous peroxidase and normal goat serum (chromogranin A) and normal rabbit serum (synaptophysin) to block nonspecific binding sites, were incubated overnight at 4°C with the primary antibody. They were incubated with biotinylated goat anti-rabbit IgG (chromogranin A) and rabbit anti-mouse IgG+IgA+IgM (synaptophysin) for 10 minutes followed by peroxidated streptavidin for 5 minutes. The peroxidase activity was visualized with 3,3'-diaminobenzidine. Sections were counterstained with hematoxylin.

Electron microscopy was performed on 11 large cell carcinoma cases because Epon-embedded blocks were available in these cases. Resected tumor was cut into pieces and fixed in 2.5% glutaraldehyde with 0.1 mol/L cacodylate buffer at 4°C, postfixed in 1% osmium tetroxide for 1 hour, dehydrated through ascending series of alcohols, and embedded in EPON 812 (Electron Microscopy Sciences, Fort Washington, PA). Semithin sections were cut from the Epon-embedded blocks from cases, stained with toluidine blue, and used for light microscopical orientation. Ultrathin sections were cut from selected areas, mounted on coated copper grids, and stained with uranyl acetate and lead citrate. They were examined under a JEM1200EXS electron microscope (JEOL, Tokyo, Japan) at 80 kV.

Neuroendocrine differentiation was detected by positive immunohistochemical staining for anti-chromogranin A or anti-synaptophysin, or neuroendocrine granules by electron microscopy, and large cell carcinomas were classified as LCNEC or LCCND if they had evidence of neuroendocrine differentiation. LCNFs are large cell carcinomas with neuroendocrine morphology or neuroendocrine differentiation, which combined LCNEC, LCCND, and LCCNM.

Tumors were classified as SCLC (Fig 5) if they had evidence of the following: (1) small size (generally less than the diameter of three small resting lymphocytes); (2) scant cytoplasm; (3) nuclei with finely granular chromatin and absent or faint nucleoli; (4) a high mitotic rate (> 10 mitoses per 2 mm2); or (5) necrosis (often large zone).



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  		Fig 5. Histological features of small cell carcinoma. Light microscopy (hematoxylin and eosin stain, x40). The tumors consist of small cells, which are round, oval, and spindle-shaped, and generally less than the diameter of three small resting lymphocytes, with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.

 
We compared the clinicopathological findings of LCNF with those of other pulmonary neuroendocrine tumors. Patient gender, age, smoking index, surgical procedure, TNM stages, chemotherapy, and patient outcome were determined from medical records.

Statistical analysis
Fisher’s exact test was used to compare binomial proportions. The {chi}2 test was used to assess differences in gender. The unpaired t test was used to detect significant differences between groups in patient age, smoking index, and tumor mitotic rates. Mann-Whitney U test was performed for tumor size. Survival time was calculated from the date of surgery until the time of first local or distant recurrence (disease-free survival) or death (overall survival), and was evaluated using the method of Kaplan and Meier. The curves obtained were compared with the log-rank test. The prognostic impact of the following pretreatment variables was investigated using Cox’s proportional hazards multivariable regression model: gender (male versus female), age (< 60 years old versus >= 60 years old), smoking index (< 600 versus >= 600), histological type (carcinoid [typical and atypical] versus LCNF versus SCLC), tumor size (<= 3 cm versus > 3 cm), tumor T (T1, T2 versus T3, T4), and N classification (N0 versus N1, N2, and N3). A p value < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Histological types
In large cell carcinomas, 61 cases had evidence of neuroendocrine differentiation by immunohistochemical staining or electron microscopy. Neuroendocrine differentiation was detected by immunohistochemical staining in 60 cases and by electron microscopy in 1 case whose paraffin-embedded materials were not available. Sixty-eight cases demonstrated neuroendocrine morphology by light microscopy. Seventy-seven (57.9%) were classified as LCNF, which combined 52 cases of LCNEC, nine cases of LCCND and 16 cases of LCCNM. Eleven cases (8.3%) were done as TC, 14 (10.5%) as AC, and 31 (23.3%) as SCLC (see Table 1).


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  		Table 1. Patient Characteristics of Pulmonary Neuroendocrine Tumors

 
Patient characteristics
Patients with LCNF were significantly older than patients with TC and AC (p < 0.001) or SCLC (p < 0.001). In addition, the mean age of patients with SCLC was significantly higher than that of patients with TC and AC (p < 0.001). Patients with LCNF or SCLC were predominantly male, whereas patients with TC or AC were not biased to either gender (LCNF, p < 0.001; SCLC, p = 0.022). The smoking index of TC and AC was significantly lower than LCNF (p < 0.001) and SCLC (p = 0.005). The tumor size of TC and AC was significantly smaller than LCNF (p < 0.001) and SCLC (p = 0.009). On gender, smoking index, tumor size, and mitotic rate, there was no significant difference between LCNF and SCLC.

We could not examine the effect of adjuvant chemotherapy in pulmonary neuroendocrine tumors because this study was retrospective and it entailed a wide variety of chemotherapeutic agents.

Patient survival
Median follow-up time of 133 neuroendocrine tumors was 21.0 months. The 5-year and 10-year overall survival rates for patients with TC were both 100%, and those for patients with AC were 90.0%. The 5-year and 10-year overall survival rates for patients with LCNF were 32.4% and 29.9%, respectively. The 5-year and 10-year overall surival rates for patients with SCLC were 16.4% and 12.3%, respectively (Fig 6). The overall survival for patients with AC was significantly higher than that for those with LCNF (p < 0.001) and with SCLC (p < 0.001), whereas there was no significant difference between LCNF and SCLC.



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  		Fig 6. The overall survival curves for each tumor histological type. The overall survival for patients with atypical carcinoid was significantly higher than for those with large cell carcinoma with neuroendocrine features (p < 0.001) and with small cell lung carcinoma (p < 0.001). (AC = atypical carcinoid; LCNF = large cell carcinoma with neuroendocrine features; SCLC = small cell lung carcinoma; TC = typical carcinoid.)

 
The 5-year and 10-year disease-free survival rates for patients with TC were both 100%, and those for patients with AC were 90.0% and 79.5%, respectively. The 5-year and 10-year disease-free survival rates for patients with LCNF were 25.6% and 18.6%, respectively. The 5-year and 10-year disease-free survival rates for patients with SCLC were 16.6% and 12.4%, respectively (Fig 7). The disease-free survival for patients with AC was significantly higher than that for those with LCNF (p < 0.001) and SCLC (p < 0.001), whereas there was no significant difference between LCNF and SCLC.



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  		Fig 7. The disease-free survival curves for each tumor histological type. The disease-free survival for patients with atypical carcinoid was significantly higher than for those with large cell carcinoma with neuroendocrine features (p < 0.001) and small cell lung carcinoma (p < 0.001). (AC = atypical carcinoid; LCNF = large cell carcinoma with neuroendocrine features; SCLC = small cell lung carcinoma; TC = typical carcinoid.)

 
Multivariate analyses for survivals were performed to determine differences in overall survival and disease-free survival of neuroendocrine lung tumors (Table 2). The presence of tumors with LCNF or SCLC, lymph node metastasis, and age impacted markedly upon both overall survival and disease-free survival.


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  		Table 2. Multivariate Analyses for Survivals

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The current study was designed to examine the clinicopathological features of pulmonary neuroendocrine tumors with particular reference to large cell carcinoma with neuroendocrine features.

LCNEC is an aggressive tumor. Travis and associates [7] revealed that the survival for LCNEC was worse than that for atypical carcinoid and was not different from that for small cell lung carcinoma. Dresler and associates [11] showed that the 5-year survival for the stage I LCNEC patients was 18%, and all-stage 5-year survival was 13%, and referred that LCNEC had a remarkably poor prognosis even in very early-stage disease. Jiang and associates [5] reported 22 cases of LCNEC and indicated that the 5-year survival for patients with LCNEC was 44.8%, and there was a significant difference in overall survival for LCNEC patients versus non-small cell lung carcinoma patients. Przygodzki and associates [12] performed analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors and revealed that LCNEC was more akin genetically and immunohistochemically to SCLC, although it was categorized as non-small cell carcinoma.

In a previous study [9], we found that not only LCNEC but also LCCND and LCCNM were aggressive tumors and pulmonary LCNF, which combined LCNEC, LCCND, and LCCNM, and has a poorer prognosis than classic large cell carcinoma. Therefore, we tried to compare LCNF with other neuroendocrine tumors of the lung.

TC and AC occurred equally in males and females, which is comparable with previous reports, although in our study, patients with TC and AC were younger [13, 14]. Rusch and associates [6] revealed that high-grade neuroendocrine tumors exhibit a high proliferative rate, abnormal p53, and absent pRb staining, whereas TC and AC tumors exhibit a low proliferative rate, absent p53, and normal pRb staining. Walch and associates [15] used comparative genome hybridization to demonstrate that DNA under-representations of 11q were frequent in TC and AC tumors, unlike high-grade neuroendocrine tumors. Onuki and associates [16] proposed that the low- and intermediate-grade neuroendocrine tumors have a different etiology and pathogenesis than high-grade neuroendocrine tumors because the low-grade and intermediate-grade neuroendocrine tumors are not related to smoking and do not show a male predominance. Moreover, their results of genetic alterations showed that neuroendocrine lung tumors represented a spectrum ranging from the low-grade TC and intermediate-grade AC to the highly malignant LCNEC and SCLC tumors. In survival analyses, our findings reveal that the patients with SCLC and LCNF have poor prognoses and that neuroendocrine features of large cell carcinomas and SCLC are independent prognostic factors in pulmonary neuroendocrine tumors, because the patients with SCLC and LCNF have advanced pathological stages. Therefore, LCNF, which contained not only LCNEC but also LCCND and LCCNM, should be categorized as high-grade neuroendocrine tumors, and we need to perform careful histological and immunohistochemical analysis of large cell carcinoma and distinguish TC and AC from the high-grade neuroendocrine tumors LCNF and SCLC.

In regard to the use of adjuvant chemotherapy in general, no significant data to date exist for benefit in treatment of non-small cell carcinoma [17]. However, Graziano and associates [18] studied the relationship between the neuroendocrine differentiation of non-small cell lung carcinoma and the response to chemotherapy, and found that non-small cell lung carcinoma with neuroendocrine differentiation was associated with an increased likelihood of response to chemotherapy. SCLC is sensitive to chemotherapy, and Shepherd and associates [19] referred that adjuvant chemotherapy after surgery results in prolonged survival and cure for a significant number of patients with stage I SCLC. We revealed the possibility that adjuvant chemotherapy can prolong the overall survival of patients with stage I LCNF [20]. However, adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide was not effective to prolong survival of patients with LCNF in advanced stages. A randomized control study using adjuvant chemotherapy based on cisplatin, carboplatin, cyclophosphamide, or new agents is needed to show definitively that this treatment improves the prognosis of patients with LCNF.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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