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Ann Thorac Surg 1999;67:7-9
© 1999 The Society of Thoracic Surgeons
a Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri, USA
Address reprint requests to Dr Wick, Division of Surgical Pathology, Washington University Medical Center, Suite 300, Peters Building, One Barnes Hospital Plaza, St. Louis, Missouri 63110
e-mail: wick{at}path.wustl.edu
The concept of a diffuse neuroendocrine system is not new. Feyrter developed this concept in 1938 in a philosophical attempt to unify tumors in several anatomic locations that had potential secretory functions and similar morphologic characteristics. Pearse refined and renamed the cellular network in question 35 years later, coining the acronym APUD system (for amine precursor uptake and decarboxylation) to describe its shared biochemical attributes. Inherent in the latter scheme was the presumption that all APUD cells and tumors deriving from them (ie, APUDomas) emanated from the remnants of the neural crest. In light of these and other observations, continuing nosologic revisionism over the past 10 years has pushed many pathologists away from such traditional diagnostic terms as carcinoid and islet cell tumor in describing certain potentially malignant but low-grade neoplasms of the neuroendocrine system [1], although traditionalists do remain. Similarly, the classification of poorly differentiated lesions has changed as well.
A paper by Fukai and associates [2] on thymic neuroendocrine tumors in this issue of Annals of Thoracic Surgery serves as a focus for an update on this challenging area of surgery and pathology.
Terminology pertaining to neuroendocrine neoplasms
There is, perhaps, no other single aspect of neuroendocrine neoplasia that is as perplexing as its nosology. The terms bronchial adenoma, carcinoid, atypical carcinoid, Kulchitsky cell carcinoma, argentaffinoma, APUDoma, atypical endocrine carcinoma, oat cell carcinoma, medullary thyroid carcinoma, islet cell tumor, and cutaneous Merkel cell carcinoma have all been used historically in this context, in addition to the terms neuroblastoma, esthesioneuroblastoma, olfactory neuroblastoma, medulloblastoma, pineoblastoma, retinoblastoma, paraganglioma, pheochromocytoma, chemodectoma, and glomus jugulare tumor.
When all is said and done, this diverse lexicon reflects a basic division of neuroendocrine tumors into two broad categories—epithelial (neuroendocrine carcinomas; group 1) and neural (noncarcinomatous tumors; group 2). With that information, one can then structure a much more user-friendly and straightforward classification scheme, which, in fact, has made significant inroads in the pathology literature.
Another crucial concept in understanding the categorization and clinical behavior of neuroendocrine neoplasms is that virtually all of them are at least potentially malignant tumors, regardless of where they originate or whether they belong to group 1 or group 2. There are two notable exceptions: Pituitary adenomas and parathyroid adenomas are, of course, completely benign in most cases, and it would be a mistake to label them as grade 1 neuroendocrine carcinomas. With that said, however, it must be acknowledged that aggressive pituitary adenomas do exist, and rare carcinomas also can be encountered in each location. In selected subgroups (eg, classic carcinoid tumor, extraadrenal paraganglioma, and pheochromocytoma [intraadrenal paraganglioma]), one cannot use macroscopic or microscopic characteristics of the tumors reliably to predict whether they will behave innocuously or aggressively. Therefore, it follows logically that the modifier benign should never be applied in conjunction with any of the above-cited diagnostic terms. For example, even with regard to appendiceal or classic bronchial carcinoids—generally regarded as defining the low end of the spectrum of biological behavior in this context—there are many well-documented examples of metastasizing lesions that can be found in the literature on these tumors.
Current terminologic recommendations are, therefore, different from those that might have pertained even 10 years ago, or from those with which some practitioners might feel comfortable. The designation neuroendocrine carcinoma has been proposed as a replacement for all of the various above-cited group 1 terms, with modifiers of well differentiated (grade I/III; largely synonymous with classical carcinoid); moderately differentiated (grade II/III; sharing some homology with atypical carcinoid but not limited to those tumors); and poorly differentiated (grade III/III; including small-cell and high-grade large-cell neuroendocrine carcinomas) being appended as appropriate [3]. In contrast, most of the traditional rubric has been retained in reference to group 2 tumors, such that the terms extraadrenal paraganglioma; intraadrenal paraganglioma (pheochromocytoma); sympatheticoadrenal neuroblastoma (and congeners [eg, ganglioneuroblastoma]); olfactory neuroblastoma; retinoblastoma; and primitive neuroectodermal tumor are now recommended for the categorization of this constellation of lesions. In biopsy or resection specimen reports, the pathologist can then work within this framework, using further descriptive comments and summaries of the aggregate literature on each tumor, to provide the clinician with an outline of expected behavior for each neoplasm on the basis of its individual nuances. One might ask why it is necessary to depart from the old terminology in reference to group 1 neuroendocrine tumors. The answer lies in three truisms. The first is that recipients of pathologic reports using such terms as carcinoid might not note the modifier atypical and assume that the tumor will be indolent in behavior. The second truism concerns the tendency for some pathologists to use middle ground categories such as atypical carcinoid rather indiscriminately for all histologically unusual neoplasms that might be neuroendocrine. The third truism is that it has recently been recognized that not all high-grade neuroendocrine carcinomas are small-cell in nature, and the category of poorly differentiated large-cell neuroendocrine carcinoma is now well established. All of the subtypes of neuroendocrine carcinoma are represented in the microcosm of the thymus (and most other parenchymal organs), as described by Fukai and coworkers [2] and others.
Distribution and pathogenesis of neuroendocrine neoplasia
If one refers to basic textbooks on human embryogenesis, a common theme in all anatomic sites is that of a neuroendocrine or neuroectodermal stage of differentiation during early organ development. Because it is currently thought that oncogenesis partially (and aberrantly) recapitulates normal embryologic development, this information is central to our understanding of why neuroendocrine and neuroectodermal neoplasms have been reported in virtually every topographic location. It is true that some of the latter are, by far, more commonly hosts to such tumors, for unknown reasons. For example, the lung is the most common site of neuroendocrine carcinogenesis, where the process is clearly related etiologically to cigarette smoking and is associated with partial deletion of the short arm of chromosome 3. However, identical sporadic primary neoplasms in other organs have not yet been linked with any definitive pathogenetic factors. Group 2 neoplasms in the peripheral primitive neuroectodermal category similarly demonstrate a uniform balanced translocation between chromosomes 11 and 22, with synthesis of a unique gene product (p30/32 glycoprotein) that is recognized by a particular set of monoclonal antibodies (ie, HBA-71 and O13).
Other neuroendocrine carcinomas and group 2 tumors (especially neuroblastoma and retinoblastoma) occur in definite Mendelian-heritable (typically autosomal dominant) patterns, as seen in multiple endocrine neoplasia type 1 (pancreatic and thymic group 1 tumors) and MEN2 (medullary thyroid carcinoma and also group 2 tumors [pheochromocytomas]). Ongoing work has elucidated the locations of at least some operative aberrant gene complexes in such disorders (eg, the MEN2A locus on chromosome 10 and deletion of the Rb-1 anti-oncogene on chromosome 13 in heritable bilateral retinoblastoma), but sporadic examples of the tumors cited above do not necessarily exhibit the same karyotypic or gene-sequence abnormalities. Clearly, more work is needed to provide a complete picture of the molecular disturbances, and this is an exciting area for current and future development because it could yield clinical tests for early diagnosis and treatment.
Other pathologic aspects of neuroendocrine neoplasia
Up to this point, this discussion has focused on pure neuroendocrine and neuroectodermal neoplasms. Increasingly in recent years, however, it has been recognized that human malignancies more often show mixed or divergent differentiation than was previously known. Accordingly, surgical and medical oncologists are now faced with such diagnoses as adenocarcinoma/squamous cell carcinoma/transitional cell carcinoma with occult neuroendocrine features or mixed adenocarcinoma-small cell neuroendocrine carcinoma [4]. In the former scenario, the pathologist is attempting to convey that the tumor looks like conventional squamous cell carcinoma, adenocarcinoma, or transitional cell carcinoma with a routine hematoxylin and eosin stain, but that additional studies (eg, ultrastructural or immunohistochemical) demonstrated the presence of submicroscopic neuroendocrine differentiation in the neoplastic cells. In some organ systems, such as the lung, it is presently thought that such a constellation of findings portends a more aggressive course in certain tumor types (eg, large-cell anaplastic pulmonary carcinoma with occult neuroendocrine features) [5], but generic extrapolation of this model to other tissues would not be scientifically justified at this time and, in fact, appears to be definitely invalid in some specific settings. In the situation where one sees a truly mixed carcinoma at a light microscopic level, pathologists are describing the juxtaposition and admixture of two distinct histologic patterns such as adenocarcinoma and small-cell neuroendocrine carcinoma. Again using tumors of the lung as examples, it would be expected that the responses to therapy and behavior of such mixed lesions would also be a hybrid of those attending each component (ie, adenocarcinoma or small cell carcinoma) in pure form. Nonetheless, uniform validation of that premise and delineation of optimal therapeutic approaches for each of these amalgam tumors have yet to occur.
Specific comments on thymic neuroendocrine neoplasms
As implied in the foregoing discussion, neuroendocrine tumors of the anterior mediastinum, as depicted by Fukai and coworkers [2], recapitulate the histologic appearances of such tumors in other organ sites. Pure neuroendocrine carcinomas (NECs) of grades I through III (with the last subgroup including both high-grade small-cell and large-cell NECs), thymic carcinomas with occult neuroendocrine differentiation, mixed neuroendocrine and nonneuroendocrine carcinomas, and type II neuroendocrine tumors are all represented therein. As Fukai and coworkers [2] have observed, one tends to see predominantly grade II and grade III tumors in specific reference to primary mediastinal NECs. That fact, along with the anatomically forgiving capacity of the mediastinum to accommodate large masses (with invasion of blood vessels and other adjacent structures) before symptoms appear, probably best explains the biologic aggressiveness in thymic NEC cases. However, there are still unknowns regarding the behavior of such lesions. For example, it is not known why patients with MEN1 and thymic NEC do worse than those lacking that syndrome.
In any event, the data presented by Fukai and coworkers [2] underscore the need to regard thymic NECs as distinctive, prognostically adverse tumors that are completely separate from thymomas. Second, it would appear that much therapeutic innovation will be required to change the rather grim outlook for most patients with primary neuroendocrine carcinoma of the anterior mediastinum.
References
This article has been cited by other articles:
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  A. Jaretzki III, R. J. Barohn, R. M. Ernstoff, H. J. Kaminski, J. C. Keesey, A. S. Penn, and D. B. Sanders Myasthenia gravis: Recommendations for clinical research standards Neurology, July 12, 2000; 55(1): 16 - 23. [Full Text] [PDF]
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 A. Jaretzki III, R. J. Barohn, R. M. Ernstoff, H. J. Kaminski, J. C. Keesey, A. S. Penn, and D. B. Sanders Myasthenia gravis: recommendations for clinical research standards Ann. Thorac. Surg., July 1, 2000; 70(1): 327 - 334. [Full Text] [PDF]
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