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Mpa21109 707.712The Pathologic Classification of Neuroendocrine Tumors A Review of Nomenclature, Grading, and Staging Systems David S. Klimstra, MD,* Irvin R. Modlin, MD, PhD,Þ Domenico Coppola, MD,þ Ricardo V. Lloyd, MD, PhD,§ and Saul Suster, MD|| another system. It would be of great beneﬁt for the prediction of Abstract: Neuroendocrine tumors (NETs) arise in most organs of the outcome and the determination of therapy if a single system of body and share many common pathologic features. However, a variety of nomenclature, grading, and staging could be developed for different organ-speciﬁc systems have been developed for nomenclature, NETs of all anatomic sites, and there are many similarities grading, and staging of NETs, causing much confusion. This review among NETs throughout the body. However, a number of the examines issues in the pathologic assessment of NETs that are common systems that have arisen independently are now ﬁrmly estab- among primaries of different sites. The various systems of nomenclature lished and recognized by organizations charged with standard- are compared along with new proposal for grading and staging NETs.
izing terminology, such as the World Health Organization Although differences persist, there are many common themes, such as (WHO). Also, compelling clinical data favoring one system over the distinction of well-differentiated (low and intermediate-grade) from another do not exist. Thus, abandoning some of the current poorly differentiated (high-grade) NETs and the signiﬁcance of prolif- systems in favor of a single, uniform proposal has proven im- erative rate in prognostic assessment. A recently published minimum practical. On the other hand, careful examination of the existing pathology data set is presented to help standardize the information in proposals reveals many common features that underlie the pathology reports. Although an ultimate goal of standardizing the classiﬁcation and form the basis for grading and staging.17 pathologic classiﬁcation of all NETs, irrespective of primary site, Features such as the proliferative rate of the tumor and the extent remains elusive, an understanding of the common themes among the of local spread (assessed based on similar parameters used for different current systems will permit easier translation of information non-neuroendocrine carcinomas of the same anatomic sites) are relevant to prognosis and treatment.
shared by most systems. Therefore, it is recommended that these Key Words: neuroendocrine tumor, NET, pathology, classiﬁcation, basic data elements used to stratify NETs be speciﬁed and documented in pathology reports, in addition to the use of aspeciﬁed system of nomenclature, grading, and staging. By doing this, we assure that the fundamental data necessary forprognostic assessment and therapy determination are recorded,allowing retrospective comparison of the characteristics ofNETs irrespective of the speciﬁc classiﬁcation system that may Neuroendocrine neoplasms, deﬁned as epithelial neoplasms currently be in vogue. Recently, a multidisciplinary consensus with predominant neuroendocrine differentiation, arise in group of experts in the ﬁeld of NETs has recommended such most organs of the body.21,22 Some of the clinical and pathologic an approach and has developed a minimum pathology data set features of these tumors are characteristic of the organ of origin, (Table 1) of features to be included in pathology reports.17 The but other attributes are shared by neuroendocrine neoplasms College of American Pathologists (CAP) has also developed irrespective of their anatomic site. In general, studies of neuro- similar tumor checklists for NETs that specify many of the same endocrine neoplasms have concentrated on tumors of a speciﬁc organ system such as the lung, the pancreas, or the gastrointes-tinal tract. For this reason, various proposals have appeared re- garding the classiﬁcation and nomenclature of neuroendocrine One semantic issue relates to the use of the term endocrine tumors (NETs), and many of these differ somewhat in the use of versus neuroendocrine. Originally, the concept of neuroendo- speciﬁc terminology and criteria for grading and staging.1 Most crine neoplasia reﬂected the hypothesis that the cells from which proposed systems have indeed proven useful to stratify prog- these tumors were derived originated from the embryonic neural nostic subgroups of NETs. However, the differences in criteria crest. This concept was disproved years ago, causing some have resulted in much confusion, especially because morpho- authorities to advocate abandoning the term neuroendocrine in logically similar tumors may be designated differently depend- favor of endocrine, to reﬂect that most of these epithelial neo- ing on the site of origin, and some of the terminology used in one plasms recapitulated cells of endodermal origin. However, the system suggests markedly different tumor biology based on neoplastic cells also possess features of neural and epithelialcells, and for this reason, the most recent edition of the WHOclassiﬁcation of tumors of the digestive system has once again From the *Department of Pathology, Memorial Sloan-Kettering Cancer recommended the use of neuroendocrine.3 Although there may Center, New York, NY; †Department of Surgery, Yale University School of be arguments favoring either term, it must be recognized that Medicine, New Haven, CT; ‡Anatomic Pathology Department, Moffitt they are essentially synonymous, and both are widely under- Cancer Center, Tampa, FL; §Department of Pathology and Laboratory stood. For the sake of uniformity, neuroendocrine will be used Medicine, University of Wisconsin School of Medicine and Public Health,Madison, WI; and ||Department of Pathology, Medical College of Wisconsin, throughout this manuscript. Another debated terminological issue relates to the use of tumor instead of neoplasm. Certainly, Reprints: David S. Klimstra, MD, Department of Pathology, Memorial all of the entities under discussion are neoplastic, and neoplasm Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 is therefore a more accurate term than tumor, which means only Copyright * 2010 by Lippincott Williams & Wilkins a mass. However, neuroendocrine tumor (NET) has achieved Pancreas & Volume 39, Number 6, August 2010 Copyright 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas & Volume 39, Number 6, August 2010 TABLE 1. Minimum Pathology Data Set: Information to be Included in Pathology Reports on NETs (from Klimstra et al2010)17 Presence of other pathological components (eg, non-neuroendocrine Diagnosis (functional status need not be included in the pathology report) Diagnosis (functional status need not be included in the pathology report) Presence of unusual histologic features (oncocytic, clear cell, Extent of involvement of resected tissue (percentage) Presence of unusual histologic features (oncocytic, clear cell, [OPTIONAL: immunohistochemical staining for general neuroendocrine [OPTIONAL: immunohistochemical staining for general neuroendocrine Peptide hormones, IF a specific clinical situation suggests that the correlation with a functional syndrome may be helpful Peptide hormones, IF a specific clinical situation suggests the correlation Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2; count 50 high-power fields in the most mitotically active regions, Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2; count 50 high-power fields in the most mitotically active regions and [OPTIONAL: Ki67 labeling index (count multiple regions with highest provide separate mitotic rate for each major separate site of disease) labeling density, report mean percentage; eyeballed estimate is [OPTIONAL: Ki67 labeling index (count multiple regions with highest labeling density, report mean percentage; eyeballed estimate is Presence of other pathological components (eg, non-neuroendocrine Presence of other pathological components Extent of invasion (use anatomic landmarks for the AJCC T staging of Resection margins (positive/negative/close) [OPTIONAL measure analogous carcinomas of the same anatomic sites) Stomach: depth of invasion into/through gastric wall Small bowel: depth of invasion into/through bowel wall Large bowel: depth of invasion into/through bowel wall Appendix: depth of invasion into/through appendiceal wall; presence Diagnosis (functional status need not be included in the pathology report) Pancreas: presence of extrapancreatic invasion or invasion of bile duct, Presence of unusual histologic features (oncocytic, clear cell, All sites: involvement of serosal/peritoneal surfaces; invasion of Immunohistochemical staining for general neuroendocrine markers Presence of vascular invasion [OPTIONAL: perform immunohistochemical stains for endothelial markers if needed] [OPTIONAL: peptide hormones, IF a specific clinical situation suggests the correlation with a functional syndrome may be useful] Grade for adequate biopsy specimens; fine needle aspiration specimens may not be adequate (specify grading system used) Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2; TNM staging (specify staging system used) Resection margins (positive/negative/close) [OPTIONAL: measure Ki67 labeling index (count multiple regions with highest labeling density, report mean percentage; eyeballed estimate is adequate) Proliferative changes or other abnormalities in non-neoplastic Presence of other pathological components (eg, non-neuroendocrine Diagnosis (functional status need not be included in the pathology report) Presence of unusual histologic features (oncocytic, clear cell, gland [OPTIONAL: immunohistochemical staining for general neuroendocrine widespread acceptance in many systems and will be used here in lieu of the more correct but less accepted alternative, neuroen- The terminology for NETs varies by anatomic site. The use Peptide hormones, IF a specific clinical situation suggests that the of the term carcinoid tumor has been repeatedly criticized8,32 correlation with a functional syndrome may be helpful because of concerns that the term does not adequately convey the potential for malignant behavior that accompanies many of Mitotic rate (number of mitoses per 10 high-power fields or 2 mm2; these neoplasms. However, carcinoid tumor remains in use, both in the ofﬁcial WHO classiﬁcation of NETs of the lung34 and Ki67 labeling index, for biopsies in which a diagnosis of high-grade neuroendocrine carcinoma cannot be excluded (count multiple as a synonym for NETs of other sites that retains widespread regions with highest labeling density, report mean percentage; In general, neuroendocrine neoplasms are divided into well- differentiated and poorly differentiated categories. The con-cept of differentiation is linked to the grade of the tumors, but Copyright 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pancreas & Volume 39, Number 6, August 2010 Pathologic Classification of Neuroendocrine Tumors with elements of non-neuroendocrine carcinoma (usually adeno- TABLE 2. Grade Versus Differentiation in Neuroendocrine carcinoma or squamous cell carcinoma) are also well recognized.
The distinction of well-differentiated from poorly differentiatedNETs is probably one of the most important pathologic assess- ments related to these neoplasms, as the biologic behavior of the well-differentiated group is often rather indolent, whereas poorly differentiated neuroendocrine carcinomas are very highlyaggressive; therapy also differs signiﬁcantly between these 2 categories of tumors. The term carcinoma also has been appliedto well-differentiated tumors, however. In some systems (par-ticularly the prior 2001 and 2004 versions of the WHO classi- there are subtle differences between the concepts of differen- ﬁcations of digestive and pancreatic NETs5,13,18), carcinoma tiation and grade. Differentiation refers to the extent to which the was used in the place of tumor for neoplasms with obvious neoplastic cells resemble their non-neoplastic counterparts. In evidence of malignant behavior, such as vascular invasion, gross NETs, well-differentiated examples have characteristic organoid local invasion, or metastases. Others have argued to use the term arrangements of the tumor cells, with nesting, trabecular, or carcinoma for all NETs to specify that all are regarded to be gyriform patterns. The cells are relatively uniform and produce malignant.23 However, the use of the same term for all grades abundant neurosecretory granules, reﬂected in the strong and of NETs implies a relationship between the well-differentiated diffuse immunoexpression of neuroendocrine markers such as and poorly differentiated groups that does not exist in most chromogranin A and synaptophysin. Poorly differentiated NETs instances. It is most important to recognize that the unqualiﬁed less closely resemble non-neoplastic neuroendocrine cells and terms neuroendocrine carcinoma and neuroendocrine tumor, have a more sheetlike or diffuse architecture, irregular nuclei, without reference to grade or differentiation, are inadequate and less cytoplasmic granularity. Immunoexpression of neuro- for prognostication or therapy and considered inappropriate in endocrine markers is usually more limited. Grade, on the other hand, refers to the inherent biologic aggressiveness of the tumor.
Well-differentiated (low and intermediate grade) NETs have Low-grade NETs are relatively indolent, high-grade tumors are been variably termed carcinoid tumor (typical and atypical), extremely aggressive, and intermediate grade examples have a neuroendocrine tumor (grade 1 and grade 2), or neuroendocrine less predictable, moderately aggressive course. In general, well- carcinoma (low grade and intermediate grade), among other differentiated NETs are either low or intermediate grade, and options. Table 3 displays a comparison of the various systems of poorly differentiated NETs are considered high grade in all cases nomenclature currently in use for NETs, along with the organ (Table 2). The concept that some well-differentiated tumors could systems most commonly using each system. Although the cri- nonetheless be biologically high grade has been proposed but is teria that deﬁne each category do not perfectly match among the various systems, there are several common themes. Each system The systems of nomenclature reﬂect differentiation and recognizes 3 grades. In each, the low and intermediate grades are grading features of NETs. In essentially all systems, a sharp closely related, well differentiated, and distinguished largely by division is made between well-differentiated and poorly differ- proliferative rate (or necrosis). Finally, each system generally entiated tumors, with the latter group being clearly designated as recognizes that individual tumors rarely display hybrid well- high-grade neuroendocrine carcinomas (neuroendocrine carci- differentiated and poorly differentiated features.
noma, grade 3), including small-cell carcinoma and large-cell The issue of functionality of NETs also impacts on neuroendocrine carcinoma variants. Combined (mixed) forms nomenclature. Functioning NETs are deﬁned based on the TABLE 3. Systems of Nomenclature for Neuroendocrine Tumors pancreatic endocrineneoplasm,intermediate grade The grade of the tumor MUST be included in the pathology report, along with a reference to the speciﬁc grading system being used. Unqualiﬁed terms such as neuroendocrine tumor or neuroendocrine carcinoma without reference to grade do not provide adequate pathology information.
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Pancreas & Volume 39, Number 6, August 2010 presence of clinical symptoms due to excess hormone secretion NETs. When the amount of tumor tissue is limited (eg, in a by the tumor and include functioning carcinoid tumors and a biopsy from a primary tumor or a metastatic focus), it may not be variety of other functioning NETs arising in the pancreas or possible to perform an accurate mitotic count because it is elsewhere. Terms reﬂecting the clinical syndromes may be recommended to count 40 to 50 high-power ﬁeldsVmore than applied to these NETs, such as insulinoma, glucagonoma, and most biopsy samples contain. In these cases, Ki67 staining gastrinoma, although the term carcinoid tumor is used for provides a more accurate assessment of proliferative rate, and tumors with or without the carcinoid syndrome. Although there it is particularly helpful to separate well-differentiated (low or are prognostic implications to some of the functional categories intermediate grade) tumors from poorly differentiated (high (eg, insulinomas are generally very indolent), the biologic grade) neuroendocrine carcinomas, which usually have dra- behavior of most functioning NETs is still deﬁned by the grade matically different Ki67 labeling rates.7,20,27 However, when and stage of the tumor (although the clinical consequences of adequate tissue is present to perform an accurate mitotic count, the hormone hypersecretion can be signiﬁcant). Furthermore, the there are no data to demonstrate that the Ki67 labeling index functional status of the tumor is deﬁned by the clinical ﬁndings, adds important additional information, and in some cases, the 2 not by the pathologic appearance or immunohistochemical measures of proliferative rate may provide conﬂicting informa- proﬁle. Thus, the pathologic diagnosis of functioning NETs should be the same as for analogous nonfunctioning NETs of thesame anatomic site, with the descriptive functional designation appended to the diagnosis when there is knowledge of a clinical A few years ago, no formal TNM-based staging systems existed for NETs. Data submitted to the Surveillance, Epide-miology, and End Results (SEER) program of the National Cancer Institute separated tumors into localized, regional, and The proliferative rate has been repeatedly shown to provide distant stages based on the presence of lymph node or distant signiﬁcant prognostic information for NETs,2,12,16,19,24,26,35 and metastases, but substratiﬁcation of the extent of the primary most systems of grading rely extensively on the proliferative rate tumor was not performed.40 Recently, TNM staging systems to separate low-, intermediate-, and high-grade tumors. Some have been proposed. The American Joint Committee on Cancer systems (such as the WHO classiﬁcation for lung and thymus) has recently published a new TNM staging manual that includes include the presence of necrosis as a feature to distinguish NETs of all anatomic sites,10 and the ENETS has previously intermediate grade from low grade within the well-differentiated published recommendations for TNM staging of gastroentero- group.34 The proliferative rate can be assessed as the number of pancreatic NETs.25,28,29 There are some differences between mitoses per unit area of tumor (usually expressed as mitoses per these systems, particularly for primary tumors of the pancreas 10 high-power microscopic ﬁelds or per 2 mm2) or as the per- and the appendix, but there is also considerable overlap. Addi- centage of neoplastic cells immunolabeling for the proliferation tionally, the staging criteria for both systems rely predominantly marker Ki67.28,29 The WHO classiﬁcation of lung and thymus on the size of the tumor and the extent of invasion into similar tumors relies only on the mitotic rate,34 whereas the system landmarks as used for the staging of non-neuroendocrine car- recently proposed for gastroenteropancreatic NETs by the cinomas of the same sites. It is recommended that the extent of European Neuroendocrine Tumor Society (ENETS) and also involvement of these structures be speciﬁcally indicated in the now recommended by the WHO uses either mitotic rate or Ki67 pathology reports in addition to providing a TNM stage using a labeling index.3,29 A comparison of the most widely used grading system that is speciﬁcally referenced.
systems is shown in Table 4. As can be seen, the cut-points to Until very recently, the WHO classiﬁcations for NETs of distinguish the 3 grades vary somewhat among the different the tubular gastrointestinal tract (2000) and pancreas (2004) used systems, and deﬁnitive clinical data to determine the optimal cut- a hybrid classiﬁcation system that incorporated both staging points do not exist. In fact, some studies suggest that the optimal information (size and extent of tumorVlimited to the primary cut-points may differ between organ systems.9,11,12,14 For these site versus having metastases) and grading information (prolif- reasons, it is recommended to specify the actual proliferative rate erative rate) into a single prognostic prediction system, with a in the pathology report, in addition to designating a grade based different name being applied to the tumors in each prognostic on a system that is speciﬁcally referenced.
group.4Y6,13 Although this system did allow prognostic stratiﬁ- The use of mitotic counts versus Ki67 index is controver- cation of NETs, it did not allow for grading information to be sial. In Europe, where the ENETS system is already in wide- applied to advanced stages of disease, preventing prognostica- spread use, Ki67 labeling indices are commonly reported for all tion once metastases occurred and therefore limiting information TABLE 4. Grading Systems for Neuroendocrine Tumors In the pathology report, the actual proliferative rate (mitotic count and/or Ki67 index) should be speciﬁed, and a grade should be provided, with the speciﬁc grading system used to be speciﬁed in the report.
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Pancreas & Volume 39, Number 6, August 2010 Pathologic Classification of Neuroendocrine Tumors for therapeutic decision making.12 Furthermore, the implications & Basic information should be included in the pathology of this classiﬁcation were that the name for a NET limited to the reports, including a grade and stage along with a reference to primary site was different than that to be used for the same tumor the speciﬁc systems being used to deﬁne these parameters.
once metastases occurred in the future, a relatively commonoccurrence for some NETs. Because of these limitations, the most recent WHO classiﬁcation that applies to all gastro- The authors thank Mark R. Wick, MD, Department of enteropancreatic NET has abandoned the hybrid classiﬁcation Pathology, University of Virginia, Charlottesville, VA, for his system in favor of separately grading and staging the tumors critical reading of the manuscript and discussion of concepts (Tables 3 and 4).3 This will bring the WHO system more closely in line with other widely used systems.
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