|Year : 2017 | Volume
| Issue : 3 | Page : 556-559
Primary neuroendocrine carcinoma of the thymus: A retrospective analysis from a regional cancer center in Western India
Sandeep Ramesh Kukkar, Harsha Panchal, Asha Anand
Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
|Date of Web Publication||24-May-2018|
Dr. Sandeep Ramesh Kukkar
Department of Medical and Paediatric Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Primary neuroendocrine tumors of the thymus are unusual anterior mediastinal tumors with a variable prognosis. A retrospective analysis of five patients with primary neuroendocrine tumors of the thymus admitted to the Gujarat Cancer and Research Institute, Ahmedabad, between 2012 and 2016, was done to study the clinical profile and outcome of these patients. The role of various prognostic factors such as surgical resection, histological grade, and Masaoka-Koga staging was also analyzed. Majority of the patients present with signs and symptoms related to a rapidly expanding mediastinal mass, such as breathlessness, facial puffiness, edema over the neck and extremities, chest pain, and other features of superior vena cava (SVC) syndrome. Collateral venous dilatation over the neck and chest and edema over neck were the most common physical signs. All the patients enrolled in the study presented in advanced stages with a poor differentiation on histopathological examination. Thymic neuroendocrine tumors usually manifest as large, lobulated, and locally invasive anterior mediastinal masses surrounding the great vessels of the neck and thorax. None of the diagnosed patients underwent surgical resection in view of extensive vascular encasement in the neck and thorax, and all of them were started on platinum-based palliative chemotherapy. The median survival of the patients was 12 months with the longest survival of 16 months for one patient. Possibility of this potentially rare entity should be kept in mind when a patient presents with features of SVC syndrome and large mediastinal mass. Complete surgical resection of the tumor is prognostic of improved treatment outcome and long-term survival. Large tumor size could be a determinant of poor overall outcome, and tumor size should strongly be considered as a factor in the revised (NETT) Neuroendocrine tumours of thymus staging. Histological grade and Masaoka-Koga stage are the important prognostic factors, but this study emphasizes the utmost need to further validate the prognostic factors.
Keywords: Mediastinum, neuroendocrine carcinoma, thymus
|How to cite this article:|
Kukkar SR, Panchal H, Anand A. Primary neuroendocrine carcinoma of the thymus: A retrospective analysis from a regional cancer center in Western India. Indian J Cancer 2017;54:556-9
|How to cite this URL:|
Kukkar SR, Panchal H, Anand A. Primary neuroendocrine carcinoma of the thymus: A retrospective analysis from a regional cancer center in Western India. Indian J Cancer [serial online] 2017 [cited 2020 Sep 28];54:556-9. Available from: http://www.indianjcancer.com/text.asp?2017/54/3/556/233143
| » Introduction|| |
Thymomas are the most common mediastinal tumors while the neuroendocrine tumors of the thymus are extremely rare. These potentially rare tumors have a high propensity to develop distant metastasis even after long intervals. The possible origin of the tumor can be from ectopic tissues in the mediastinum or within the thymus itself.
The prognosis and treatment of primary neuroendocrine carcinomas of the thymus remain extremely variable. As per the World Health Organization (WHO) classification, neuroendocrine tumors are included in the thymic carcinoma group and are divided into two histopathological types: well-differentiated neuroendocrine carcinomas (typical and atypical carcinoid) and poorly differentiated neuroendocrine carcinomas (small-cell carcinoma and large-cell neuroendocrine carcinoma). The well-differentiated neuroendocrine carcinomas are low grade and biologically less aggressive, whereas poorly differentiated neuroendocrine carcinomas are high-grade tumors. We carried out a retrospective analysis of five patients to study the clinical profile, associated prognostic factors, and outcome of patients with primary neuroendocrine tumors of the thymus.
| » Patient Characteristics|| |
This retrospective analysis was conducted at the Gujarat Cancer and Research Institute, Ahmedabad, after obtaining approval from the Institutional Ethics Committee. The total of five patients diagnosed as primary neuroendocrine tumors of the thymus, who were treated at the Gujarat Cancer and Research Institute, Ahmedabad, between 2012 and 2016, were included in this study. The patients were staged according to the Masaoka-Koga system, and the histological type was determined according to the 2004 WHO classification.
| » Results|| |
The baseline clinical characteristics of the enrolled patients are summarized in [Table 1]. Of the total five patients enrolled in the present study, three were males and two were females, with a median age of 61.6 years. Majority of the patients presented in the advanced stages with Stage 4 patients accounting for 80% (n = 4) of the total cases. As per the WHO criteria, all the patients (n = 5) had poorly differentiated tumors on histopathological examination. The majority of the patients presented with large mediastinal masses encasing the great vessels of neck and thorax with a mean tumor size of 9.2 cm in the longest dimension. The summary of clinic-pathologic features and treatment outcome of the enrolled patients is depicted in [Table 2].
|Table 2: Summary of clinicopathologic features and treatment outcome in 5 patients with thymic neuroendocrine tumor|
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The presenting symptoms and signs of our study patients are depicted in [Table 3] and [Table 4], respectively. Majority of the patients presented with symptoms of neck swelling, dyspnea, swelling of the upper extremities, and facial puffiness. Other common symptoms included dysphagia, stridor, bone pains, and weight loss. Collateral venous dilation over the neck and chest and edema over neck were the most common physical signs in this study.
As majority of the patients presented in the advanced stages, these patients did not undergo surgical resection and were started on palliative chemotherapy. Carboplatin with etoposide was the most common chemotherapy regimen used in the enrolled patients. The median survival of the patients in the study was 12 months with the longest survival of 16 months in one patient.
Patients were asked to follow-up every 2–3 months after the completion of palliative chemotherapy. The patients underwent detailed clinical examinations and interim thoracic and abdominal computed tomography (CT) scans to look for possible disease progression.
| » Discussion|| |
Primary neuroendocrine tumors of the thymus, previously classified as carcinoid tumors, are a distinct clinicopathological entity accounting for <5% of all anterior mediastinal neoplasms. Rosai and Higa first described primary neuroendocrine tumors of the thymus in 1972. Only very few single case reports and short series of cases have been reported in the literature so far. Earlier, the term mediastinal carcinoids was coined for these tumors, and later on, the term neuroendocrinoma was suggested for these tumors. However, the term thymic carcinoid tumor is most commonly used for these tumors. Moran and Suster proposed the designation of thymic neuroendocrine carcinoma for this family of tumors as these tumors are aggressive in behavior as compared to their foregut counterparts.
The median age at diagnosis ranges between 40 and 60 years with a slightly male predominance, which is consistent with the findings of our study. The median age in our study population was 61.6 years with males accounting for 60% of the study group.
The neuroendocrine tumors of thymus were earlier classified into four distinct types – typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma, and small-cell carcinoma, quite similar to the classification used for lung neuroendocrine tumors. Majority of the patients in our study were diagnosed as small-cell carcinoma.
Thymic neuroendocrine carcinomas may have a varied presentation, but usually, these tumors present in four different ways: (i) incidentally detected on routine chest radiography, (ii) they may present with symptoms of thoracic structure displacement or compression like superior vena cava (SVC) syndrome, (iii) they may present with symptoms related to an associated endocrine abnormalities due to secretion by the thymic carcinoid, or (iv) symptoms related to a distant metastasis, most commonly to the liver, lung, pleura, and bone.
Approximately over one-third of patients are asymptomatic and are incidentally discovered. Majority of the patients present with signs and symptoms related to a rapidly expanding mediastinal mass, such as breathlessness, facial puffiness, edema over the neck and extremities, chest pain, and other features of SVC syndrome. Distant metastasis is seen in at least 20% of affected patients at presentation, while the frequency of extrathoracic metastasis may be as high as 20%–30%. In this study, majority of the patients presented in advanced stages with symptoms either arising from compression of SVC or the symptoms related to distant metastasis. None of the patients in our study had symptoms related to endocrine abnormalities.
On the histopathological basis, the thymic neuroendocrine carcinomas have been classified into three different types: low-grade (well-differentiated), intermediate-grade (moderately differentiated), and high-grade (poorly differentiated) tumors. Most tumors of thymic origin fall into the category of well-differentiated neuroendocrine carcinomas. Moran and Suster  in their report of 80 cases concluded that almost 36% of the cases had low-grade tumors, 45% had intermediate grade, whereas only 19% had high-grade poorly differentiated tumor. In contrast, all the patients in our study had high-grade poorly differentiated carcinomas. Immunohistochemical studies were carried out in all cases with markers such as chromogranin, neuron-specific enolase, bombesin, and synaptophysin to characterize these lesions.
Thymic neuroendocrine tumors usually manifest as large, lobulated, and locally invasive anterior mediastinal masses with areas of hemorrhage and necrosis. It is often difficult to distinguish them from thymomas on plain chest radiograms, but they are usually larger compared to thymomas. CT scan images show a heterogeneously enhancing large lobulated thymic mass with central areas of low attenuation secondary to necrosis or hemorrhage. The most common differential diagnosis for these lesions includes other primary mediastinal tumors, mainly thymoma and lymphoma. Other rare differentials are paraganglioma, parathyroid adenoma or carcinoma, and medullary carcinoma of the thyroid arising in mediastinal location. Thymoma, particularly of the spindle cell variety, is the most important and difficult differential diagnosis as they often exhibit foci with neuroendocrine appearance.
Primary neuroendocrine tumors of the thymus are a group of highly aggressive neoplasms where majority of patients usually die as a result of locally invasive or distant metastatic disease. Management of these tumors is often difficult and challenging as the tumors present in advanced stages. Complete surgical resection of the tumor remains the gold standard treatment for the management of thymic tumors compared to nonsurgical options, showing a statistically significant better survival as per the Surveillance, Epidemiology, and End Results (SEER) database analysis. Surgery involves extended resections with en bloc excision of the tumor together with the pericardium, pleura, or great vessels (or a combination).
Preoperatively and postoperatively, radiotherapy should be considered, particularly in patients with capsular invasion, because the biological behavior of these tumors is uncertain and these tumors tend to recur even after long treatment-free intervals. Overall, the role of adjuvant radiation therapy and chemotherapy is still controversial and both the modalities have been used with variable success. Chemotherapeutic agents such as 5-fluorouracil, streptozocin, carmustine, VP-16, cisplatin, and others have been used either as single agents or in combination for the management of these tumors.
The median survival in our study was 12 months with the longest survival of 16 months seen in one patient. Fukai et al. in their case series of 15 patients reported a 5-year survival rate of 33%, whereas the 5-year survival rate of 31% was reported by de Montpréville et al. in their study. High propensity for local recurrence and metastatic disease after surgical excision accounts for the poor prognosis of these patients. The possible reason for shorter median overall survival in our study could be that majority of the patients in our study presented had extensive tumor infiltrations in and around the great vessels of thorax and pericardium; therefore, complete resection of the tumor was not possible.
Overall, the histological grade, Masaoka-Koga stage, and surgical resection status have been identified as important prognostic factors, but their use remains controversial. Masaoka-Koga stage remains an important determinant of outcome as patients with Stage III and IV show a poor prognosis compared to Stage I and II patients. Similarly, Detterbeck et al. emphasized the prognostic value of tumor stage and complete surgical resection, but the prognostic impact of histologic classification and tumor size remained unclear. In the present study, majority of the patients had surgically unresectable high-grade tumors and were associated with a poor prognosis. Cardillo et al. reported tumor size as the single most important and statistically significant prognostic factor for thymic neuroendocrine tumors. A large number of patients in our study presented with tumor size >9 cm which is greater than the median cutoff reported in the SEER study. Therefore, large tumor size could be a determinant of poor overall outcome and tumor size should strongly be considered as a factor in the revised NETT staging.
The major limitations of the present study are as follows: this analysis is retrospective in nature and the study group was obtained from a single institution. However, the results of the current study are still meaningful as the disease is extremely rare.
| » Conclusion|| |
- Possibility of this potentially rare entity should be kept in mind when a patient presents with features of SVC syndrome and mediastinal mass.
- Majority of the patients present with signs and symptoms related to a rapidly expanding mediastinal mass and the classical features of SVC syndrome.
- Majority of the patients had high-grade tumors and presented in the advanced stages.
- Complete surgical resection of the tumor is prognostic of improved treatment outcome and long-term survival.
- Large tumor size could be a determinant of poor overall outcome and tumor size should strongly be considered as a factor in the revised NETT staging.
- The histological grade and Masaoka-Koga stage are the important prognostic factors, but this study emphasizes the utmost need to further validate the prognostic factors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
de Montpréville VT, Macchiarini P, Dulmet E. Thymic neuroendocrine carcinoma (carcinoid): A clinicopathologic study of fourteen cases. J Thorac Cardiovasc Surg 1996;111:134-41.
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. editors. WHO Classification of Tumors: Pathology & Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. p. 145-7.
Koga K, Matsuno Y, Noguchi M, Mukai K, Asamura H, Goya T, et al.
Areview of 79 thymomas: Modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44:359-67.
Chaer R, Massad MG, Evans A, Snow NJ, Geha AS. Primary neuroendocrine tumors of the thymus. Ann Thorac Surg 2002;74:1733-40.
Rosai J, Higa E. Mediastinal endocrine neoplasm, of probable thymic origin, related to carcinoid tumor. Clinicopathologic study of 8 cases. Cancer 1972;29:1061-74.
Gould VE. Neuroendocrinomas and neuroendocrine carcinomas: APUD cell system neoplasms and their aberrant secretory activities. Pathol Annu 1977;12 Pt 2:33-62.
Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000;114:100-10.
Arora R, Gupta R, Sharma A, Dinda AK. Primary neuroendocrine carcinoma of thymus: A rare cause of Cushing's syndrome. Indian J Pathol Microbiol 2010;53:148-51.
] [Full text]
Economopoulos GC, Lewis JW Jr, Lee MW, Silverman NA. Carcinoid tumors of the thymus. Ann Thorac Surg 1990;50:58-61.
Teh BT. Thymic carcinoids in multiple endocrine neoplasia type 1. J Intern Med 1998;243:501-4.
Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: A SEER database analysis of 160 patients. Ann Surg 2010;251:1117-21.
Kvols LK. Therapy of the malignant carcinoid syndrome. Endocrinol Metab Clin North Am 1989;18:557-68.
Wang DY, Chang DB, Kuo SH, Yang PC, Lee YC, Hsu HC, et al.
Carcinoid tumours of the thymus. Thorax 1994;49:357-60.
Fukai I, Masaoka A, Fujii Y, Yamakawa Y, Yokoyama T, Murase T, et al.
Thymic neuroendocrine tumor (thymic carcinoid): A clinicopathologic study in 15 patients. Ann Thorac Surg 1999;67:208-11.
Detterbeck F, Youssef S, Ruffini E, Okumura M. A review of prognostic factors in thymic malignancies. J Thorac Oncol 2011;6 7 Suppl 3:S1698-704.
Cardillo G, Rea F, Lucchi M, Paul MA, Margaritora S, Carleo F, et al.
Primary neuroendocrine tumors of the thymus: A multicenter experience of 35 patients. Ann Thorac Surg 2012;94:241-5.
[Table 1], [Table 2], [Table 3], [Table 4]