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Ann Thorac Surg 1999;67:208-211
© 1999 The Society of Thoracic Surgeons

Original Articles

Thymic neuroendocrine tumor (thymic carcinoid): a clinicopathologic study in 15 patients

Ichiro Fukai, MDa, Akira Masaoka, MD, PhDa, Yoshitaka Fujii, MD, PhDa, Yosuke Yamakawa, MDa, Tomoki Yokoyama, MDa, Takayuki Murase, MDb, Tadaaki Eimoto, MD, PhDb

a Department of Surgery II, Nagoya City University Medical School, Nagoya, Japan
b Department of Pathology II, Nagoya City University Medical School, Nagoya, Japan

Accepted for publication June 18, 1998.

Address reprint requests to Dr Fukai, Department of Surgery II, Nagoya City University Medical School, Mizuho-ku, Nagoya, 467-8601, Japan
e-mail: i.fukai{at}med.nagoya-cu.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Thymic neuroendocrine tumor (carcinoid tumor) is rare, and prognosis for patients with this tumor has been difficult to predict.

Methods. The medical records of 15 patients were reviewed, and the patients were classified according to tentative TNM classification and histologic grade.

Results. Ten (66.7%) of 15 patients were male. Lymph node metastases were identified in 9 (60%) of 15 patients at the time of resection. There were one grade 1, nine grade 2, and five grade 3 tumors. Total resection was possible in 13 patients. Distant metastases developed in 10 (76.9%) of these 13 patients, although no local recurrence developed. Of these 10 patients, 6 died of distant metastases 5 to 25 months after the recurrence. Three patients are still alive, with metastases to the bone, spleen, and pleura 1 to 24 months after the diagnosis of recurrence. Two patients are presently tumor free (T1N0, grade 3 and T3N2, grade 2), but only 1 has survived beyond 5 years.

Conclusions. Thymic neuroendocrine tumor must be regarded as a malignant neoplasm that is prone to metastasize to mediastinal lymph nodes and to distant sites, even after total excision. Neither T and N classification nor histologic grade has been successful in predicting the outcome of a patient with this tumor. More aggressive management, including adjuvant therapies and reexcision of subsequent tumors, may result in increased survival.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Thymic carcinoid is a distinct clinicopathologic entity that was confused with thymoma before Rosai and Higa [1] described this tumor as a separate entity in 1972. Histologically, most of these tumors are identical to well-differentiated neuroendocrine carcinoma of foregut derivation [2, 3]. It is a potentially malignant tumor and often develops distant metastases, sometimes after long intervals [3–5]. However, the behavior of this unusual tumor is unpredictable [4], and there has been no satisfactory classification system to predict its progression. In 1991, we reported that in patients with thymic neuroen

docrine tumor, the percentage with stage IVB disease was much higher than that in patients with thymoma [6]. Lymphogenous spread was observed around the thymus or in the mediastinum in noninvasive cases [6]. These findings have led us to propose a TNM classification for thymic neuroendocrine tumor (Table 1) [6]. To provide prognostic data about this unusual tumor, we looked for a relation between long-term prognosis, tumor–node classification, and histologic appearance.


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  		Table 1. Tentative TNM Classification of Thymic Neuroendocrine Tumor

 

   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Thymic epithelial tumors seen at multiple hospitals in Japan over an 8-year period (1981 to 1989) were reviewed. Fifteen cases of thymic neuroendocrine tumor were identified. The criterion for selection included the absence of a primary neuroendocrine tumor at sites other than the mediastinum at the time of presentation. The classification of each case at presentation was established according to the staging proposed for thymomas [7] and TNM classification (Table 1) [6]. Follow-up was possible for all patients.

All tumor tissue was fixed in 10% formalin and embedded in paraffin. All tissue was stained with hematoxylin and eosin and Glimerius stains, and sections were examined by two pathologists (T.E., T.M.). Tumors were subclassified into three groups according to histologic grade. Grade 1 thymic neuroendocrine tumors are those composed of round to polygonal cells exhibiting little pleomorphism. Mitoses are rare. Grade 2 tumors show mild to moderate cellular pleomorphism with one or two mitotic figures per 20 high-power fields (x400). Grade 3 tumors have a higher degree of cellular pleomorphism and a higher nuclear to cytoplasmic ratio than grade 2 tumors (Fig 1). Mitoses were identified more easily, with six to eight mitoses per 10 high-power fields (x400) (Table 2). Grade 1 tumor corresponds to the carcinoid tumor, which is a distinct subset of neuroendocrine tumors, comprising the better differentiated members of that category [2]. Grades 2 and 3 tumors correspond to well-differentiated neuroendocrine carcinomas [2].



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  		Fig 1. (Patient 9, T2N1.) Grade 3 neuroendocrine tumor of thymus. Arrow indicates mitosis. (Hematoxylin and eosin; x400 before 32% reduction.)

 

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  		Table 2. Histologic Features of Grade 1, 2, and 3 Thymic Neuroendocrine Tumors

 

   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Results are summarized in Table 3. The age of our patients at the time of diagnosis ranged from 19 to 73 years, with an average age of 50.6 years. Ten (66.7%) of 15 patients were male. Lymph node metastases were identified in 9 (60%) of 15 patients at the time of resection. There were one grade 1, nine grade 2, and five grade 3 tumors. Computed tomographic scans successfully revealed the lesions in all patients (Fig 2). Total resection was possible in 13 (86.7%) of 15 patients (Fig 3). One biopsy (patient 15, T3N3) and one subtotal resection (patient 14, T4N0) were performed. Two patients had Cushing’s syndrome. Patient 1 was admitted to the Nagoya City University Hospital after having been diagnosed with myasthenia gravis. Computed tomographic scans revealed a large cystic mass in the right lobe of the thymus and a small homogenous solid mass in the left lobe of the thymus. Microscopically, the cystic tumor was found to be thymoma, and the solid tumor was a thymic neuroendocrine carcinoma. Electron microscopy revealed numerous neurosecretory granules in the neoplastic cells of the solid tumor [8]. Eight patients received adjuvant irradiation. Of these 8, 2 patients (patients 11 and 13) received neoadjuvant chemotherapy that gave little benefit. Distant metastases developed in 10 (76.9%) of 13 patients who received total resection, although no local recurrence developed. Of these 10 patients, 6 died of distant metastases 5 to 25 months after recurrence. Three patients are still alive, with metastases to the bone, spleen, and pleura 1 to 24 months after the diagnosis of recurrence. In these patients, the metastases did not become evident until 99, 72, and 73 months after the initial operation, respectively. Two patients are presently tumor free (T1N0, grade 3 and T3N2, grade 2), but only 1 has survived beyond 5 years. The best prognosis was observed in patient 14 (T4N0, grade 3) who received adjuvant irradiation and chemotherapy. He lived 127 months with disseminated pleural disease. The earliest recurrence was noted 4 months after the operation in patient 7 (T1N1, grade 1).


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  		Table 3. Summary of Clinicopathologic Findings in 15 Patients with Thymic Neuroendocrine Tumor

 


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  		Fig 2. (Patient 6.) Computed tomographic scan of the chest reveals a large mass in the anterior mediastinum.

 


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  		Fig 3. (Patient 6.) Gross appearance of thymic neuroendocrine tumor. The tumor lacks internal fibrous septation. Foci of hemorrhage are apparent.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Since Rosai and Higa [1] described thymic carcinoid tumor as a separate entity in 1972, this tumor has been the subject of several reports indicating that it (1) occurs predominantly in male subjects; (2) can be complicated by endocrine abnormalities, either because of adrenocorticotrophic hormone secretion by the thymic carcinoid itself or its association with other endocrine neoplasms; and (3) develops distant metastases in approximately 20% to 30% of patients, often with a protracted clinical course [3]. Long-term follow-up of the 15 patients in our series showed that metastases occurred in 10 (76.9%) of 13 patients despite total resection. Only 3 of 13 patients did not develop distant metastases, but in only 1 was follow-up longer than 5 years. These results indicate that the long-term prognosis of patients with this tumor is poor [9–11].

In view of the histologic features, most tumors of thymic origin should fall into the category of well-differentiated neuroendocrine carcinomas [2, 3]. So-called carcinoid tumors, a distinct subset of neuroendocrine tumors, comprising the better differentiated tumors, are rare [2, 3]. Well-differentiated neuroendocrine carcinoma could be subclassified into grades 2 and 3 by the degree of cellular atypia and mitotic activity. However, our series illustrates the difficulty of predicting the outcome of a patient according to histologic grade alone. Even the patient with grade 1 tumor (so-called carcinoid tumor) showed anterior mediastinal lymph node metastasis at the time of presentation (T1N1) and developed cervical lymph node metastases only 4 months after the initial operation.

Extracapsular invasion of mediastinal structures at the initial exploration may indicate a poorer prognosis [4, 5]; however, neither T nor N classification is a good predictor of the prognosis of the patient with well-differentiated neuroendocrine carcinoma. The prognosis depends on the development of distant metastases or the lack thereof. In the present study, there were no survivors who lived longer than 25 months after the development of recurrence. It is safe to say that the earlier the recurrence, the poorer the prognosis.

It has been implied that Cushing’s syndrome on clinical presentation is associated with a poorer prognosis [2]. Despite the same tumor–node classification (T1N0) and higher histologic grade in patient 1 than in patient 2, the clinical outcome of these 2 patients was considerably different. Patient 2, who had Cushing’s syndrome, died of bone metastases 53 months after operation. Patient 1, without Cushing’s syndrome, is now in good condition 103 months after operation. Patient 7, who also had Cushing’s syndrome, developed cervical lymph node metastasis only 4 months after operation, despite a grade 1, very well differentiated neuroendocrine tumor. We speculate that the degree of neuroendocrine potential of the tumor may reflect the malignancy itself.

No local recurrence was reported. Seven of 13 patients in whom total resection was possible received postoperative radiation therapy. Although the role of adjuvant irradiation has not been adequately assessed, radiotherapy may be helpful in preventing local recurrence after total excision. The role of chemotherapy is uncertain.

Economopoulos and colleagues [5] have claimed that long-term survival can only be achieved by aggressive excision not only of the initial tumor but of subsequent recurrences and metastases. This approach would be possible only in patient 4 who developed splenic metastasis 99 months after the initial operation, and splenectomy is now under consideration.

In conclusion, thymic neuroendocrine tumor (even grade 1) must be regarded as a malignant lesion that is prone to metastasize to mediastinal lymph nodes and to distant sites even after total excision. Unfortunately, neither T and N classification nor histologic grade has been successful in predicting the outcome of a patient with this tumor. More aggressive management, including routine adjuvant therapy and reexcision of the subsequent recurrent tumor, might result in increased survival.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank the following physicians for providing follow-up information about their patients and histologic specimens: Dr. Yasushi Yamato, Niigata University, Niigata; Dr. Tetsuya Mitsudomi, Aichi Cancer Center, Nagoya; Dr. Yoshinori Kusajima, Toyama City Hospital, Toyama; Dr. Masahiro Yoshimura, Hyogo Medical Center for Adults, Akashi; Dr. Norimichi Nemoto, Nippon University, Tokyo; Dr. Yukio Shimizu, Gunma Cancer Center, Ota; Dr. Koji Kawano, Naha City Hospital, Naha; Dr. Yuji Matsumura, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Dr Masaoka is the organizer of the project "Function of Thymoma," which is supported by a grant from the Ministry of Health and Welfare of Japan.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Rosai J., Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Cancer 1972;29:1061-1075.[Medline]
  2. In: Verley J.M., Hollmann K.H., eds. Tumors of the mediastinum. Dordrecht, the Netherlands: Kluwer Academic, 1992:102-108.
  3. de Montpreville T.V., 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]
  4. 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]
  5. Economopoulos G.C., Lewis J.W., Jr, Lee M.W., Silverman N.A. Carcinoid tumor of the thymus. Ann Thorac Surg 1990;50:58-61.[Abstract]
  6. Yamakawa Y., Masaoka A., Hashimoto T., et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68:1984-1987.[Medline]
  7. 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]
  8. Mizuno T., Masaoka A., Hashimoto T., et al. Coexisting thymic carcinoid tumor and thymoma. Ann Thorac Surg 1990;50:650-652.[Abstract]
  9. Wick M.R., Bernatz P.E., Carney J.A., Brown L.R. Primary mediastinal carcinoid tumors. Am J Surg Pathol 1982;6:195-205.[Medline]
  10. Herbst W.M., Kummer W., Hofmann W., Otto H., Heym C. Carcinoid tumors of the thymus. Cancer 1987;60:2465-2470.[Medline]
  11. Wick M.R., Rosai J. Neuroendocrine neoplasms of the thymus. Pathol Res Pract 1988;183:188-199.[Medline]



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