Neuroendocrine Neoplasia Current Concepts

AJCP / EDITORIAL

Neuroendocrine Neoplasia Current Concepts Mark R. Wick, MD

Feyrter, a German pathologist, developed the concept of the “diffuse neuroendocrine system” more than 60 years ago, in a thoughtful attempt to unify tumors in diverse topographic sites that had potential secretory activity and similar histologic attributes.1 Since then, his model has been refined and renamed by others, and a variety of diagnostic terms for “neuroendocrine” lesions has come into the clinical sphere. In fact, there is, perhaps, no other single facet of neuroendocrine neoplasia that is as confusing as the nomenclature that has been attached to it. This commentary shall attempt to provide a simplified and modern approach to such terminology, with direct clinical ramifications. In addition, it summarizes selected etiologic factors and current pathologic diagnosis of neuroendocrine tumors.

The Taxonomy of Neuroendocrine Neoplasms Historically—and, to a significant extent, currently as well—the classification of neuroendocrine tumors has encompassed a long list of designations. These include such names as apudoma (referring to tumors capable of amine precursor uptake and decarboxylation)2; Kulchitsky-cell carcinoma; argentaffinoma; pituitary adenoma and carcinoma; medullary thyroid carcinoma; carcinoid tumor (typical and atypical); oat cell (small cell undifferentiated) carcinoma; islet cell (endocrine) tumors of the pancreas; pheochromocytoma, chemodectoma, glomus jugulare tumor, and paraganglioma; neuroblastoma (and congeners such as ganglioneuroblastoma); retinoblastoma; medulloblastoma; pineoblastoma; peripheral neuroepithelioma of soft tissue (peripheral neuroblastoma); and Merkel cell (trabecular) carcinoma of the skin3-6 ❚Table 1❚. © American Society of Clinical Pathologists

This bevy of terms is difficult to organize concisely or maintain in perspective for anyone not having constant contact with such lesions. By using traditional schemes of classification, biologically similar lesions in various organ systems often have been given entirely different names and have been subject to nonuniform grading systems. As a result, there is a distinct possibility that miscommunications may occur about the diagnosis and recommended management of various neuroendocrine tumors. Simplified terminology in this area of practice would be useful, and, in fact, a more straightforward classification system is emerging that removes the terminological idiosyncrasy from neuroendocrine lesions. The diagnostic scheme pertaining to neuroendocrine tumors can be summarized to reflect a basic division of these neoplasms into 2 major categories: epithelial (group 1), including such historic entities as carcinoid, atypical carcinoid, oat cell carcinoma, islet cell (pancreatic endocrine) tumor, medullary thyroid carcinoma, parathyroid neoplasms, and pituitary tumors; and neural (group 2).4 The second of these categories retains the “traditional” designations of paraganglioma, pheochromocytoma, and neuroblastoma but introduces the unifying name of primitive neuroectodermal tumor to describe embryonic tumors of the nervous system7 ❚Table 2❚. At the end of the 1990s, therefore, terminological recommendations for neuroendocrine proliferations differ from those that might have been used even 10 years ago and from those with which some practitioners may feel comfortable. The designation of neuroendocrine carcinoma now is used widely as a replacement for most older terms for group 1 tumors (with the exceptions of pituitary and parathyroid adenomas). Modifiers of well-differentiated (grade 1), moderately differentiated (grade 2), and poorly Am J Clin Pathol 2000;113:331-335

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classic carcinoid (grade 1 neuroendocrine carcinoma) with unusual microscopic features, and, in so doing, may undertreat the lesion clinically. In that context, the term grade 2 (moderately differentiated) neuroendocrine carcinoma is much more apropos for conveying the true biologic features of such a neoplasm.7 In addition, attention has been given for a number of years to separating small cell carcinomas from non–small cell carcinomas of the lung, because of putatively divergent treatment options for these lesions (which have, in fact, become less different over time10). Nevertheless, it now is recognized that there is a large cell–form and a small cell–form of grade 3 neuroendocrine carcinoma and that both are aggressive tumor types.11 Thus, the simple designation of grade 3 neuroendocrine carcinoma avoids the potential confusion surrounding the “baggage” attached to the terms small cell and large cell carcinoma of the lung.

❚Table 1❚ Traditional Terminology for Neuroendocrine Neoplasms Tumor Location

Designation

Pituitary Thyroid Lung Several sites Several sites Gut Pancreas Adrenal ANS Adrenal/ANS Nose Eye CNS CNS Soft tissue Skin

Pituitary adenoma/carcinoma Medullary carcinoma Bronchial carcinoid/bronchial adenoma “Atypical carcinoid”/apudoma Oat cell (small cell) carcinoma Carcinoid/argentaffinoma/apudoma Islet cell tumor/apudoma Pheochromocytoma Paraganglioma/chemodectoma Neuroblastoma Esthesio (olfactory)-neuroblastoma Retinoblastoma Medulloblastoma Pineoblastoma Peripheral neuroepithelioma Merkel cell (trabecular) carcinoma

ANS, autonomic nervous system; CNS, central nervous system.

differentiated (grade 3) are appended as appropriate.8 In the report on a biopsy or resection specimen, the pathologist can then work within this framework—as well as that pertaining to group 2 neoplasms—to provide the clinician with an outline of the expected behavior of each neoplasm based on its individual characteristics. In this issue of the Journal, Moran and Suster9 describe the use of such a scheme in specific reference to neuroendocrine carcinomas of the thymus. Furthermore, they show that mixtures of grades are not uncommon in those neoplasms (or, indeed, in epithelial neuroendocrine malignant neoplasms in general). In practical terms, updated terminology can be used to provide the oncologist with unifying information that is related directly to treatment protocols. For example, in reference to pulmonary tumors, the term atypical carcinoid 3 has been used by many authors to describe a wide variety of pathologic entities because of the imprecision of that designation. Furthermore, the uninitiated surgeon might interpret this term to mean that the patient actually has a

Distribution and Pathogenesis of Neuroendocrine Neoplasms If one refers to treatises on human embryogenesis, a common theme that is seen in all anatomic sites is that of a neuroendocrine or neuroectodermal stage of differentiation during early organ development.4,12 Because it currently is 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 sites are, by far, more commonly involved than others, for unknown reasons. For example, the lung is a very frequent organ of origin for neuroendocrine carcinogenesis; the process is clearly related etiologically to cigarette smoking and is associated with partial deletion of the short arm of chromosome 3 in the tumor cells. 13 However, identical sporadic primary neoplasms in other locations have, as yet, not been linked with any definitive

❚Table 2❚ Updated Terminology for Neuroendocrine Neoplasms Group I Tumors (Epithelial) Neuroendocrine carcinoma Grades 1, 2, and 3*

Group II Tumors (Neural) Classic neuroblastoma Olfactory neuroblastoma Pheochromocytoma and paraganglioma Primitive neuroectodermal tumors Medulloblastoma Retinoblastoma Pineoblastoma Peripheral neuroepithelioma

* Grade 1 neuroendocrine carcinoma is a synonym for classic carcinoid; grade 2 neuroendocrine carcinoma is a synonym for atypical carcinoid (but also applies to such lesions as medullary thyroid carcinomas, some malignant pancreatic endocrine tumors); and grade 3 neuroendocrine carcinoma includes small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma.

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AJCP / EDITORIAL

pathogenetic or karyotypic factors.14 In contrast, group 2 neoplasms in the peripheral primitive neuroectodermal category (formerly termed peripheral neuroepithelioma or peripheral neuroblastoma) demonstrate a uniformly balanced translocation between chromosomes 11 and 22, with synthesis of a glycoprotein (p30/32MIC2 or CD99) that is recognized by a well-characterized group of monoclonal antibodies.7,15 Still other neuroendocrine carcinomas and group 2 neuroendocrine tumors, especially neuroblastoma and retinoblastoma, occur in definite mendelian (typically autosomal dominant) patterns of inheritance, as seen in the multiple endocrine neoplasia syndromes (MEN). MEN I features the potential concurrence of pituitary, parathyroid, pancreatic, thymic, and intestinal group 1 tumors in the same person or the same kindred; similarly, patients with MEN II may have group 1 tumors of the thyroid and parathyroid and group 2 neoplasms of the adrenal (pheochromocytoma).4,5 Studies have shown the locations of at least some aberrant gene complexes in such disorders (eg, the MEN IIa locus on chromosome 10,16 and complete deletion of the Rb-1 “antioncogene” locus on chromosome 13 in heritable bilateral retinoblastoma13), but sporadic examples of the aforementioned tumors do not necessarily show the same abnormalities.

Pathologic Evaluation of Neuroendocrine Neoplasms The recognition of many well-differentiated neuroendocrine tumors is not difficult for pathologists.4-6 These lesions have a reproducibly organoid growth pattern— forming islands, uniform nests, “festoons,” and ribbons of tumor cells—and their cytologic features also are sufficiently distinctive to allow for a confident interpretation on the basis of routine tissue staining procedures and conventional light microscopy.4 If desired, histochemical techniques may be performed that decorate neurosecretory granules with silver salts (the so-called argentaffin and argyrophil reactions17); however, the results of those procedures are not specific to neuroendocrine tissues. In a more realistic scenario, one usually is dealing with a poorly differentiated malignant neoplasm that may be neuroendocrine in nature18 or with a challenging regional histologic differential diagnosis, such as that of adrenocortical adenoma vs pheochromocytoma.19 Those problems are not always solved easily with standard microscopy alone. In these circumstances, pathologists may use electron microscopy or immunohistochemistry in additional assessments, and both of these methods are effective for definitive diagnosis.20-24


Concepts of Mixed and Occult Neuroendocrine Differentiation To this point, this discussion has focused on pure neuroendocrine neoplasms that demonstrate differentiation into only 1 cell lineage. Increasingly during the last 20 years, it has been recognized by pathologists and oncologists alike that mixed malignant tumors—particularly carcinomas—are relatively common in many sites. These lesions may exhibit mixtures of adenocarcinoma with squamous cell carcinoma or transitional cell carcinoma, and any of the 3 tumor types just cited also may be admixed with neuroendocrine carcinoma at a routine light microscopic level. 25 For example, one may encounter carcinomas of the lung that show relatively equal proportions of adenocarcinoma or squamous cell carcinoma and grade 3 neuroendocrine carcinoma. The question of how these lesions must be treated is still under consideration, but it would seem that management of the tumor as a pure squamous cancer or a pure high-grade neuroendocrine carcinoma is probably inadvisable in this specific setting. Occult neuroendocrine differentiation is defined as that detectable only through the use of electron microscopy or immunohistology in a neoplasm that otherwise has the light microscopic appearance of an undifferentiated carcinoma and that lacks the conventional architectural and cytologic attributes of neuroendocrine tumors.26-30 Recommended diagnostic terminology for such lesions includes such designations as “poorly differentiated carcinoma with neuroendocrine features” or “poorly differentiated carcinoma with occult neuroendocrine differentiation.” It again should be emphasized that one would not suspect the presence of a neuroendocrine lineage in these tumors unless special studies were done. At this point, it is unclear whether occult neuroendocrine differentiation is important with regard to alterations in therapy. Indeed, that question may have different answers in the context of different organ systems. In other words, large cell lung cancer with occult neuroendocrine features may behave more aggressively than other comparable tumors27,29; the same statement, however, may not be valid for similar lesions of the colon.30 Some academic centers currently evaluate all poorly differentiated carcinomas for potential neuroendocrine differentiation; however, in my view, this approach should by no means be considered necessary until more definitive data are available on how the results might alter treatment, if at all.

Summary and Recommendations It can be stated safely that there is much to be gained in clarity of communication by using the terms grade 1 Am J Clin Pathol 2000;113:331-335

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neuroendocrine carcinoma, grade 2 neuroendocrine carcinoma, and grade 3 neuroendocrine carcinoma to replace historic designations for epithelial neuroendocrine malignant neoplasms. Nonepithelial tumors in this general class still are described by traditional nomenclature, but this too may change in the future. In helping clinical colleagues to make the transition that any new diagnostic paradigm introduces, the current and the “old” terminology may both be included in pathology reports, at least during a predefined period. Therapy for some “new” pathologic neuroendocrine entities (especially grade 3 large cell neuroendocrine carcinoma of the lung) will depend on the development of prospective treatment trials that are based on uniform pathologic identification. Thus, it is particularly important for pathologists to serve a hospital-wide educational role in the use of modern diagnoses, as well as to encourage clinical colleagues to develop new therapies for new tumors. It makes little sense, for example, to keep treating large cell neuroendocrine carcinoma of the lung as large cell undifferentiated carcinoma, simply because that approach is the familiar one. In addition, the concepts of mixed and occult neuroendocrine differentiation in malignant neoplasms should be well understood by pathologists and oncologists. In the mixed category, neuroendocrine components usually are obvious on conventional microscopic examination, whereas occult neuroendocrine differentiation requires adjunctive studies for its definition. The question of whether those measures are necessary must await the results of further studies, and those analyses should take specific anatomic locations and outcomes data into account before final recommendations are made. From the Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Medical Center, Charlottesville, VA.

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8. Warren WH, Faber LP, Gould VE. Neuroendocrine neoplasms of the lung: a clinicopathologic update. J Thorac Cardiovasc Surg. 1989;98:321-332. 9. Moran C, Suster S. Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma: a clinicopathologic and immunohistochemical study of 11 cases. Am J Clin Pathol. 2000;113:345-350. 10. Lassen U, Hansen HH. Surgery in limited stage small cell lung cancer. Cancer Treat Rev. 1999;25:67-72. 11. Jiang SX, Kameya T, Shoji M, et al. Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases. Am J Surg Pathol. 1998;22:526-537. 12. Gould VE, Linnoila RI, Memoli VA, et al. Neuroendocrine components of the bronchopulmonary tract. Lab Invest. 1983;49:519-537. 13. Yunis JJ. Genes and chromosomes in the pathogenesis and prognosis of human cancers. Adv Pathol Lab Med. 1989;2:147-188. 14. Johnson BE, Whang-Peng J, Naylor SL, et al. Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies. J Natl Cancer Inst. 1989;81:1223-1228. 15. Fletcher JA. Cytogenetic aberrations in malignant soft tissue tumors. Adv Pathol Lab Med. 1991;4:235-246. 16. Simpson NE, Kidd KK, Goodfellow PJ, et al. Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature. 1987;328:528-530. 17. Williams ED. The classification of carcinoid tumors. Lancet. 1963;1:238-239. 18. Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site: a newly recognized clinicopathologic entity. Ann Intern Med. 1988;109:364-371. 19. Lloyd RV, Shapiro B, Sisson JC, et al. An immunohistochemical study of pheochromocytomas. Arch Pathol Lab Med. 1984;108:541-544. 20. van de Velde RI. Ultrastructural methods for the classification of malignant tumors of the lung. In: Marchevsky AM, ed. Surgical Pathology of Lung Neoplasms. New York, NY: Marcel Dekker; 1990:569-594. 21. Said JW, Vimadalal S, Nash G, et al. Immunoreactive neuron-specific enolase, bombesin, and chromogranin A as markers for neuroendocrine lung tumors. Hum Pathol. 1985;16:236-240. 22. Hainsworth JD, Wright EP, Johnson DH, et al. Poorly differentiated carcinoma of unknown primary site: clinical usefulness of immunoperoxidase staining. J Clin Oncol. 1991;9:1931-1938. 23. Gould VE, Lee I, Wiedenmann B, et al. Synaptophysin: a novel marker for neurons, certain neuroendocrine cells, and their neoplasms. Hum Pathol. 1986;17:979-983. 24. Wick MR. Monoclonal antibodies to chromogranin: characterization and comparison with other neuroendocrine markers. In: Wick MR, Siegal GP, eds. Monoclonal Antibodies in Diagnostic Immunohistochemistry. New York, NY: Marcel Dekker; 1988:521-537. 25. Adelstein DJ, Tomashefski JF, Snow NJ, et al. Mixed smallcell and non–small-cell lung cancer. Chest. 1986;89: 699-704. 26. McDowell EM, Wilson TS, Trump BF. Atypical endocrine tumors of the lung. Arch Pathol Lab Med. 1981;105:20-28. © American Society of Clinical Pathologists

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27. Wick MR, Berg LC, Hertz MI. Large cell carcinoma of the lung with neuroendocrine differentiation. Am J Clin Pathol. 1992;97:796-805. 28. Skov BG, Sorenson JB, Hirsch FR, et al. Prognostic impact of histologic demonstration of chromogranin A and neuron specific enolase in pulmonary adenocarcinoma. Ann Oncol. 1991;2:355-360. 29. Piehl MR, Gould VE, Warren WH, et al. Immunohistochemical identification of exocrine and neuroendocrine subsets of large cell lung carcinomas. Pathol Res Pract. 1988;183:675-682. 30. Foley EF, Gaffey JM, Frierson HF Jr. The frequency and clinical significance of neuroendocrine cells within stage III adenocarcinomas of the colon. Arch Pathol Lab Med. 1998;122:912-914.


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