ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Joseph I. Miller
Kamal A. Mansour
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gal, A. A.
Right arrow Articles by Mansour, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gal, A. A.
Right arrow Articles by Mansour, K. A.
Related Collections
Right arrow Mediastinum

Ann Thorac Surg 2001;72:1179-1182
© 2001 The Society of Thoracic Surgeons

Original article: general thoracic

Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study

Anthony A. Gal, MDa, Michael J. Kornstein, MDb, Cynthia Cohen, MDa, Ignacio G. Duarte, MDc, Joseph I. Miller, MDc, Kamal A. Mansour, MDc

a Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
b Department of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
c Department of Pathology and Laboratory Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA

Accepted for publication June 18, 2001.

Address reprint requests to Dr Gal, Department of Pathology and Laboratory Medicine, Emory University Hospital, H-171, 1364 Clifton Rd, NE, Atlanta, GA 30322
e-mail: agal{at}emory.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Neuroendocrine tumors of the thymus are rare, histologically diverse neoplasms with an unpredictable clinical behavior. This study provides a useful clinicopathological classification and determines the relevance of specific prognostic factors.

Methods. Ten neuroendocrine tumors of the thymus were analyzed for specific clinical and pathological features. Prognostic factors of these cases and 71 previously published cases were evaluated by Kaplan-Meier survival curves and Cox multivariate hazard model.

Results. There were 7 males and 3 females, with ages ranging from 26 to 77 years. Cases were classified as carcinoid tumor (2), atypical carcinoid tumor (6), and small cell carcinoma (2). An advanced clinical stage was evident in all instances with frequent recurrence (4) and metastases (8), and a short disease-free survival. Overall mortality was 60%. Statistical analysis of current and previously published cases (n = 81 total) revealed that unresectability (p = 0.0001), extent of surgical resection (p = 0.0002), and advanced clinical stage at presentation (p = 0.03) were associated with higher mortality. By multivariate Cox regression analysis, unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival.

Conclusions. Neuroendocrine tumors of the thymus can be classified into distinct clinicopathological entities, and specific factors have prognostic relevance.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Neuroendocrine tumors of the thymus (NETT) are rare and histologically diverse [1]. Their clinical behavior is difficult to predict, and many tumors are associated with a short disease-free survival and high mortality. In most instances, NETT behave aggressively with advanced disease due to invasion of adjacent mediastinal structures, local recurrence, or metastases [2–14].

In the past few decades, there has been an increased awareness of the histological diversity of NETT [1, 4–6, 13, 15, 16]. The existence of a three-tiered pathological classification of low-grade, intermediate-grade, and high-grade NETT was initially proposed by Rosai and associates [17] more than 25 years ago. While differences in histopathology of neuroendocrine tumors of the lung correlate with clinical behavior, this is not necessarily true for NETT. Fukai and associates [13] did not find an association between histological grade and outcome in a group of 15 patients. However in a larger study, Moran and Suster [14] recently showed an inverse correlation between survival and tumor differentiation in NETT: low-grade, intermediate-grade, and high-grade tumors showed a 5-year survival of 50%, 20%, and 0%, respectively.

In view of the debatable role of histopathology in predicting outcome for NETT, the prognostic relevance of other factors has not been formally examined. The purpose of this study is to see if a modified three-tiered pathological classification is relevant and to determine if specific variables have prognostic significance in predicting survival.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
A retrospective review was undertaken from the surgical pathology files at the Departments of Pathology and Laboratory Medicine at Emory University Hospital (EUH) and at the Medical College of Virginia/Virginia Commonwealth University (MCV-VCU). Ten patients were identified at EUH (7) and MCV-VCU (3). Two patients were previously reported [18, 19].

Metastases from pulmonary neuroendocrine tumors were excluded in all instances by a thorough review of clinical, pathological, and radiographic data. The clinical stage was determined by the criteria of Masaoka and associates [20] for thymic tumors. Follow-up data were obtained by contacting thoracic surgeons, pathologists, oncologists, and other physicians. Median duration of follow-up was 49 months (range 5 to 156 months). The patients were classified as alive with no evidence of disease (ANED), alive with disease (AWD), or died with disease (DWD).

NETT were classified into typical carcinoid (TC), atypical carcinoid (AC), or small cell carcinoma (SCC) using a slight modification of the World Health Organization criteria for neuroendocrine thymic tumors [21]. The mitotic count at 100 x was assessed per 100 high-power fields (hpf). Carcinoid tumors with less than 10 mitoses/100 hpf were classified as TC, whereas tumors with more than 10 to less than 100 mitoses/100 hpf were regarded as AC (Table 1). Immunohistochemistry for neuroendocrine markers was performed in 7 patients in which archival tissue was available to exclude thymoma and nonneuroendocrine thymic carcinoma.


View this table:
[in this window]
[in a new window]
  		Table 1. Histological Criteria for Neurendocrine Tumors of the Thymus

 
Statistical analysis
We analyzed 10 patients in this series and 71 previously published patients in which specific follow-up and outcome data were reported [2–7, 9, 10, 12, 13]. Survival curves were generated by the Kaplan-Meier method using SPS statistical software (version 7.5 for Windows). The statistical significance between curves was tested by the log-rank test. For factors deemed statistically relevant, a multivariate Cox proportional hazard regression model was developed. Survival times were recorded from the date of operation to the termination of follow-up.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Clinical findings
There were 7 males and 3 females, with overall median age of 52 years (range 26 to 77 years). At initial presentation, all patients had a radiographic mediastinal mass associated with various clinical presentations: asymptomatic (1), chest pain (1), shoulder pain (1), dyspnea (2), post-coronary artery bypass graft (1), or chronic diarrhea (1). Three patients had Cushing’s syndrome, which eventually led to the detection of NETT. One patient had a subsequent pancreatic endocrine tumor, suggesting a multiple endocrine neoplasia-1 (MEN-1) syndrome.

In nine resectable tumors, surgical therapy included thymectomy alone (1), thymectomy plus en bloc resection of adjacent tissues (6), and thymectomy plus resection of adjacent tissues and biopsy of thoracic viscera (2). In 1 patient with extensive unresectable tumor, an open biopsy was performed.

At initial operation, the tumor was found at an advanced clinical stage [Masaoka Stage 3 (3), 4a (1), or 4b (6)]. There was gross invasion of tumor into adjacent mediastinal and thoracic organs: lung (4), major blood vessels (4), pericardium (3), phrenic nerve (2), and other mediastinal structures (1). Metastatic tumor was identified in 4 of 5 patients with lymphadenopathy found during the initial surgical procedure.

In several patients, adjuvant therapy was employed in the postoperative management of NETT. Of 3 patients who received a combination of chemotherapy (VP-16, Cisplatin, and other agents) and radiotherapy, 2 showed a decrease in tumor burden and 1 patient showed no change. Two other patients only received radiotherapy; both initially demonstrated a response, but subsequently developed recurrence 6 and 10 years later, respectively.

Postoperative recurrence typically occurred in the first 2 years after surgery. Intrathoracic recurrence developed in the mediastinum (3), pulmonary artery (1), or chest wall (1). Metastases were identified in 8 patients: in the lung (4), intrathoracic lymph nodes (4), extrathoracic lymph nodes (2), liver (2), bone or vertebrae (2), brain (1), head and neck (1), and heart (1). At the conclusion of the study, 1 patient was ANED, 3 patients were AWD, and 6 patients were DWD.

Pathologic findings
Resected NETT were described as solitary (5) or multiple masses (4) with median tumor size of 8 cm (range 2.5 to 18 cm). In one unresectable case, the tumor diffusely encased mediastinal structures. Histologically, the tumors were classified as TC (2), AC (6), SCC (2; 1 pure SCC and 1 mixed AC/SCC) (Fig 1). Angioinvasion was present in all instances: extensive (6) or focal (4). Tumor necrosis in AC and SCC exhibited comedo or infarct patterns. Surgical margins were positive (5), negative (3), or could not be evaluated (2). At least one neuroendocrine marker was expressed in tumors evaluated by immunohistochemistry: neuron-specific enolase (100%), synaptophysin (86%), and chromogranin (71%).



View larger version (150K):
[in this window]
[in a new window]
  		Fig 1. Composite photomicrograph of neuroendocrine tumors of the thymus: typical carcinoid tumor (A), atypical carcinoid tumor (B), and small cell carcinoma (C). Hematoxylin and eosin stain, 100 x.

 
Correlation of survival with histology
The mean survival period was 102 months for TC, 63 months for AC, and 19 months for SCC. At the conclusion of follow-up, the histopathological categories of NETT were correlated with survival: TC (AWD, 2), AC (ANED, 1; AWD, 1; DWD, 4), and SCC (DWD, 2).

Statistical analysis of current and previously published cases
Statistical analysis showed that unresectability (p = 0.0001, extent of surgical resection (p = 0.0002) (Fig 2), and advanced clinical stage at presentation (p = 0.03) (Fig 3) were associated with mortality. Gender, age, Cushings’s syndrome, MEN-I syndrome, chemotherapy, radiation therapy, recurrence, and local or distant metastasis had no impact on survival. Multivariate Cox regression analysis of prognostic factors disclosed that unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival.



View larger version (15K):
[in this window]
[in a new window]
  		Fig 2. Kaplan-Meier survival analysis with log-rank test for patients with neuroendocrine tumors of the thymus according to extent of surgery. (PR = partial resection; TR = total resection; UR = unresectable.)

 


View larger version (19K):
[in this window]
[in a new window]
  		Fig 3. Kaplan-Meier survival analysis with log-rank test for patients with neuroendocrine tumors of the thymus according to Masaoka clinical staging.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Unlike carcinoids and neuroendocrine tumors of the lung and foregut, NETT behave aggressively with endocrinologic complications of Cushing’s syndrome, frequent recurrence and metastases, and a short disease-free survival. Our patients presented at an advanced clinical stage, which warranted a complete en bloc resection. Tumor involvement of adjacent mediastinal structures made resection difficult and led to less than optimal surgical therapy in some instances. Only 1 patient has remained in complete remission without evidence of disease 58 months after surgery. The majority of our patients (60%) have died of disease and a minority (30%) are alive with residual disease.

A major goal of this study was to determine if specific factors are predictive of survival. Because it can be argued that the number of patients is too small for analysis, we included our cases with others published in the literature in which specific outcome data were available [2–7, 9, 10, 12, 13]. This analysis showed that unresectability, extent of surgical resection, and advanced clinical stage were univariate factors associated with mortality. Moreover, a multivariate Cox regression analysis disclosed that unresectability and advanced stage were independent factors associated with poor survival. Unfortunately, we could not perform a statistical analysis to determine whether tumor histology is an independent prognostic factor because different pathological classification criteria were employed in the 71 previously reported cases of NETT.

Several authors have commented that thoracic surgeons should take an aggressive approach in the management of NETT [4, 5, 8–10, 12, 13]. The importance of total surgical resection (ie, removal of tumor and dissection from adjacent involved mediastinal structures) is affirmed through our statistical analysis. However, the corollary is true: the prognosis is poor in the setting of partial or incomplete surgical resection. This has particularly been the case in the setting of unresectable tumor.

The role of chemotherapy and radiotherapy in the postoperative management of NETT continues to be debated. Adjuvant therapy may have mixed short-term results, although it had little impact on long-term survival. Furthermore, our analysis indicates that neither chemotherapy nor radiotherapy leads to differences in survival. While it can be argued that adjuvant therapy may offer local disease control, it is not effective in eradicating tumor, nor does it prevent the development of recurrence or metastases [6, 11, 13].

In conclusion, our study has shown that NETT are potentially aggressive tumors that can be morphologically grouped into distinct tumor categories. Unresectability and advanced clinical stage were statistically significant independant prognostic factors associated with poor outcome by our analysis of current and previously published cases. Whether these determinants are unique to NETT, or mirror the behavior of other thymic tumors, is uncertain. Additional studies should adopt a uniform approach to clinical staging and histopathological classification to explore the intriguing and unpredictable biology of NETT.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors thank Diane Lawson and Deborah Sexton for assistance with immunohistochemistry and Robert Santoianni for expertise with photography.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Klemm K.M., Moran C.A. Primary neuroendocrine carcinomas of the thymus. Semin Diagn Pathol 1999;16:32-41.[Medline]
  2. Rosai J., Higa E. Mediastinal endocrine neoplasm of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 1972;29:1061-1074.[Medline]
  3. Rosai J., Higa E., Davie J. Mediastinal endocrine neoplasm in patients with multiple endocrine adenomatosis. A previous unrecognized association. Cancer 1972;29:1075-1083.[Medline]
  4. Salyer W.R., Salyer D.C., Eggleston J.C. Carcinoid tumors of the thymus. Cancer 1976;37:958-973.[Medline]
  5. Wick M.R., Scott R.E., Li C.Y., Carney J.A. Carcinoid tumor of the thymus: a clinicopathologic report of seven cases with a review of the literature. Mayo Clin Proc 1980;55:246-254.[Medline]
  6. Wick M.R., Carney J.A., Bernatz P.E., Brown L.R. Primary mediastinal carcinoid tumors. Am J Surg Pathol 1982;6:195-205.[Medline]
  7. Wick M.R., Scheithauer B.W. Thymic carcinoid. A histologic, immunohistochemical, and ultrastructural study of 12 cases. Cancer 1984;53:475-484.[Medline]
  8. Economopoulos G.C., Lewis J.W., Jr, Lee M.W., Silverman N.A. Carcinoid tumors of the thymus. Ann Thorac Surg 1990;50:58-61.[Abstract]
  9. Zhang Z., Ren H., Yu H., Li Z., Liu H., Lu Z. Thymic carcinoid tumor. A report of 7 cases. Chin Med Sci J 1993;8:48-51.[Medline]
  10. Wang D.Y., Chang D.B., Kuo S.H., et al. Carcinoid tumors of the thymus. Thorax 1994;49:357-360.[Abstract/Free Full Text]
  11. Best L.A.E., Westbrook B.M., Trastek V.F., Payne W.S., Pairolero P.C. Surgery in the management of mediastinal carcinoid. J Cardiovasc Surg (Torino) 1994;34(Suppl 1):133-135.
  12. de Montpreville V.T., Macchiarini P., Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996;111:134-141.[Abstract/Free Full Text]
  13. Fukai I., Masaoka A., Fujii Y., et al. Thymic neuroendocrine tumor (thymic carcinoid): a clinicopathologic study in 15 patients. Ann Thorac Surg 1999;67:208-211.[Abstract/Free Full Text]
  14. Moran C.A., Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000;114:100-110.[Abstract/Free Full Text]
  15. Wick M.R., Rosai J. Neuroendocrine neoplasms of the mediastinum. Semin Diag Pathol 1991;8:35-51.
  16. Shimosato Y., Mukai K. Tumors of the mediastinum. In: Rosai J., Sobin L.H., eds. Atlas of tumor pathology, third series, fascicle 21. Washington DC: American Registry of Pathology, 1997:158-183.
  17. Rosai J., Levine G., Weber W.R., Higa E. Carcinoid tumors and oat cell carcinomas of the thymus. Pathol Annu 1976;12:201-226.
  18. Kay S., Willson M.A. Ultrastructural studies of an ACTH-secreting thymic tumor. Cancer 1970;26:445-452.[Medline]
  19. Lynch M., Blevins L.S., Martin R.P. Acquired supravalvular pulmonary stenosis due to extrinsic compression by a metastatic thymic carcinoid tumor. Int J Card Imag 1996;12:61-63.
  20. Masaoka A., Monden Y., Nakahara K., Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485-2492.[Medline]
  21. Rosai J., Sobin L.H. World Health Organization International histological classification of tumors: histological typing of tumors of the thymus, 2nd ed. Berlin: Springer Verlag, 1999:15-18.



This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
V. Van Brandt, S. Heyman, E. Van Marck, J. Hendriks, and P. Van Schil
Atypical presentation of an atypical carcinoid.
Ann. Thorac. Surg., December 1, 2009; 88(6): 2004 - 2006.
[Abstract] [Full Text] [PDF]

Home page
 ICVTSHome page
R. Dutta, A. Kumar, T. Jindal, and S. R. Mathur
Neuroendocrine carcinoma of the thymus gland with sternal invasion
Interactive CardioVascular and Thoracic Surgery, June 1, 2009; 8(6): 694 - 696.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Ekeblad, A. Sundin, E. T. Janson, S. Welin, D. Granberg, H. Kindmark, K. Dunder, G. Kozlovacki, H. Orlefors, M. Sigurd, et al.
Temozolomide as Monotherapy Is Effective in Treatment of Advanced Malignant Neuroendocrine Tumors
Clin. Cancer Res., May 15, 2007; 13(10): 2986 - 2991.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
F. C. Detterbeck and A. M. Parsons
Thymic tumors
Ann. Thorac. Surg., May 1, 2004; 77(5): 1860 - 1869.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
P. L. Filosso, G. M. Actis Dato, E. Ruffini, S. Bretti, F. Ozzello, and M. Mancuso
Multidisciplinary treatment of advanced thymic neuroendocrine carcinoma (carcinoid): Report of a successful case and review of the literature
J. Thorac. Cardiovasc. Surg., April 1, 2004; 127(4): 1215 - 1219.
[Full Text] [PDF]

Home page
 ChestHome page
O. Tiffet, A. G. Nicholson, G. Ladas, M. N. Sheppard, and P. Goldstraw
A Clinicopathologic Study of 12 Neuroendocrine Tumors Arising in the Thymus
Chest, July 1, 2003; 124(1): 141 - 146.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
R. Chaer, M. G. Massad, A. Evans, N. J. Snow, and A. S. Geha
Primary neuroendocrine tumors of the thymus
Ann. Thorac. Surg., November 1, 2002; 74(5): 1733 - 1740.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Joseph I. Miller
Kamal A. Mansour
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gal, A. A.
Right arrow Articles by Mansour, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gal, A. A.
Right arrow Articles by Mansour, K. A.
Related Collections
Right arrow Mediastinum

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS