Primary neuroendocrine carcinomas of the mediastinum: review of current criteria for histopathologic diagnosis and classification

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Primary neuroendocrine neoplasms occurring in the mediastinum are rare. The spectrum of such tumors can range from low- to high-grade neoplasms. The histogenesis of these tumors is varied, and some of them may originate from ectopic tissues in the mediastinum whereas others represent tumors native to the thymus. Primary thymic neuroendocrine carcinomas therefore need to be separated from other neuroendocrine neoplasms of the mediastinum, namely ectopic parathyroid tumors and paragangliomas. The histopathologic classification of primary neuroendocrine carcinomas of the mediastinum is still under debate and continues to be controversial, as is attested to by the different publications on the topic. Some authors continue to use old terms such as “carcinoid” and “atypical carcinoid” to designate these lesions, whereas others favor the use of a more unifying nomenclature that acknowledges the malignant nature of these lesions, namely that of neuroendocrine carcinoma. However, one aspect that all agree on is that, when they occur in the thymic region, these tumors should be considered as aggressive neoplasms capable of local recurrence and distant metastasis. This review will center on the morphologic spectrum of neuroendocrine carcinomas of the thymus, with special emphasis on diagnostic features and criteria for classification.

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Clinical features

Thymic neuroendocrine carcinomas are a group of tumors more commonly associated with the MEN type I endocrinopathy,3 which in the view of some authors may influence the prognosis of these tumors.1 In this regard, it is possible that previous cases of thymoma associated with endocrinopathies, such as Cushing’s syndrome, may in fact have represented thymic neuroendocrine carcinomas.18, 20, 29, 61, 62, 63 Other conditions that can be associated with thymic neuroendocrine carcinomas include

Gross features

The tumors may be well circumscribed and limited to the anterior mediastinum or can infiltrate the pleura, pericardium, and lung. On cut surface they show a tan color with a homogeneous surface. Some tumors can show areas of hemorrhage and/or necrosis.

Histopathologic features

Thymic neuroendocrine carcinomas recapitulate the features of comparable tumors arising at other anatomic sites, such as the lung or the gastrointestinal tract. The spectrum of morphologic appearances and growth patterns that these tumors can adopt has been expanded in several publications in recent years.66, 67, 68, 69, 70

These tumors are characterized on scanning magnification by a prominent nesting pattern and homogenous growth. The tumor cells form nests that are separated by thin

Immunohistochemistry and ultrastructure

In the largest study of primary thymic neuroendocrine carcinomas,59 all cases showed strong positivity for CAM5.2 low-molecular weight cytokeratin, whereas broad-spectrum keratin was positive in only 88% of the cases studied. Of the neuroendocrine markers tested, chromogranin was positive in 75% of cases, synaptophysin in 73%, and Leu-7 in 68%. In only 60% of the cases studied, did the tumors show both chromogranin and synaptophysin positivity, underlying the importance of ordering both stains

Classification

Although histologically speaking, thymic neuroendocrine carcinomas are similar to those seen in other areas such as lung and gastrointestinal tract, proper classification is of importance in the thymus because the prognosis for these tumors in this area is different than for those in the lung or gastrointestinal tract. For this reason, we proposed a modified approach to the nomenclature of these tumors in the thymus.59 Our proposed nomenclature was based on the premise, also supported by

Prognosis

Based on our experience, the prognosis for thymic neuroendocrine carcinomas is directly linked to their degree of differentiation.59 The tumors showing better differentiated features have a survival rate of about 50% at 5 years; those showing moderately differentiated features have a 25% 5-year survival rate; and those with poorly differentiated features have 0% survival at 5 years. Therefore, we believe that every attempt should be made to properly classify these tumors according to their

Differential diagnosis

The most important consideration in the differential diagnosis of primary neuroendocrine carcinomas of the thymus is a metastatic neuroendocrine carcinoma from another source such as the lung. Other conditions that may also enter into the differential diagnosis are mediastinal paragangliomas and ectopic parathyroid tumors. In cases of metastatic tumors from the lung, a good clinical history coupled with precise interpretation of thoracic imaging studies will play an important role in properly

Summary

Primary neuroendocrine carcinomas of the thymus are rare tumors that can show a wide range of morphologic features with varying degrees of differentiation. These tumors generally follow a much more aggressive behavior when arising in mediastinal location than in other foregut sites. In fact, even the morphologically well-differentiated variants of these tumors behave more aggressively than comparable tumors in the lung.59 Because of marked differences in biologic behavior, it is of importance

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