We performed a clinicopathologic examination of primary thymic neuroendocrine tumors. Thymic epithelial tumors, predominantly or exclusively composed of neuroendocrine cells, are classified as NECs of the thymus. Thymic NECs are rare, constituting 2-5% of thymic epithelial tumors.6
There is a sufficient amount of statistical data for pulmonary NECs. But there is a paucity of data about the clinicopathologic correlations among the thymic NECs. Considering this, the first edition of the WHO classification of tumors of the thymus suggests that pathologists classify thymic neuroendocrine tumors based on the same criteria as NECs of the lung.6
It is known that a vast majority of carcinoids in the thymus would correspond to ACs if the same criteria are applied as the lung.6
In addition, several studies have reported that a substantial number of cases of AC are associated with ectopic hormone secretion.5
In the current study, our clinical series of patients (n=21) comprised 18 cases of AC and 3 cases of LCNEC. In addition, three cases of AC had endocrine manifestations. Furthermore, these three cases of AC were accompanied by Cushing's syndrome. It is well known that AC shows a better clinical behavior than LCNEC. However there were two patients with AC, associated with ectopic hormone secretion, both of whom died of tumor progression and metastasis although they had a small-sized tumor and low mitotic counts. Furthermore, there was another patient with ectopic hormone secretion who developed a pulmonary metastasis. In conclusion, our results indicate that ACs associated with ectopic hormone secretion show a poorer prognosis as compared with conventional ones. In our series, there were no cases of TC. This implies that TC is a very rare entity unlike the pulmonary NECs. Over the past few decades, a three-tiered pathologic classification has been used and NECS are classified into low grade, intermediate-grade, and high-grade ones.13
Based on this classification system, some previously diagnosed cases of low- or intermediate-grade NECs actually correspond to AC. Those who were diagnosed with low or intermediate grade neuroendocrine carcinoma underwent post-operative CCRT while only post-operative RT was added to AC patients according to the current treatment trend.
With regard to the clinical behavior of NECs, our results are in agreement with the previous reports that thymic neuroendocrine tumors show a poor prognosis. During the follow-up period, 100% (3/3) of patients with LCNEC and 16.7% (3/18) of those with AC died of tumor progression. However no statistical analysis has been attempted to determine whether the classification of tumors is not dependent on a prognosis of patients because of a limited number of cases enrolled in the current study.
Thymic neuroendocrine tumors are histologically classified according to tumor differentiation, presence or absence of necrosis and mitotic counts.6
ACs are therefore classified as a carcinoid tumor having architectural features of the classic type but exhibiting 2-10 mitoses per 10 HPF and/or foci of necrosis. AC is actually classified as a group of well-differentiated NEC. In our series, Cases 12, 15, and 16 were classified as an AC despite a high mitotic index of >10 mitoses per 10 HPF. In these cases, high mitotic counts may pose a diagnostic challenge to pathologists. However, tumor differentiation is one of the most important factors by which pathologists can make a differential diagnosis of carcinoid tumor from SCNEC and LCNEC. According to the WHO criteria, both TC and AC are classified a well-differentiated tumor and both SCNEC and LCNEC are classified a poorly differentiated tumor. Cases 12, 15, and 16 showed the similar characteristics of carcinoid tumor and they had a lack of the typical histologic characteristics of LCNEC such as extensive necrosis or poorly-differentiated pattern. Not including high mitotic counts, the histologic findings did not seem to correlate with a poorly-differentiated carcinoma which usually reveals aggressive clinical behavior. In addition, some tumors exhibited large tumor size and mitotic counts varied depending on the part of the tumor. We thought that high mitotic counts could be seen as the tumor grew. Therefore we classified such tumors as an AC rather than a LCNEC. Considering all LCNEC patients died of the tumor, the fact those patients were alive without evidence of relapse might support out diagnosis. Our results indicate that mitotic counts do not fully reflect morphology of the tumor. It can also be presumed that the current WHO classification needs a more detailed explanation because it might pose a diagnostic challenge to pathologists. Further studies are therefore warranted to examine the tumor classification.
The clinical behavior of AC varies in several studies. It has been reported that even "innocent" looking and encapsulated carcinoids bear a significant risk for recurrence, metastasis and tumor-associated death.6
On the other hand, one of the recent studies has shown a better prognosis of atypical thymic carcinoids as compared to pulmonary carcinoids.6
In our series, 16.7% (3/18) of patients with AC patients died of tumor progression, two of whom had a concurrent presence of ectopic hormone secretion. This implies that hormone-expressing tumors show an unfavorable prognosis.
Further, regarding the view that thymic neuroendcrine tumors are clinically more aggressive than morphologically identical neuroendocrine tumors of the lung, we also observed that primary thymic LCNECs tended to exhibit less neuroendocrine differentiation, such as trabeculae, nesting, rossettes and perilobular palisading patterns, which is commonly seen in pulmonary LCNECs. This may suggest that thymic LCNECs are higher-grade tumors than pulmonary LCNECs.
In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that TC is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.