HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mezzetti, M. Articles by Conforti, S. Search for Related Content PubMed PubMed Citation Articles by Mezzetti, M. Articles by Conforti, S. Related Collections Lung - cancer

Ann Thorac Surg 2003;76:1838-1842
© 2003 The Society of Thoracic Surgeons

---

Original article: general thoracic

Assessment of outcomes in typical and atypical carcinoids according to latest WHO classification

^a School of Specialization of Thoracic Surgery, S. Paolo Hospital, Milan, Italy

Accepted for publication June 30, 2003.

^* Address reprint requests to Dr Mezzetti, Via Boccaccio 27, 20123 Milan, Italy
e-mail: maurizio.mezzetti{at}unimi.it

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Pulmonary carcinoid tumors represent a group of malignant neoplasms comprised of neuroendocrine cells. In 1999, the World Health Organization (W.H.O.) proposed the definitive classification of neuroendocrine tumors based on the criteria from Travis and associates. The W.H.O. described two different groups of carcinoid tumors: typical carcinoids (TC) and atypical carcinoids (AC). Few reports have reviewed their data according to the current classification, and therefore, prognosis and standard therapy for TC and AC are still uncertain.

METHODS: From 1980 to 2001, 98 pulmonary resections have been performed for primary bronchial carcinoid tumors in our Thoracic Department of the University of Milan. We reviewed original histology using the current W.H.O. criteria and identified 88 patients with TC and 10 with AC. We reviewed the outcomes in each group.

RESULTS: The 5 year-overall survival rate was 91.9% for TC and 71% for AC. The 10-year overall survival rate was 89.7% for TC and 60% for AC. The 5-year TNM-related survival rates in the TC group were: IA-B, 100%; IIA-B, 75%; and IIIA, 50%. At 10 years, they were: IA-B, 100%; IIA-B, 75%; and IIIA, 0%. The 5-year survival rates in the AC group were: IA-B, 100%; IIA-B, 100%; and IIIA, 0%. At 10 years, they were: IA-B, 100%; IIA-B, 66%; and IIIA, 0%.

CONCLUSIONS: Prognosis is favorable for both subtypes in the early stage. Advanced stages are related to better prognosis in TC. Recurrences rate is worse in the AC subtype. Our data suggest avoiding limited resections when feasible in AC. Parenchyma-sparing resections should be encouraged in TC.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Since carcinoids were described as bronchial adenomas in 1882, they have been classified with several different schemes. Initially, they were classified as "bronchial adenoma," which comprised other bronchial tumors with benign behavior. Subsequently, they were included in a heterogeneous group of tumors called "bronchial carcinoids." They were associated with relatively benign growth and clinical behavior, except for a smaller subset distinguishable by more aggressive clinical course and atypical histologic features. The distinction between typical and atypical carcinoids was better described in 1944 [1]; in 1972, Arrigoni and associates proposed the histologic criteria to separate these tumors [2]. In spite of these criteria, several classifications have been proposed, but none has been universally accepted. In 1999, the World Heath Organization (W.H.O.) reduced confusion and proposed a definitive classification based on strict criteria from Travis and associates [3]. These criteria have been widely accepted; they described carcinoids as well-differentiated neuroendocrine malignant tumors. Typical and atypical carcinoids were definitively classified as two distinctive tumors with different histologic features, different clinical course, and different prognosis. The spectrum of neuroendocrine tumors also included large cell neuroendocrine carcinoma (LCNC) and small cell carcinoma (SCC) [3].

Ideas concerning behavior and clinical treatment of carcinoids have been confusing for decades because of unclear classification and rare occurrence. Nowadays, surgical exeresis in selected patients has been universally accepted as the treatment of choice because of the malignant tumor's behavior. Many studies have reported the outcomes in patients surgically treated for bronchial carcinoids, but few authors reviewed their data according to the established pathologic guidelines (1999 W.H.O.).

The prognosis of typical and atypical carcinoid tumors is still uncertain and the appropriate surgical management remains controversial.

We reclassified the original tumor histology of surgically treated patients for bronchial carcinoids according to the 1999 W.H.O. classification in order to obtain survival rates related to definitive typical and atypical subset.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
From 1980 to 2001, 98 patients underwent parenchyma lung resection for carcinoid tumors in our Thoracic Department of the University of Milan. There were 52 men and 46 women. The original histologic diagnosis has been reclassified according to the 1999 W.H.O. classification by a spectrum of pathologists from different departments. Therefore, using actual criteria, there were 88 cases of typical carcinoid and 10 cases of atypical carcinoid.

We used contrast-enhanced computed tomography (CT) for noninvasive intrathoracic staging. FDG-positron emission tomography (PET) imaging has supported CT in mediastinal nodal staging in the last 20 months [4]. Patients operated on before 1980 are not included in our report, because they were not completely staged with whole-body CT. Bronchoscopy was always carried out to define the airway involvement and the extent of the pathologic tissue in the bronchus. In centrally situated tumors (80% of all cases), we always performed multiple endoscopical biopsies and brushing to obtain a preoperative histology. We used fine-needle transparietal aspirated biopsy (FNAB) in peripheral forms [5]. We obtained correct preoperative diagnosis in 83% of bronchoscope biopsies and 80% of FNABs.

All patients had pulmonary function tests and cardiac evaluation. No one had preoperative chemotherapy. All patients underwent pulmonary resection by postero-lateral thoracotomy. Patients with compromised pulmonary function underwent sparing resection as wedge and segmental resection or sleeve lobectomy. We always performed hilar and mediastinal nodal sampling or complete nodal dissection in case of macroscopic involvement.

The 88 patients with typical carcinoid included 46 men and 42 women. In this group, 30% of patients smoked. The mean age was 54.5 years. Operations performed included three pneumonectomies (two T2N1, one T3N2), 62 classic lobectomies (25 T1N0, 23 T2N0, 8 T1N1, 5 T2N1, 1 T3N2), and 23 parenchimal sparing resections (two sleeve lobectomies [two T2N0], 21 wedge resections [12 T1N0, 8 T2N0, 1 T1N1]). Limited resections were performed to save lung parenchyma because of compromised preoperative pulmonary function.

The postoperative TNM stage, according to TNM classification, was as follows: 37 IA (T1N0), 33 IB (T2N0), nine IIA (T1N1), seven IIB T2N1, and two IIIA (T3N2) (Table 1).

Follow-up in all patients was performed through periodic clinical and radiographic controls (included standard chest film and CT scanning) until patient's death. Fibrobronchoscopy was performed in those patients who presented with endobronchial carcinoids or in the suspect of bronchial recurrence.

In case of suspected relapse, we also performed PET or Octreoscan to support CT scan [6] over the last 20 months.

Survival and disease-free survival rates were calculated on the basis of the Kaplan-Meier method [7]. The log-rank test was used to test for significance of the differences in survival and disease-free survival.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
We did not have any intraoperative deaths. The 90-day mortality rate was 2% of patients: one myocardial infarction and one stroke. We never had severe postoperative surgical complications; we noted four cardiac arrhythmias and five pneumonias pharmacologically recovered.

At the time of last follow-up in 2001, information for typical carcinoid group was noted as follows: 6 (6.8%) of the 88 patients died from recurrence of disease. Five were N1 (31.2% of all N1 in typical carcinoid subtype) and 1 was N2 (50% of all N2 in typical carcinoid subtype). The overall 5-year survival rate was 91.9%. The overall 10-year survival rate was 89.7%. The 5-year survival rate related to stage was: IA-B, 100%; IIA-B, 75%; and IIIA, 50%. At 10 years after operation, it was IA-B, 100%; IIA-B, 75%; and IIIA, 0%.

Among the 10 patients with atypical carcinoid tumors, 3 died from relapse of disease. One case was in N1 postoperative subgroup and two in N2 group. The overall 5-year survival rate was 71%. The overall 10-year survival rate was 60%. The 5-year survival rate related to stage was IA-B, 100%; IIA-B, 100%; and IIIA, 0%. At 10 years, it was IA-B, 100%; IIA-B, 66%; IIIA, 0%.

We used the Kaplan-Meier [7] method to generate three sets of survival curves, one comparing typical carcinoids group to atypical carcinoids group independently by nodal involvement (Fig 1), the second comparing typical carcinoids to atypical carcinoids in case of nodal spread (Fig 2), and the third comparing disease-free survival (Fig 3). We classified typical and atypical carcinoids into two categories (stage I, stage II-III) in order to obtain survival curves concerning nodal involvement.

View larger version (30K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves: survival in patients undergoing resection comparing those with typical carcinoids to those with atypical carcinoids. data 1 (circles) = typical carcinoids; data 2 (triangles) = atypical carcinoids; log-rank p = 0.006.

View larger version (34K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves: survival in patients undergoing resection comparing those with typical carcinoids and nodal involvement to those with atypical carcinoids and nodal involvement (stage II and III). data 1 (circles) = typical carcinoids (stage II and III); data 2 (triangles) = atypical carcinoids (stage II and III); log-rank p = 0.331.

View larger version (32K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curves: disease free survival in patients undergoing surgical resection comparing those with typical carcinoids to those with atypical carcinoids. data 1 (circles) = typical carcinoids; data 2 (triangles) = atypical carcinoids; log-rank p less than 0.001.

At the time of last follow-up, 6 patients developed recurrent parenchimal and nodal cancer and they were still alive. Four of these patients had typical carcinoid (4.8% of the patients alive in this histologic group), and they were 1N0, 2N1, and 1N2 at the time of diagnosis. None of these patients underwent parenchimal-sparing resections. Two patients had atypical carcinoid (28.5%) and they were T1N0 and T2N1 at time of diagnosis. The patient with T1N0 underwent a wedge resection. We found that freedom from recurrence was more likely for patients with typical carcinoid (log-rank p < 0.001; Fig 3).

We also related the TNM staging and relapse of disease to the surgical technique performed (Table 2). The 6 patients dead from relapse in the typical carcinoid subgroup had undergone a wide resection such as lobectomy or pneumonectomy because of important lymph node involvement. We did not note relapse in patients who underwent parenchimal-sparing resections even if with local bronchial nodal involvement. The 3 patients dead from relapse in the atypical carcinoid subgroup presented nodal involvement at postoperative stage and 1 of these underwent parenchimal-sparing resection.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

Because, unfortunately, most reports regarding prognosis and management of these tumors have been published before the 1999 W.H.O. one, currently, the appropriate standard surgical management of typical and atypical carcinoids is still unclear [8].

We renewed the histology of our patients surgically treated for carcinoid using the 1999 classification to determine the outcomes related to correct histotype.

Our data suggest an equal gender distribution in both typical and atypical histotypes. According to many authors [9, 10], we found that atypical carcinoids had a significative association with tobacco. At the moment of diagnosis, atypical carcinoids presented more often at an advanced stage.

The most recent review of literature [6, 8], coupled with our findings, suggest a significative different prognosis between typical and atypical forms. Typical carcinoids had excellent overall long-term survival rate; on the other hand, atypical carcinoids presented worse survival rate, which shows the aggressiveness of this form and its bad prognosis especially in advanced stages (Fig 1 and 3).

The results of this study confirm that 1999 W.H.O. classification scheme is essential in clinical management of carcinoid tumors to determine the prognosis of both typical and atypical subtypes.

These data reveal that preoperative histologic identification is essential to decide the appropriate management of the disease. Bronchoscopy should be always performed to define histology, because 75% of all carcinoids are visible endoscopically [6, 9, 11]. This procedure, when carefully performed, should be considered quite safe. In peripheral lesions, we suggest fine-needle aspiration by CT when bronchoscopic examination is not diagnostic [5].

We also found that in both typical carcinoids and atypical carcinoids, survival rate is strictly related to lymph node status, with significant difference between N0 and N1-N2 (Fig 2) [8]. Nodal involvement worsens prognosis in both typical and atypical subtype. We think that all carcinoids should be staged similarly to other malignant epithelial lung tumors before surgery. Classic modalities for clinical staging, such as CT, are universally accepted to determine preoperative TNM stage, and newer modalities, such as PET and Octeoscan, are available when nodal status or tumor spread are dubious [4, 6, 12]. Because we have not routinely used PET scans, the size of our group does not permit an informed commentary on its utility. Actually, the benefit of PET imaging to increase the accuracy of preoperative staging is still unclear.

Although our numbers are relatively small, they demonstrated a different prognosis between typical and atypical histotype, and allow us to suggest that different surgical management should be considered [13–16].

We related patients presenting relapse of disease to the surgical technique performed (pneumonectomy, lobectomy, sparing resection) in both histologic subtypes (Table 2). The paucity of data in each group, especially for patients with atypical carcinoid, does not permit a meaningful statistical analysis. However, we never found patients with relapse of disease when a parenchimal sparing resection was performed for an early-stage typical carcinoid. On the other hand, patients who underwent a sparing resection, with an early stage atypical carcinoid, had relapse of disease.

We think that sparing resection should be considered in early-stage typical carcinoid, when feasible, because of excellent survival and unlikely relapse in this subtype.

We suggest resections such as wedge resection or segmentectomy and nodal sampling when tumor is peripheral. For central lesions, sleeve resections should be considered to avoid large parenchimal loss in patients with poor pulmonary functions [17]. Advanced stage, such as IIIA, should be managed with wide resections to permit complete exeresis and lymph node dissection.

Atypical carcinoids have worse long-term survival rates and recurrence patterns [18] also in their early stage because of the their aggressiveness; in our view, a wide surgical resection, followed by nodal dissection, should be considered in order to avoid an early relapse of disease. We think that a surgical approach including standard lobectomy or pneumonectomy (when indicated) could provide a benefit even in early stages when feasible.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Engelbreth-Holm J. Benign bronchial adenomas. Acta Chir Scand 1944;90:383-409.
2. Arrigoni M.G., Woolner L.B., Bernatz P.E. Atypical carcinoid tumor of the lung. Thorac Cardiovasc Surg 1972;64:413-421.
3. Travis W.D., Sobin L.H. Histologic typing of lung and pleural tumours: international histologic classification of tumours (No. 1). . New York, NY: Springer-Verlag, 1999.
4. Erasmus JJ, McAdams HP, Patz EF Jr, Coleman RE, Ahuja V, Goodman PC. Evaluation of primary pulmonary carcinoid tumors using FDG PET. Am J Roentgenol 1998:1369–73
5. Aderson C., Ludwig E., O'Donnell M., et al. Fine needle aspiration cytology of pulmonary carcinoid tumors. Acta Cytol 1990;34:505-510.[Medline]
6. Ferguson M.K., Landreneau R.J., Hazelrigg S.R., et al. Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardio Thorac Surg 2000;18:156-161.[Abstract/Free Full Text]
7. Kaplan E.L., Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481.
8. Thomas C.F., Jr, Tazelaar H.D., Jett J.R. Typical and atypical pulmonary carcinoids: outcome in patients presenting with regional lymph node involvement. Chest 2001;119:1143-1150.[Abstract/Free Full Text]
9. Fink G., Krelbaum T., Yellin A., et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001;119:1647-1651.[Abstract/Free Full Text]
10. Corrin B. Neuroendocrine neoplasm of the lung. Curr Diag Pathol 1997;4:239-250.
11. Rozenman J., et al. Bronchial adenoma. Chest 1987;92:145.[Free Full Text]
12. Matte J., et al. Ectopic Cushing's syndrome, and pulmonary carcinoid tumor identified by octreotide. Postgrad Med J 1998;74:108.[Abstract]
13. Ducrocq X., Thomas P., Massard G., Barsotti P., et al. Operative risk and prognostic factors of typical bronchial carcinoid tumors. Ann Thorac Surg 1998;65:1410-1414.[Abstract/Free Full Text]
14. Marty-Ane C.-H., Costes V., Pujol J.-L., et al. Coid tumors of the lung: do atypical features require aggressive management?. Ann Thorac Surg 1995;59:78-83.[Abstract/Free Full Text]
15. Stamatis G., Freitag L., Greschuchna D. Limited and radical resection for tracheal and bronchopulmonary carcinoid tumour. Eur J Cardiothorac Surg 1990;4:527-532.[Abstract]
16. Chughtai T.S., Morin J.E., Sheiner N.M., et al. Bronchial carcinoid: twenty years' experience defines a selective surgical approach. Surgery 1997;122:801-808.[Medline]
17. Cerfolio R.J., Deschamps C., Allen M.S., et al. Mainstem bronchial sleeve resection with pulmonary preservation. Ann Thorac Surg 1996;61:1458-1462.[Abstract/Free Full Text]
18. Travis W.D., Rush W., Flieder D.B., et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22:934-944.[Medline]

This article has been cited by other articles:

				A. Bini, J. Brandolini, N. Cassanelli, F. Davoli, G. Dolci, F. Sellitri, and F. Stella Typical and atypical pulmonary carcinoids: our institutional experience Interactive CardioVascular and Thoracic Surgery, June 1, 2008; 7(3): 415 - 418. [Abstract] [Full Text] [PDF]

				R. L. Young, J. D. Mitchell, C. Cool, and S. P. Nana-Sinkam Wheezing and Exertional Dyspnea in a 25-Year-Old Mountaineer Chest, March 1, 2008; 133(3): 820 - 825. [Full Text] [PDF]

				F. Rea, G. Rizzardi, A. Zuin, G. Marulli, S. Nicotra, R. Bulf, M. Schiavon, and F. Sartori Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients Eur. J. Cardiothorac. Surg., February 1, 2007; 31(2): 186 - 191. [Abstract] [Full Text] [PDF]

				M. Garcia-Yuste, J. M. Matilla, A. Cueto, J. M. R. Paniagua, G. Ramos, M. A. Canizares, I. Muguruza, and Members of the Spanish Multi-centric Study of Neur Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung Eur. J. Cardiothorac. Surg., February 1, 2007; 31(2): 192 - 197. [Abstract] [Full Text] [PDF]

				L. Bertoletti, R. Elleuch, D. Kaczmarek, R. Jean-Francois, and J. M. Vergnon Bronchoscopic cryotherapy treatment of isolated endoluminal typical carcinoid tumor. Chest, November 1, 2006; 130(5): 1405 - 1411. [Abstract] [Full Text] [PDF]

				T. C. Mineo, G. Guggino, D. Mineo, G. Vanni, and V. Ambrogi Relevance of Lymph Node Micrometastases in Radically Resected Endobronchial Carcinoid Tumors Ann. Thorac. Surg., August 1, 2005; 80(2): 428 - 432. [Abstract] [Full Text] [PDF]

				J. E. Ippolito, J. Xu, S. Jain, K. Moulder, S. Mennerick, J. R. Crowley, R. R. Townsend, and J. I. Gordon An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers PNAS, July 12, 2005; 102(28): 9901 - 9906. [Abstract] [Full Text] [PDF]

				N. Zaffaroni, R. Villa, U. Pastorino, R. Cirincione, M. Incarbone, M. Alloisio, M. Curto, S. Pilotti, and M. G. Daidone Lack of Telomerase Activity in Lung Carcinoids Is Dependent on Human Telomerase Reverse Transcriptase Transcription and Alternative Splicing and Is Associated with Long Telomeres Clin. Cancer Res., April 15, 2005; 11(8): 2832 - 2839. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mezzetti, M. Articles by Conforti, S. Search for Related Content PubMed PubMed Citation Articles by Mezzetti, M. Articles by Conforti, S. Related Collections Lung - cancer