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Ann Thorac Surg 2000;70:258-263
© 2000 The Society of Thoracic Surgeons

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Original articles: General thoracic

Prognostic factors in neuroendocrine lung tumors: a Spanish multicenter study

^a Services of Thoracic Surgery and Pathology, University Hospital, Valladolid, Spain; and Members of the Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR)

Address reprint requests to Dr García-Yuste, Thoracic Surgery Service, University Hospital, C/. Ramón y Cajal, 3, 47005 Valladolid, Spain

	Abstract

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Background. This study examines the experience of the Spanish Multicenter Study of Neuroendocrine Tumors of the Lung through the clinical data and behavior of patients treated for this pathologic process.

Methods. From 1980 to 1997, 361 cases of neuroendocrine carcinomas (NEC) were treated surgically. Patients were enrolled in a protocol using the pathologic and follow-up reports. According to Dreslers’ criteria, the cases were segregated into grade 1 (typical carcinoid), grade 2 (atypical carcinoid), grade 3 large cell type, and grade 3 small cell type. Several variables were reviewed in all patients. Statistical analysis was performed to determine whether clinical characteristics and differentiation were associated with significant differences in the prognosis.

Results. A total of 261 cases of NEC were identified with grade 1, 43 with grade 2, and with grade 3: 22 of large and 35 of small cells. Five-year survival for different grades was as follows: grade 1, 96%; 2, 72%; 3 large cell type, 21%; and 3 small cell type, 14%. When a comparative analysis between typical and atypical carcinoids was performed a significant difference for mean age, tumor size, nodal metastases, and recurrence was observed. However, female sex, nodal metastases, and recurrence rate differed between atypical carcinoids and grade 3 NEC of large cells. A difference in recurrence rate was found between patients with both types of grade 3 NEC.

Conclusions. The progressive deterioration of tumor organization highlights that neuroendocrine tumors constitute a continuous spectrum. A careful observation of pathologic findings is necessary to individualize their prognostic factors.

	Introduction

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The normal lung contains a cellular population of neuroendocrine (NE) cells although the significance of their presence is not yet clear. They can be found in different pathologic processes, with neuroendocrine lung tumors being the most interesting cases.

Neuroendocrine lung tumors are represented by a wide spectrum of pathologic entities. Based on histologic characteristics and clinical behavior, at one end typical carcinoid tumors are found, and at the other end small cell carcinomas. Intermediate degrees of differentiation and behavior define the other neoplasias belonging to this tumor range.

As a consequence of clinical and prognostic controversies, the initial classification of these tumors has been modified at various times. At present the investigation centers on the causes of the specific differentiation, behavior, and therapeutic possibilities. The data compiled by the Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR) allows us to provide and contrast our experience with these tumors.

	Material and methods

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A total of 361 cases of lung neoplasm with neuroendocrine cytoarchitectural features were seen and treated surgically between 1980 and 1997. They were obtained from 12 Spanish hospitals by the Spanish Multicenter Study of Neuroendocrine Tumors of the Lung (EMETNE-SEPAR).

Determination of histologic neuroendocrine features was performed on a selection of cases by routine microscopy. The definition of the criteria to classify every tumor was based on that of Arrigoni and complemented with that predefined for the diagnosis of large cell neuroendocrine carcinoma. The pathologist reviewed all slides and when there was dispute, cases were reexamined and consensus reached about the fulfilled criteria for neuroendocrine carcinoma (NEC). When the pathologic material and reports were reviewed, the tumors were initially classified according to the revised World Health Organization classification of lung carcinoma (WHO, 1981) [1], bearing in mind the modifications introduced by Travis and colleagues in 1991 [2] and Dresler and colleagues in 1997 [3]. Four categories were finally established: (1) Typical carcinoid (grade 1 NEC); (2) Atypical carcinoid (grade 2 NEC); (3) Large cell neuroendocrine carcinoma (grade 3 NEC, large cell type); and (4) Small cell neuroendocrine carcinoma (grade 3 NEC, small cell type). Some, but not all (55 of 362) of the tumors were stained by immunohistochemical stains (chromogranin and synaptophisyn) for dense-core neurosecretory granule and other neuroendocrine markers as antibodies to structural epitopes of neural cells (N-CAM).

All patients studied were enrolled in EMETNE-SEPAR protocol by using information derived from the clinical outcome and pathologic reports. A retrospective analysis was then carried out. Sex, age (mean and range), localization (central or peripheral), size (maximum diameter in millimeters), endocrine syndromes (Cushing’s, acromegaly, carcinoid), nodal metastases, their status (N0, N1, or N2) and tumor stage derived from various TNM combinations were taken into account in each of the cases that were classified according to the 1986 versus the 1997 classification [4] to reclassify T3N0M0 tumors (stage IIIa, 1986) into stage IIb.

Clinical follow-up and statistical analysis
Survival data were available for the clinical case notes of several reviews of patients of each hospital. The percentage of metastases and local recurrence was determined for all patients of the different tumor groups, as well as the cause of death for those who died during follow up. Survival was calculated by the Kaplan-Meier method, and the log-rank test was used for comparisons. Correlation of categorical variables between different groups was assessed using ² and Student’s t test, respectively. A probability value (p) less than or equal to 0.05 was considered significant.

	Results

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Typical carcinoid tumor (grade 1 neuroendocrine carcinoma)
Among 304 patients affected with carcinoid tumors, 261 (85%) had a typical carcinoid. In all, 44% were men and 56% were women. Mean age was 47 years, ranging from 11 to 81 years. Eight patients presented with endocrine symptoms (two carcinoid syndrome, three acromegaly, and three Cushing’s syndrome). The tumor had a central location in 73% of the cases and was peripheral in 27%. Mean size of the tumors was 26.6 mm, ranging from 13 to 90 mm. Lymph node metastases were found in 11 patients (4.15%). Distribution by stages according to the 1986 classification was: 234 patients (89.6%) in stage I, 8 (3.06%) in stage II, 17 (6.51%) in stage IIIa (10 of them T3N0M0, which might be considered stage IIb of the newer, 1997 classification), and 2 T4N0M0 because of their location (0.76%) in stage IIIb.

During follow-up, 8 patients died from unrelated causes. Four patients, all in stage I, presented with recurrence at distant sites at 12, 24, 33 and 56 months; 2 of them died because of metastatic recurrence 6 and 7 months later, and the other 2 are alive 12 and 36 months, respectively, after chemotherapy treatment. In contrast, 2 patients (the first patient in stage I and the second in stage IIIa) had a local recurrence at 23 and 60 months; after mediastinal radiotherapy one of them is alive after 60 months and the other one died because of his local recurrence 40 months later. The overall survival at 5 and 10 years was 96% and 93%, respectively.

Atypical carcinoid (grade 2 neuroendocrine carcinoma)
A total of 43 patients with tumors of these characteristics were treated; 47% were men and 53% were women. Mean age was 56 years, ranging from 26 to 74 years. Most patients (65%) had a tumor localized in a central position, whereas the tumor was peripheral in 35%. Mean tumor size was 36.47 mm, ranging from 23 to 99 mm. Clinical expression of neuroendocrine syndrome was found in only 2 patients (4.65%); one presented with Cushing’s syndrome, the other acromegaly; but carcinoid syndrome was not observed in any of the patients. A complete resection of the tumor could be carried out in all cases and in 10 of them (23.25%) nodal metastases were found. The final nodal status was N1 in 6 patients, N2 in 4, and N0 in the rest. A total of 27 patients (62.7%) were classified in stage I, 9 (21%) in stage II, 4 (9.3%) in stage IIIa, and 2 (7%) in stage IIIb. All patients with N2 affectation were treated with postoperative mediastinal radiation. No adjuvant therapy treatment was given to the 6 patients with N1 disease.

During follow-up, 9 patients (5 in stage I, 2 in II, and 1 in IIIa and IIIb, respectively) presented with tumors at distant sites and the other had local recurrence. Four patients died of unrelated causes and 9 died of metastases. The patient with local recurrence is alive after radiotherapy 75 months later. Mean survival time after disease recurrence was 18 months. The overall survival at 5 and 10 years was 72% and 43%, respectively, but this was with a significant statistical difference smaller than that of the patients affected by typical carcinoid tumors (Fig 1). In the analysis of survival by stages (stage I, 94% and 81%; stage II, 33% and 33%; stage IIIa, 50% and 0%; stage IIIb, 0%), a significant statistical difference was found between them.

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival and log-rank test for patients with typical and atypical carcinoids.

View larger version (13K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival and log-rank test for patients with atypical carcinoids and grade 3 neuroendocrine carcinoma large cell type.

View larger version (11K): [in this window] [in a new window]   Fig 3. Kaplan-Meier survival and log-rank test for patients with grade 3 neuroendocrine carcinoma large and small cell type.

	Comment

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Based on these facts, different classification schemes have been proposed. The one put forward by the World Health Organization (WHO) in 1982 [1] was widely accepted; this divided the tumors into typical carcinoid, atypical carcinoid, small cell carcinomas of intermediate type, oat-cell carcinoma and small cell carcinoma of combined type with squamous cell carcinoma or adenocarcinoma. In 1983 Gould and colleagues [8] substituted the term atypical carcinoid for well-differentiated neuroendocrine carcinoma because of its aggressiveness and the similarity of its behavior with that of other carcinomas. The classification with histogenic criteria put forward by Paladugu and colleagues in 1985 [9] of Kulchitsky cell carcinoma type I, II, and III did not provide any essential clinical–pathologic advantages over the previous classifications, except for the graduation of deterioration in histological pattern. In 1991 Travis and coworkers [2], attempting to define tumors with wide histologic similarity with oat-cell carcinoma but formed by larger cells, established the denomination of large cell neuroendocrine carcinoma. In addition, they added a new category of non–small cell carcinoma to the spectrum of these neoplasms with neuroendocrine findings demonstrable exclusively by immunohistochemical techniques. Finally, in 1997 Dresler and associates [3], based on the criteria of Travis and colleagues, proposed the following nomenclature: neuroendocrine carcinomas (NEC) grade 1 (typical carcinoid), NEC grade 2 (atypical carcinoid), NEC grade 3 large cell type, NEC grade 3 small cell type, and large cell carcinomas without visible neuroendocrine pattern and with occult neuroendocrine differentiation. The proposed classification of Dresler and colleagues is precise because it joins previous criteria, unmistakeably defines the epithelial and neuroendocrine character of these tumors, and establishes an acceptable graduation of malignancy.

Significant differences have been observed in average age and sex. In our experience a decade separates average age in patients with typical and atypical carcinoid, both resulting significantly smaller than those presenting a NEC grade 3 large or small cell type. The concordance with other authors [3, 10] lets us state that a correlation exists between increase in histologic degradation and tumor aggressiveness with average patient age. Variations in the occurrence in patients of one or the other sex are also significant. In our experience, the tumors of best prognosis (typical carcinoid) affect female patients with a frequency significantly above that of atypical carcinoid and greater than those of NEC grade 3. This tendency, observed in several series [11–15], allows the establishment of a proportional relation between greater degree of malignancy and incidence in male patients.

Tumor size and localization have been related to modifications in prognosis [11, 12]. A significant difference in tumor size was found between typical and atypical carcinoid in our patients. However, the differences between atypical carcinoid and NEC grade 3 (both large and small cell) were not significant. In our experience it seems that a larger tumor size is united with tumor lack of differentiation and a worse prognosis, except for typical carcinoid.

A greater potential malignancy has likewise been found when tumor localization is peripheral [13, 14]. In our experience the predominance of central tumors was noteworthy in carcinoid tumors, with peripheral localization percentages slightly higher in atypical versus typical. Significant increase in peripheral location was found in NEC grade 3, in the two subgroups. These facts allow us to correlate peripheral tumor localization with a worse prognosis. However, the influence of this factor should be sought both in the potential evolution represented by histologic characteristics as well as the possibility of a prolonged tumor evolution before discovery because of its localization.

As in the case of bronchogenic carcinomas, in neuroendocrine tumors nodal affectation is a factor with high, differential prognostic value. In our study of typical carcinoid, 90% corresponded to stage I. The rest were tumors in more advanced stages; but only in 4% was it caused by affection of regional lymph nodes, with the other 6% caused solely by tumor localization or T factor. A different behavior was found in atypical carcinoid. Among these patients, the percentage of nodal affectation was significantly higher than the 4% observed in patients with typical carcinoid tumors. Likewise, in agreement with other authors [9], a significantly greater incidence of nodal metastasis was found in patients with NEC grade 3 being for NEC grade 3 large cell type of 41%, but paradoxically only 20% of those who presented a NEC grade 3 small cell type. In the latter the fact that surgical treatment is indicated almost exclusively for tumors cataloged preoperatively as stage I could explain the contradictory small percentage of ganglion metastasis.

In neuroendocrine tumors not only the incidence of nodal affection is different but also its prognosis. All of the patients with typical carcinoid who presented with metastasis or local recurrence at follow-up were in stage I. However, among the atypical carcinoid cases with this evolution, 50% had lymph node metastases. Analyzing the incidence of nodal affection in NEC grade 3 patients, a significant increase in N2/N1 proportion was found with respect to the previous group. In addition, this was found in all cases of local recurrence or at distant site recurrence during evolution. In agreement with other authors [16–18], we can state that nodal affectation and its magnitude significantly increase with deterioration of the histologic pattern.

These considerations can also be of great interest in the new classification system of 1997 [4]. Based on nodal invasion results, in the case of typical and atypical carcinoid, subclassifying stage I tumors larger or smaller than 3 cm into stage Ia or Ib does not seem to have any important application. However, changing cases without nodal affectation from IIIa to stage IIb because of the T component (T3) is justified by the different significance that the nodal status has in the therapeutic scheme and prognosis. Central T3, in the absence of nodal affectation, allow curative resections. In central tumors such resections can be conservative of the parenchyma, avoiding unnecessary pneumonectomies by sleeve lobectomy when conditions indicating new classification in stage IIb are fulfilled.

Local or at distant sites recurrence and its evolution also show different behavior for different groups. In our experience, in typical carcinoid there was recurrence in a very little percentage. In contrast, the corresponding values were significantly higher in atypical carcinoids. The number of patients with NEC grade III who presented with recurrence during evolution was much larger. The evolutionary dynamics of tumor relapse were also markedly different among the distinct groups for both the free disease interval and the survival after treatment. We think, as do Martini and colleagues [18], that in typical and atypical carcinoids there is no evidence that postoperative radiation therapy is beneficial in local control of disease or overall survival. Because of the NEC grade III we agree with Dresler and coworkers [3] about treating these patients with adjuvant chemotherapy or radiation, despite their stage I classification.

Bearing in mind the relationship between the gradual deterioration of the histologic pattern and the prognosis, different studies with immunohistochemical techniques have been performed attempting to discover the occult neuroendocrine differentiation in non–small cell carcinomas. Although there is discrepancy in the literature, most of the studies of patients treated only with surgery have not demonstrated that the presence of this finding influenced survival [19, 20]. On the other hand, in advanced stages the response to the treatment with chemotherapy is greater than that of patients with similar tumors in which occult neuroendocrine differentiation could not be found [21, 22]. Taking these points into consideration, we should ask ourselves if the determination of occult neuroendocrine differentiation can be used as a prognostic marker for treatment results.

In summary, it can be concluded that progressive deterioration of tumor organization from typical and atypical carcinoid to small cell carcinoma highlights the fact that neuroendocrine tumors constitute a continuous spectrum. In addition, a careful observation of pathologic findings is necessary to individualize the distinct types and their prognostic factors. In our judgment, the future of investigation in neuroendocrine tumors should progressively focus on the study of the different genetic anomalies that, together with evident or occult neuroendocrine differentiation, help to explain the behavior of the distinct tumor groups.

	Footnotes

 
^* Members of the EMETNE-SEPAR are listed in the Appendix.

	Appendix

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The Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR)
Coordinator: Mariano García-Yuste, MD (University Hospital, Valladolid). Members and coworkers: José M. Matilla, MD, Guillermo Ramos, MD, and Tomás Alvarez-Gago, MD. (University Hospital, Valladolid). Juan Lago, MD, and David Saldaña, MD (Ramón y Cajal Hospital); Gerardo Ferrer, MD, and Juan Moya, MD (Bellvitge Hospital, Barcelona); Gonzalo Vidal, MD, and Laureano Molins, MD (Sagrado Corazón Hospital, Barcelona); Javier López-Pujol, MD (Reina Sofía Hospital, Córdoba); Antonio Cueto, MD (Virgen de las Nieves Hospital, Granada); José M. Rodriguez-Paniagua, MD (University Hospital, Alicante); Emilio Folqué, MD, and Federico González-Aragoneses, MD (Gregorio Marañón Hospital, Madrid); Jorge Freixinet, MD (Virgen del Pino Hospital, Las Palmas); Manuel Torres, MD (Virgen del Rocío Hospital, Sevilla); Antonio Cantó, MD and Miguel A. Cañizares, MD (University General Hospital, Valencia); Julio Astudillo, MD (German Trías i Pujol Hospital, Barcelona); Luis López-Rivero, MD, and Santiago Quevedo, MD (Insular Hospital, Las Palmas); Juan Torres, MD (Virgen de la Arrixaca Hospital, Murcia, Spain).

	References

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