Thymic Carcinoma, Part 1: Immunohistochemical Study
Thymic Carcinoma, Part 1: Immunohistochemical Study
Thymic epithelial neoplasms comprise a rare group of tumors that encompass thymomas and thymic carcinomas. The latter are exceedingly rare, representing only about 15% to 20% of all thymic epithelial tumors. Their rarity reflects the lack of larger series studying these tumors, thus precluding implementation of uniform treatment strategies and the collection of more reliable prognostic data.
Thymic carcinomas can show diverse differentiation and are histologically undistinguishable from various types of carcinoma of other organ systems. Thymic carcinoma subtypes include squamous cell carcinoma, lymphoepithelioma-like carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, sarcomatoid carcinoma, clear cell carcinoma, papillary adenocarcinoma, nonpapillary adenocarcinoma, carcinoma with t(15;19) translocation, anaplastic carcinoma, and neuroendocrine carcinoma. Our study confirms the histologic spectrum of these tumors, reflected by the 9 different histologic types found in our tumors. Among these, squamous cell carcinoma was by far the most common subtype.
The clinical features and manifestations in our patients are similar to those reported in previous studies: a peak age at diagnosis in the sixth decade and main symptoms of chest pain, shortness of breath, and superior vena cava syndrome. None of our patients had any associated paraneoplastic syndrome; however, well-known associations with thymoma and MTC were confirmed in 10 and 7 cases, respectively.
Immunohistochemically, thymic carcinoma demonstrates an epithelial phenotype. In this respect, our results confirm the findings of previous studies by demonstrating diffuse immunoreactivity for CK, CK5/6, CK7, and p63. In addition, data from prior studies suggesting reactivity for c-Kit (73%–86%), FoxN1 (76%), and calretinin (36%) were supported by our series, showing expression for these markers in 65%, 68%, and 10% of cases, respectively.
It is important to note that CDX2 is often positive in mucinous adenocarcinomas of the thymus, and this was also true in our study. Furthermore, a lack of expression of TTF-1 and CD30 has been noted, and none of our tumors showed staining for these markers. Contrary to other studies that showed high rates of immunoreactivity for CD5 (30%–70%) and CD205 (59%), our results for these markers were less convincing (<10% each), casting some doubt on the diagnostic value of these antibodies in this context. Besides, CD5 is also expressed by a range of other neoplasms, including mesothelioma, adenocarcinoma, and atypical thymoma (WHO type B3), limiting its use in the differential diagnosis of mediastinal neoplasms. An interesting finding was the strong and diffuse expression of Pax8 in 77% of our thymic carcinomas, supporting similar, albeit preliminary, results on a smaller number of thymic epithelial neoplasms. Another intriguing observation was that Pax8 and FoxN1 staining overlapped in all but 3 tumors. FoxN1 was described as a relatively sensitive and specific marker for thymic carcinoma; taking into account the even higher rate of Pax8 expression of these tumors, their combination markers may prove to be a valuable diagnostic tool in the differential diagnosis of malignant anterior mediastinal neoplasms.
The expression of napsin, to the best of our knowledge, has not been described in thymic epithelial neoplasms and was absent in all of our tumors.
Some of the most compelling observations of our study pertain to the following aspects:
In the absence of a more refined staging system for thymic carcinoma, it is common for tumors to be staged using the Masaoka staging system, which was originally devised as a clinical staging system for thymomas. In our series, 53 cases were staged accordingly. By using this staging system, we could not find any statistically significant differences between the different stages. In contrast, a significant difference was identified only when the patients with Masaoka stages I, II, and III tumors were considered in a single group (86.4% and 73.1%, respectively) and compared with stage IV (65.9% and 52.5%, respectively) (P = .02207 and P = .03577, respectively). Our results are in keeping with several other studies that have suggested that the usefulness of the Masaoka staging system is limited to thymoma and does not seem to predict outcome in patients with thymic carcinoma. As a consequence, the introduction of a new staging system for thymic carcinoma seems warranted.
It seems that lymphogenous spread is not an uncommon occurrence in thymic carcinoma; in fact, lymph node involvement was seen in approximately 40% of our cases in which lymph nodes were sampled. In addition, we were able to demonstrate significant statistical correlation between lymph node status and survival, emphasizing the need for systematic lymph node dissection in these tumors. Based on our experience, lymph node sampling is not performed in all thymic carcinomas, nor is it performed in any systematic way when done, often yielding only small numbers of randomly sampled nodes. The high importance of lymph node sampling has also been highlighted by other authors in an attempt to develop more standardized operative procedures.
Our data suggest that larger tumors most likely correspond to advanced stage disease, as they are more likely to compromise adjacent structures.
This point should not be surprising given that the tumors included in our series were all high-grade lesions except for 1 well-differentiated squamous cell carcinoma. It is also important to note that most histologic subtypes encountered in our series were represented only in small numbers, precluding more meaningful assessment.
This factor did not seem to have a dramatic benefit on the survival of our patients. On that issue, there are conflicting views in the literature with regard to the efficacy of adjuvant treatment; while some reports advocate the use of postoperative cytotoxic or radiation therapy, others failed to prove the effectiveness of such a multimodal approach. This seems to indicate that a surgical approach is still the most crucial step in the treatment of patients with thymic carcinoma. In this context, although statistical significance could not be demonstrated, we observed a trend toward an apparent survival benefit in patients whose tumors were completely resected, confirming the results of several previous studies.
Follow-up information for our patients revealed a mean survival of 47.5 months and 3- and 5-year overall survival rates of 76.6% and 65.7%, respectively. Whereas previous reports have labeled thymic carcinomas as aggressive neoplasms with a mean survival of only 18 to 35.4 months and 5-year overall survival rates ranging from 14.5% to 50%, our data seem to indicate that thymic carcinomas may run a less aggressive course. Because our study findings do not seem to differ significantly from those of previous studies in terms of clinical patient characteristics (male predominance, peak age), tumor size, tumor stage distribution, or percentage of completely resected tumors, we consider that the potential factor for better survival in our series is the fact that neuroendocrine thymic neoplasms were not included in our study. These tumors are known to behave more aggressively when originating in the anterior mediastinum, and inclusion of these tumors in most of the other series may account in part for the less favorable clinical course observed in those studies.
Finally, in the evaluation of thymic carcinoma, it is important to consider and rule out other neoplasms. The differential diagnosis of thymic carcinoma primarily includes distinction from metastatic disease, direct invasion from neighboring organs, and primary nonepithelial thymic neoplasms. Owing to a lack of a specific immunohistochemical marker for thymic carcinoma and its morphologic variability, exclusion of metastatic disease to the thymus still heavily relies on clinical and radiologic investigations. The presence of an isolated anterior mediastinal mass with absence of tumor elsewhere would point toward primary thymic carcinoma. In addition, direct invasion from neighboring organs, like tumors of primary lung or thyroid origin, often have to be excluded by clinical or imaging criteria.
Thymic carcinomas with a large cell component or glandular differentiation may be mistaken for primary mediastinal germ cell tumors, eg, embryonal carcinoma or yolk sac tumor. These tumors generally occur in a younger age group with heavy male predominance and show a different immunohistochemical phenotype, being positive for CD30 and α-fetoprotein. Primary mediastinal lymphomas will also have to be considered in the differential diagnosis. These neoplasms demonstrate a discohesive growth pattern and lack immunoreactivity for CKs, which distinguish these lesions from thymic carcinoma. Last, primary sarcomas, like synovial sarcoma (primarily the monophasic type), may enter the differential diagnosis, especially when dealing with a tumor with spindle cell morphologic features. The spindle cells in thymic carcinoma, however, show a greater degree of cytologic atypia and a different immunohistochemical staining pattern displaying more diffuse reactivity for CK and lacking the expression of vimentin, bcl-2, and CD99 associated with synovial sarcoma.
We have described the clinicopathologic and immunohistochemical characteristics of 65 thymic carcinomas and confirmed previous data regarding histologic variability and clinical manifestations. The importance of tumor size, lymph node sampling, and complete surgical resection in these tumors is emphasized. Contrary to other reports that describe thymic carcinomas as highly aggressive tumors with low overall survival, our data seem to suggest better biologic behavior. In addition, we were able to demonstrate that the Masaoka staging system is insufficient to predict the clinical outcome of these neoplasms, making the introduction of a new staging system highly desirable.
Discussion
Thymic epithelial neoplasms comprise a rare group of tumors that encompass thymomas and thymic carcinomas. The latter are exceedingly rare, representing only about 15% to 20% of all thymic epithelial tumors. Their rarity reflects the lack of larger series studying these tumors, thus precluding implementation of uniform treatment strategies and the collection of more reliable prognostic data.
Thymic carcinomas can show diverse differentiation and are histologically undistinguishable from various types of carcinoma of other organ systems. Thymic carcinoma subtypes include squamous cell carcinoma, lymphoepithelioma-like carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, sarcomatoid carcinoma, clear cell carcinoma, papillary adenocarcinoma, nonpapillary adenocarcinoma, carcinoma with t(15;19) translocation, anaplastic carcinoma, and neuroendocrine carcinoma. Our study confirms the histologic spectrum of these tumors, reflected by the 9 different histologic types found in our tumors. Among these, squamous cell carcinoma was by far the most common subtype.
The clinical features and manifestations in our patients are similar to those reported in previous studies: a peak age at diagnosis in the sixth decade and main symptoms of chest pain, shortness of breath, and superior vena cava syndrome. None of our patients had any associated paraneoplastic syndrome; however, well-known associations with thymoma and MTC were confirmed in 10 and 7 cases, respectively.
Immunohistochemically, thymic carcinoma demonstrates an epithelial phenotype. In this respect, our results confirm the findings of previous studies by demonstrating diffuse immunoreactivity for CK, CK5/6, CK7, and p63. In addition, data from prior studies suggesting reactivity for c-Kit (73%–86%), FoxN1 (76%), and calretinin (36%) were supported by our series, showing expression for these markers in 65%, 68%, and 10% of cases, respectively.
It is important to note that CDX2 is often positive in mucinous adenocarcinomas of the thymus, and this was also true in our study. Furthermore, a lack of expression of TTF-1 and CD30 has been noted, and none of our tumors showed staining for these markers. Contrary to other studies that showed high rates of immunoreactivity for CD5 (30%–70%) and CD205 (59%), our results for these markers were less convincing (<10% each), casting some doubt on the diagnostic value of these antibodies in this context. Besides, CD5 is also expressed by a range of other neoplasms, including mesothelioma, adenocarcinoma, and atypical thymoma (WHO type B3), limiting its use in the differential diagnosis of mediastinal neoplasms. An interesting finding was the strong and diffuse expression of Pax8 in 77% of our thymic carcinomas, supporting similar, albeit preliminary, results on a smaller number of thymic epithelial neoplasms. Another intriguing observation was that Pax8 and FoxN1 staining overlapped in all but 3 tumors. FoxN1 was described as a relatively sensitive and specific marker for thymic carcinoma; taking into account the even higher rate of Pax8 expression of these tumors, their combination markers may prove to be a valuable diagnostic tool in the differential diagnosis of malignant anterior mediastinal neoplasms.
The expression of napsin, to the best of our knowledge, has not been described in thymic epithelial neoplasms and was absent in all of our tumors.
Some of the most compelling observations of our study pertain to the following aspects:
The limitation of the Masaoka staging system for thymic carcinomas
In the absence of a more refined staging system for thymic carcinoma, it is common for tumors to be staged using the Masaoka staging system, which was originally devised as a clinical staging system for thymomas. In our series, 53 cases were staged accordingly. By using this staging system, we could not find any statistically significant differences between the different stages. In contrast, a significant difference was identified only when the patients with Masaoka stages I, II, and III tumors were considered in a single group (86.4% and 73.1%, respectively) and compared with stage IV (65.9% and 52.5%, respectively) (P = .02207 and P = .03577, respectively). Our results are in keeping with several other studies that have suggested that the usefulness of the Masaoka staging system is limited to thymoma and does not seem to predict outcome in patients with thymic carcinoma. As a consequence, the introduction of a new staging system for thymic carcinoma seems warranted.
Lymph node status
It seems that lymphogenous spread is not an uncommon occurrence in thymic carcinoma; in fact, lymph node involvement was seen in approximately 40% of our cases in which lymph nodes were sampled. In addition, we were able to demonstrate significant statistical correlation between lymph node status and survival, emphasizing the need for systematic lymph node dissection in these tumors. Based on our experience, lymph node sampling is not performed in all thymic carcinomas, nor is it performed in any systematic way when done, often yielding only small numbers of randomly sampled nodes. The high importance of lymph node sampling has also been highlighted by other authors in an attempt to develop more standardized operative procedures.
Tumor size
Our data suggest that larger tumors most likely correspond to advanced stage disease, as they are more likely to compromise adjacent structures.
Limited importance of histologic subtype as a prognostic factor
This point should not be surprising given that the tumors included in our series were all high-grade lesions except for 1 well-differentiated squamous cell carcinoma. It is also important to note that most histologic subtypes encountered in our series were represented only in small numbers, precluding more meaningful assessment.
Limited impact of adjuvant therapy
This factor did not seem to have a dramatic benefit on the survival of our patients. On that issue, there are conflicting views in the literature with regard to the efficacy of adjuvant treatment; while some reports advocate the use of postoperative cytotoxic or radiation therapy, others failed to prove the effectiveness of such a multimodal approach. This seems to indicate that a surgical approach is still the most crucial step in the treatment of patients with thymic carcinoma. In this context, although statistical significance could not be demonstrated, we observed a trend toward an apparent survival benefit in patients whose tumors were completely resected, confirming the results of several previous studies.
Follow-up information for our patients revealed a mean survival of 47.5 months and 3- and 5-year overall survival rates of 76.6% and 65.7%, respectively. Whereas previous reports have labeled thymic carcinomas as aggressive neoplasms with a mean survival of only 18 to 35.4 months and 5-year overall survival rates ranging from 14.5% to 50%, our data seem to indicate that thymic carcinomas may run a less aggressive course. Because our study findings do not seem to differ significantly from those of previous studies in terms of clinical patient characteristics (male predominance, peak age), tumor size, tumor stage distribution, or percentage of completely resected tumors, we consider that the potential factor for better survival in our series is the fact that neuroendocrine thymic neoplasms were not included in our study. These tumors are known to behave more aggressively when originating in the anterior mediastinum, and inclusion of these tumors in most of the other series may account in part for the less favorable clinical course observed in those studies.
Finally, in the evaluation of thymic carcinoma, it is important to consider and rule out other neoplasms. The differential diagnosis of thymic carcinoma primarily includes distinction from metastatic disease, direct invasion from neighboring organs, and primary nonepithelial thymic neoplasms. Owing to a lack of a specific immunohistochemical marker for thymic carcinoma and its morphologic variability, exclusion of metastatic disease to the thymus still heavily relies on clinical and radiologic investigations. The presence of an isolated anterior mediastinal mass with absence of tumor elsewhere would point toward primary thymic carcinoma. In addition, direct invasion from neighboring organs, like tumors of primary lung or thyroid origin, often have to be excluded by clinical or imaging criteria.
Thymic carcinomas with a large cell component or glandular differentiation may be mistaken for primary mediastinal germ cell tumors, eg, embryonal carcinoma or yolk sac tumor. These tumors generally occur in a younger age group with heavy male predominance and show a different immunohistochemical phenotype, being positive for CD30 and α-fetoprotein. Primary mediastinal lymphomas will also have to be considered in the differential diagnosis. These neoplasms demonstrate a discohesive growth pattern and lack immunoreactivity for CKs, which distinguish these lesions from thymic carcinoma. Last, primary sarcomas, like synovial sarcoma (primarily the monophasic type), may enter the differential diagnosis, especially when dealing with a tumor with spindle cell morphologic features. The spindle cells in thymic carcinoma, however, show a greater degree of cytologic atypia and a different immunohistochemical staining pattern displaying more diffuse reactivity for CK and lacking the expression of vimentin, bcl-2, and CD99 associated with synovial sarcoma.
We have described the clinicopathologic and immunohistochemical characteristics of 65 thymic carcinomas and confirmed previous data regarding histologic variability and clinical manifestations. The importance of tumor size, lymph node sampling, and complete surgical resection in these tumors is emphasized. Contrary to other reports that describe thymic carcinomas as highly aggressive tumors with low overall survival, our data seem to suggest better biologic behavior. In addition, we were able to demonstrate that the Masaoka staging system is insufficient to predict the clinical outcome of these neoplasms, making the introduction of a new staging system highly desirable.
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