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Ann Thorac Surg 2004;77:1168-1172
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

Large cell neuroendocrine carcinoma of the lung: an aggressive disease potentially treatable with surgery

^a Department of Thoracic Surgery, Marseille, France
^b Department of Thoracic Oncology, Marseille, France
^c Department of Pathology, Université de la Méditerranée (Aix-Marseille II), Faculty of Medicine, Sainte-Marguerite Hospital, Assistance Publique, Hôpitaux de Marseille, Marseille, France

Accepted for publication September 11, 2003.

^* Address reprint requests to Dr Doddoli, Sainte-Marguerite Hospital, 270 Bd de Sainte-Marguerite, Marseille Cedex 09 13274, France
e-mail: christophe.doddoli{at}mail.ap-hm.fr

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Assessment of clinical and pathologic features of large cell neuroendocrine carcinoma to confirm its specificity in the setting of high grade neuroendocrine pulmonary tumors.

METHODS: From 1989 to 2001, 123 patients with a neuroendocrine carcinoma were surgically treated in a curative intent at a single institution. According to the 1999 World Health Organization classification, 20 patients were reviewed as having a large cell neuroendocrine carcinoma. Clinical data as well as detailed pathologic analysis and survival were collected.

RESULTS: There were 18 men and 2 women. The median age was 62 years. Four patients had a preoperative diagnosis of large cell neuroendocrine carcinoma. The resections consisted of 14 lobectomies and 6 pneumonectomies. There was no operative death. Complications occurred in 7 patients (35%). Four patients had a stage I of the disease, 4 had stage II, 9 had stage III, and 3 had stage IV. At follow-up (median, 46 months), 13 patients died from general recurrence and 7 patients were still alive. Median time to progression was 9 months (range, 1 to 54 months). The 5-year survival rate was 36% (median, 49 months) and it seemed to be negatively influenced by the disease stage (54% for stage I-II vs 25% for stage III-IV; p = 0.07), the presence of metastatic lymph node (45% for N0/N1 vs 17% for N2; p = 0.12), or vessel invasion (66 vs 25%; p = 0.18).

CONCLUSIONS: Large cell neuroendocrine carcinoma predominantly occurred in men. An accurate tissue diagnosis was rarely obtained preoperatively. Although overall survival after resection was substantial, large cell neuroendocrine carcinoma frequently showed pathologic features of occult metastatic disease, such as lymph node or vessel invasion, or both.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Histologic classification of neuroendocrine tumors of the lung has evolved during the last decades. The most recent World Health Organization classification of lung neoplasms [1] recognizes different categories of morphologically identifiable neuroendocrine tumors, ranging from low and intermediate grade tumors (typical carcinoid and atypical carcinoid) to high grade tumors (small cell lung carcinoma, combined small cell lung carcinoma, and large cell neuroendocrine carcinoma [LCNEC]).

Large cell neuroendocrine carcinoma is a newly defined entity [1]. Its pathologic diagnosis is based on recognition of a neuroendocrine morphology (organoid nesting, trabecular, rosette-like, and palisading patterns) associated with nonsmall cell cytologic features (large cell size, low nuclear to cytoplasmic ratio, frequent and often prominent nucleoli). Mitotic count is high (11 or more mitotic figures per 10 high power fields) and large zones of necrosis are common. The neuroendocrine nature can be demonstrated by immunohistochemical staining for one or more neuroendocrine markers (chromogranin A, synaptophysin, and neural cell adhesion molecule) or by electron microscopy. Pathologic differential diagnosis can be difficult, mainly with small cell lung carcinoma, atypical carcinomas, and other subtypes of large cell carcinomas [2, 3].

Publications dealing with resected LCNECs are rare and based on the retrospective analysis of the surgical specimen in almost all cases, and the reports are always on a small number of patients. So it seems important to us to add our experience to the recent data published about this topic. We conducted this study to assess the clinical, surgical, and pathologic characteristics of LCNECs and the outcome of this new entity.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
All neuroendocrine lung tumor specimens obtained between 1989 and 2001 (n = 123) were reclassified independently by two pathologists according to the new 1999 World Health Organization classification. We reviewed patients classified with LCNECs (neuroendocrine morphology and evidence of neuroendocrine differentiation by immunohistochemistry) who underwent an anatomical resection (ie, lobectomy and pneumonectomy) with a complete lymph node dissection (n = 20). We excluded specimens obtained after atypical resection and biopsies done by thoracotomy. Patients diagnosed with typical carcinoid, atypical carcinoid, small cell lung carcinoma, and others large cell carcinomas were not included.

Demographic data of patients, first symptom, clinical staging of disease according to the 1997 International TNM staging system [4], and comorbidity were collected. Preoperative pathologic diagnosis was noted if applicable. Pre-therapeutic assessment systematically involved chest roentgenogram and thoracic and abdominal computed tomographic scans. Bone scanning and cerebral computed tomographic scan were performed only in the case of bone or brain metastasis clinical suspicion. Preoperative workup also included routine biochemical profile, bronchoscopy, pulmonary function tests, and arterial blood gas analysis at rest, as well as quantitative ventilation and perfusion scans in patients in whom predicted postoperative forced expiratory of volume in 1 second could be estimated lower than 1 L. Mediastinoscopy was not routinely performed as part of the preoperative workup. Prescription of an induction therapy was noted. Type of resection and postoperative complications were collected as well. Postoperative pathologic analysis included completeness of resection, pTNM assessment, and presence or absence of blood vessel invasion, lymphatic vessel invasion, and one or more nodules in the same lobe. Adjuvant therapy (chemotherapy or radiotherapy, or both) was noted when appropriate.

Follow-up was complete for all patients. Probability of survival was calculated using the Kaplan-Meier method. Comparisons were made using the log-rank test. Probability values of 0.05 or less were considered as statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
There were 18 men and 2 women. Mean age was 62 years (range, 43 to 80 years). Ten patients were still smoking, whereas 7 were former and 3 were heavy smokers. Four patients were asymptomatic, their tumors being discovered incidentally on a chest roentgenogram. In the other 16 patients, the first symptoms were hemoptysis in 5, cough in 3, dyspnea in 2, fever in 1, pneumonia in 1, weigh loss in 1, and neurologic symptoms related to a solitary brain metastasis in 3. These 3 patients had operations for their cerebral disease first. The clinical stage distribution was as follows: stage IB in 12 patients, stage IIB in 3, stage IIIA in 1, stage IIIB in 1, and stage IV in 3. Two patients were considered as having a preoperative N1 or N2 disease. Four patients had a preoperative diagnosis of LCNEC, whereas 7 patients had diagnosis of undifferentiated nonsmall cell lung carcinoma carcinoma. In the remaining 9 patients, no tissue diagnosis could be obtained preoperatively. The diagnosis of LCNEC was made at bronchoscopy in 1 patient and from the neurosurgical procedure in the 3 remaining patients. Comorbidities included aortic disease in 3 patients, coronary disease in 3, and chronic obstructive pulmonary disease in 2. The 3 stage IV patients with solitary brain metastases had routine mediastinoscopy before surgery to rule out N2 disease. Preoperative chemotherapy was administered in 1 patient (stage IV) in which no response was observed. The resections consisted of 14 lobectomies and 6 pneumonectomies. An extended resection was done in 3 patients involving the pericardium in 2 and the carina in 1. Complete R0 resection was achieved in 19 patients, with 1 who had a microscopically residual disease (R1) due to bronchial margin invasion. The postoperative stage distribution was as follows: stage IB in 4 patients, stage IIB in 4, stage IIIA in 2, stage IIIB in 7, and stage IV in 3. Nine patients had a postoperative N1 or N2 disease. Blood vessel invasion was present in 9 patients and lymphatic vessel invasion in 5. Six patients had satellite lung nodules. All of the T4 tumors (except one) were related to the presence of satellite nodules in the same lobe. There was no operative death. There were three major postoperative complications (two hemothoraxes and one adult respiratory distress syndrome), and there were four minor postoperative complications. Postoperative chemotherapy was administered to 6 patients, associated with radiotherapy in 4 patients. The median follow-up was 46 months (range, 4 to 168 months). Seven patients are currently alive without recurrence. The 13 deceased patients died from distant spreading, and 1 of these patients is also suffering from local recurrence. Median time to progression was 9 months (range, 1 to 54 months). Median survival was 49 months (95% confidence interval, 0 to 101 months), and overall 5-year survival was 36% (Fig 1). A poorer survival was shown in the cases of mediastinal lymph node involvement (45% for N0/N1 vs 17% for N2 disease at 5 years; p = 0.12) (Fig 2), presence of blood or lymphatic vessel invasion (66 vs 25% at 5 years; p = 0.18) (Fig 3), and advanced stage disease (54 vs 25% at 5 years; p = 0.07) (Fig 4).

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (11K): [in this window] [in a new window]   Fig 2. Overall survival according to the N status (N0-N1 versus N2).

View larger version (14K): [in this window] [in a new window]   Fig 3. Overall survival with reference to the presence or absence of blood or lymphatic vessel invasion, or both.

View larger version (13K): [in this window] [in a new window]   Fig 4. Overall survival according to the disease stage (I-II versus III-IV).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

According to the recent World Health Organization classification criteria [1], publications dealing with LCNECs are rare and often report only a small number of patients [5–12]. Large cell neuroendocrine carcinomas are usually reported more frequently in men [5, 6, 11]. Considering our data and the recent publications, it may be suggested that there is no specific clinical presentation for this newly defined pathologic entity.

Difficulty to assess an accurate diagnosis preoperatively of LCNEC seems usual; only 4 patients (20%) in the current series, 3 patients out of 18 (16%) for Mazières and colleagues [5], and none for Zacharias and colleagues [11]. Finally, a conclusive pathologic diagnosis is generally obtained on the basis of the analysis of the operative specimen.

The clinical staging showed early stage disease in most patients. There were 15 stage I-II patients, 1 stage IIIA ("minimal" N2 disease), 1 stage IIIB (T4 by carinal involvement, N0, resectable disease), and 3 stage IV (T1 or T2, N0 confirmed by mediastinoscopy, M1 solitary brain metastasis completely resected before the treatment of the primary lung tumor). According to current oncological rules, surgery was indicated in all patients with a clinical early stage disease. The treatment of the remaining 5 patients was decided by the multidisciplinary oncological committee of our institution with the following rationales: (1) because there are contradictory data in the literature regarding the value of induction therapy in stage IIIA, any patient with a resectable "minimal" N2 disease is considered a candidate for surgery (except if the patient accepts an enrollment in a clinical trial); (2) any T4 N0 tumor suspected to be completely resectable is referred to surgery without induction chemotherapy or radiotherapy used to minimize the surgical risk [13] and to avoid the additional morbidity linked to the combined therapies; and (3) because there are no clear guidelines for treatment of stage IV patients in this particular setting of a completely resected single brain metastasis, the treatment discussion remains open. In most cases, we consider that the disease has been downstaged by the neurosurgeon, and the treatment of lung disease is based on that of the residual disease, provided that an N2 disease has been ruled out by the use of mediastinoscopy. However, 1 patient was referred to chemotherapy. The absence of response evaluated by tumor size variations is a reason to proceed to surgery.

Lung resections that were performed corresponded to data reported elsewhere [5, 6, 11] with a majority of these that were lobectomies. Postoperative complications were frequent in our study, but without any fatality, and are seldom described in previous reports [5, 6, 11]. It is not possible to determine how many patients with LCNEC tumors were not considered for surgery during the same period. However, we guess that the surgical group of LCNECs probably represents a small part of this entity given the frequent confusion with more aggressive histologic subtypes such as pure or combined small cell disease.

Survival and prognostic factors focused our attention because of the usually poor prognosis attached with LCNEC. Five-year survival was 36% for our patients, whereas the usual rate reported ranges from 13% to 70% [2, 5–7, 9, 11]. This relatively large range is probably a consequence of the small size of the patient cohort. Furthermore, 5-year survival of our patients with early stages (54%) seems grossly comparable with that of patients with other nonsmall cell lung carcinoma types at the same stage consistently with the data reported by Takei and colleagues [6] and Zacharias and colleagues [11]. Our quite good 5-year survival of stage III-IV patients (25%) was probably explained by two characteristics: (1) All T4 tumors (except one) were related to the presence of satellite nodules in the same lobe, and (2) all our stage IV patients had a resected solitary brain metastasis. Both features are well known to be related with a less disastrous prognosis in their respective subclasses. Comparatively, Takei and colleagues [6] reported a survival rate of 45% and 0% for stage III and IV, respectively, without giving details concerning T4 or M1 patients. Neither survival related to stage nor characteristics of stage IV patients were given in the study by Mazières and colleagues [5] who reported on an overall 1-year survival of 27%.

Of note is the fact that only 1 patient in the current series presented without any of the following validated predictors of occult metastatic disease: previously resected brain metastasis, presence of lymph node metastasis, presence of satellite lung nodules, or presence of vascular invasion. Histology by itself may thus appear as a putatively strong prognosticator of poor long-term outcome. Similar findings about advanced stage and frequent N2 involvement at diagnosis and treatment were also reported by Takei and colleagues [6]. In contrast, such a high frequency of blood or lymphatic vessel invasion (70%) was not previously reported in the setting of LCNECs. Whether or not blood or lymphatic vessel invasion is more or less frequent than other nonsmall cell lung carcinoma subtypes [14–17] is still an open issue. Undoubtedly, N2 involvement and vascular invasion also correlated with distant metastatic dissemination at the time of recurrence and the relatively short time to progression.

The present results thus showed several particular features of LCNECs with limitations due to the retrospective nature of this study, the design of which was dictated by the relatively rare prevalence of the disease (ie, less than 1% of all pulmonary resections for lung cancer performed during the same period at our institution and 3.1% in other institutions [6]). As a consequence, the relatively small number of patients did not permit us to reach statistical significance levels for the studied prognostic factors. However, from a pragmatic point of view, if LCNECs belong to nonsmall cell lung carcinomas, its pathologic features (vascular invasion, high frequency of lymph node involvement, and so forth) clearly mimic those of small cell lung carcinoma. Molecular studies provide some grounds to this aggressiveness that similar proliferation pathways could contribute to their behavior [5, 18, 19]. Now our policy is to consider induction therapy in these cases while keeping surgery in the treatment armamentarium. Obviously this supposes that a conclusive pathologic diagnosis of LCNEC may be obtained at the pre-therapeutic workup. In the same way, this workup should involve a routine mediastinoscopy and probably a positron emission tomography scan.

When the pathologic diagnosis is obtained on the basis of the analysis of the operative specimen, we actually consider the potential value of an adjuvant therapy [20] for all patients, including those presenting with an early stage disease.

In conclusion, LCNECs occurred more frequently in men and preoperative diagnosis is rarely obtained. Long-term survival provided by a resection with a complete lymph node dissection remains substantial, although some clinical and pathologic features suggest an aggressive behavior. The value of adjuvant chemotherapy should be investigated as well as induction therapy if a conclusive pathologic diagnosis of LCNEC is obtained at the pre-therapeutic workup.

	References

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