ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -4 مورد

Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms

Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms
Author:
Zhaohai Yang, MD, PhD
Section Editor:
Richard M Goldberg, MD
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Apr 2025. | This topic last updated: Sep 17, 2024.

INTRODUCTION — 

Neuroendocrine cells are distributed widely throughout the body. Neuroendocrine neoplasms (NENs), defined as epithelial neoplasms with predominant neuroendocrine differentiation, can arise in most organs. While some clinical and pathologic features of these tumors are unique to the site of origin, other characteristics are shared regardless of site.

Gastroenteropancreatic (GEP) NENs arise from either the tubular gastrointestinal tract or the pancreas. This topic will present an overview of the pathology, classification, and histologic grading of GEP NENs. The pathology of NENs arising in the lungs and thymus is discussed separately. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors' and "Thymic neuroendocrine neoplasms", section on 'Pathology and classification'.)

PATHOLOGY AND TUMOR CLASSIFICATION — 

The classification and nomenclature of NENs is complex, and there is no one single system that is suitable for all NENs, independent of the primary tumor site. Classification systems initially focused on tumors arising in a specific organ system, but these site-specific classification systems differed in terminology, grading, and staging criteria. As a result, morphologically similar NENs were designated differently, depending on the site of origin. A common framework for the classification of NENs has been proposed by the World Health Organization (WHO) [1]. Specific features of this common framework (such as the proliferative rate of the tumor and the extent of local spread) are shared by most site-specific classification systems, and the proposed uniform classification system for NENs of all sites has been formally endorsed for the GEP classification system by the WHO [2].

General principles — GEP NENs are classified by tumor differentiation status and tumor grade. Tumor differentiation refers to the resemblance of the tumor histology to its normal counterparts, whereas tumor grade describes the proliferative activity of the tumor, as measured by mitotic rate or Ki-67 proliferative index. The terminology of GEP NENs has evolved to reflect a separation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) (table 1).

Well-differentiated NETs – Well-differentiated NETs show a solid, trabecular, gyriform, or glandular pattern, with uniform nuclei, coarsely stippled ("salt and pepper") chromatin, and finely granular cytoplasm (picture 1). These tumors were previously referred to as carcinoid tumors (in the tubular gastrointestinal tract) and pancreatic NETs (islet cell tumors), respectively. Although gastrointestinal NETs and pancreatic NETs may have similar characteristics on routine histologic evaluation, they have a different pathogenesis and biology. (See 'Histopathology and immunohistochemistry' below.)

Well-differentiated NETs are graded as low (G1), intermediate (G2), and high (G3) grade. (See 'Assessing tumor grade' below.)

Well-differentiated high-grade (G3) NET, which are designated as "NET G3," are a subset of NENs that are histologically and genetically well differentiated as well as high-tumor grade. The clinical behavior and prognosis of these tumors is in between that of grade 1 or 2 NETs and poorly differentiated NEC. (See 'Well-differentiated high-grade (G3) NET' below.)

Poorly differentiated NEC – Poorly differentiated NECs are by definition high-grade carcinomas that resemble small cell carcinoma or large cell NEC of the lung. Poorly differentiated NECs are often associated with a rapidly progressive clinical course. (See "Pathology of lung malignancies", section on 'Neuroendocrine tumors' and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

Well-differentiated NETs and poorly differentiated NECs share neuroendocrine differentiation and some histologic features. Although in some circumstances they can be challenging to distinguish, these two groups of NENs are not thought to be closely related at a histogenetic or molecular level, and progression from NETs to NECs occurs only rarely, if at all. There is no conceptual category of moderately differentiated GEP NEN; NETs previously designated as such are considered part of the well-differentiated group of NETs.

Histopathology and immunohistochemistry — Protocols for the examination of specimens from patients with NENs of the tubular gastrointestinal tract and pancreas are available from the College of American Pathologists (CAP) [3].

Well-differentiated NET – On gross appearance, well-differentiated NETs of the tubular gastrointestinal tract are often well-circumscribed lesions in the submucosa or extending to the muscular layer, while those that arise in the pancreas may be well circumscribed, multinodular, or infiltrative. The cut surface appears red to tan, reflecting the abundant microvasculature, or sometimes yellow because of high lipid content (picture 2).

On morphology, well-differentiated NETs have characteristic "organoid" arrangements of tumor cells, with solid/nesting, trabecular, gyriform, or sometimes, glandular patterns (picture 1). The cells are relatively uniform, and they have round to oval nuclei, coarsely stippled chromatin, and finely granular cytoplasm.

The cells produce abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin. Insulinoma-associated protein-1 (INSM-1) is another promising neuroendocrine marker [4], although its specificity for NENs is still being established. In addition, some tumors may secrete specific peptide hormones or bioamines (such as insulin, glucagon, somatostatin, vasoactive intestinal peptide [VIP], serotonin, gastrin, etc), which may produce clinically evident hormonal syndromes. (See 'Tumor functionality' below.)

Generally, the histologic features of the tumor do not correlate with anatomic location or hormone production, but there are exceptions: amyloid deposition (islet amyloid polypeptide or amylin) often indicates an insulin-secreting pancreatic NET, and a glandular architecture with psammoma body formation is usually seen in duodenal or ampullary somatostatin-secreting NETs (picture 3). Well-differentiated NETs of the midgut (ileum in particular) also have a very characteristic pattern of solid or cribriform nests punctuated by sharply outlined luminal spaces with peripheral nuclear palisading and granular eosinophilic cytoplasm set in a delicate fibrous stroma with retraction artifact.

Poorly differentiated NEC – Poorly differentiated NECs are, by definition, high-grade carcinomas that resemble small cell carcinoma or large cell NEC of the lung (figure 1 and picture 1). Poorly differentiated NECs less closely resemble nonneoplastic neuroendocrine cells on morphology and have a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity (figure 2).

Small cell carcinomas are composed of small- to medium-sized, round to oval cells with scant cytoplasm and hyperchromatic nuclei with indistinct nucleoli. The large cell subtype is composed of large cells with vesicular nuclei showing prominent nucleoli and abundant eosinophilic cytoplasm. In both cases, the tumor cells grow in sheets, forming nest-like structures, often with large confluent areas of necrosis [5]. Perineural and vascular invasions are frequently observed.

Immunohistochemical expression of neuroendocrine markers is generally more limited in extent and intensity. Nevertheless, the histologic diagnosis of a poorly differentiated NEC needs to be supported by immunohistochemical evidence of neuroendocrine differentiation (ie, staining for chromogranin and/or synaptophysin) to avoid possible misdiagnosis with the more frequent poorly differentiated adenocarcinomas (including pancreatic acinar cell cancers [6]) and squamous cell carcinomas, or with lymphomas and mesenchymal neoplasms.

Immunohistochemical staining for synaptophysin and chromogranin A (CgA) is used to determine if a tumor has neuroendocrine features. Many GEP NEC will stain for both synaptophysin and CgA, but whereas synaptophysin is almost always positive, CgA may be only focally positive or negative [7-10]. Generally, the presence of a small cell histology defines a NEC, whereas for cases in which the histology is non-small cell, synaptophysin should be present in addition to a neuroendocrine morphology. The specificity and clinical utility of immunohistochemical staining for other neuroendocrine markers, such as neuron-specific enolase, protein gene product 9.5, and CD56, are uncertain [11] and they are not used.

Classification and terminology — The classification of GEP NENs is evolving. Classification based upon morphology alone is not very useful, particularly for well-differentiated tumors, because histologic features do not accurately predict an indolent or aggressive clinical course. Although nuclear pleomorphism often correlates with differentiation (ie, the extent to which the neoplastic cells resemble their normal, nonneoplastic counterparts) and malignant behavior in other tumor types, it is of little use in NENs. Although it was previously thought that the only unequivocal evidence of malignancy was the presence of local invasion or metastasis, all well-differentiated NETs have malignant potential.

WHO classification system — GEP NENs are categorized using the WHO classification system for endocrine and neuroendocrine tumors (table 1) [2,12]. This WHO histologic grading scheme only uses proliferative rate to stratify the grades and requires both a mitotic count and the Ki-67 labeling index to be assessed. The higher of these two indices is used to define the final grade in cases where the mitotic rate and Ki-67 index are discordant. (See 'Choice of method' below.)

In 2006 and 2007, the European Neuroendocrine Tumour Society (ENETS) proposed a staging scheme similar to those for most other types of epithelial neoplasms for GEP NENs, which was accompanied by a histologic grading system that could be applied to all disease stages [13,14]. This grading proposal was later largely accepted by the 2010 WHO classification of tumors of the digestive system, and jointly endorsed by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) for the tumor, node, metastasis (TNM) staging classification of digestive system NENs, although they modified the staging parameters of the ENETS proposal. (See 'Staging system' below.)

The 2019 WHO classification of NENs of the digestive system recognizes a category of high-grade (G3) well-differentiated GEP NETs, and since poorly differentiated NECs are high grade by definition, they are no longer assigned a grade (in the 2010 classification poorly differentiated NECs were assign grade G3). This classification essentially remains the same in the 2022 WHO classification of endocrine and neuroendocrine tumors (table 1) [2].

Well-differentiated low- (G1) and intermediate- (G2) grade NET — The WHO classifies well-differentiated GEP NETs into low (G1), intermediate (G2), and high (G3) grade based on the tumor proliferative rate (table 1). Metastatic GEP NET that are grade 1 and grade 2 are generally treated differently from GEP NET that are grade 3. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors" and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)

Well-differentiated high-grade (G3) NET — Several studies, predominantly based on NENs arising in the pancreas, have led to the introduction of well-differentiated NET G3 category. The clinical behavior of well-differentiated NET G3 tumors is somewhat worse than NET G2 tumors but is better than that of bona fide poorly differentiated NECs [15,16]. The management of well-differentiated NETs G3 is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Management of metastatic disease'.)

In some cases, progression from a lower grade (G1 or G2) NET to a NET G3 can be demonstrated within an individual tumor focus or between topographically or temporally separate foci of disease [15,17]. Evidence of progression can be demonstrated by an increase in the proliferative rate, and in some cases, there is also a change in tumor morphology, an increase in nuclear atypia, or development of significant necrosis [17]. Interestingly, the underlying genomic alterations persist in the higher-grade foci, and the specific mutations that are typical of poorly differentiated NEC, such as RB1 and TP53, are generally not found in well-differentiated NET G3. Progression from NET to NEC occurs extremely rarely, if at all.

Poorly differentiated NEC — GEP NECs are classified as either small cell type NEC or a large cell type NEC. These tumors are not formally graded but are considered high grade by default [2]. For poorly differentiated NECs, the morphologic features often suggest the diagnosis [2,18]. (See 'Histopathology and immunohistochemistry' above.)

Nevertheless, all neoplasms with neuroendocrine differentiation should also be assessed for extent of tumor differentiation and tumor grade. The proliferative rate in most cases is well in excess of the cutoffs originally proposed to distinguish them from well-differentiated NETs (>20 percent Ki-67 labeling index, >20 per 2 mm2 mitotic rate). Even without an in-depth assessment, the high mitotic rate and Ki-67 labeling index (usually >70 percent) are usually readily apparent (figure 2).

While these tumors are included in many published studies of NENs of the digestive system, they represent a distinct group, with clinical behavior similar to that of small cell carcinoma or large cell NEC of the lung, which is far worse than that of well-differentiated NETs [8,17]. In an observational series of poorly differentiated pancreatic NECs, 88 percent of the patients had lymph node or distant metastatic disease at presentation, and an additional 7 percent developed metastases subsequently. The median survival was 11 months (range 0 to 104 months), and the two- and five-year survival rates were 22.5 and 16.1 percent, respectively [6].

The management of poorly differentiated NECs is discussed separately. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

How to distinguish between NET G3 and NEC — Distinguishing a well-differentiated NET G3 from a poorly differentiated NEC can be challenging in many cases, even among pathology experts.

Morphology – Histologically, when a pathologist is assessing a high-grade NEN, morphologic features may not always be reliable in separating NET G3 from NEC. Data suggests that an organoid growth pattern, in conjunction with a capillary network in direct contact to tumor cells, and absence of desmoplastic stroma can help to separate NET G3 from NEC [19].

Ki-67 and mitotic rate – Furthermore, there is no specific Ki-67 index cutoff within the G3 range (>20 percent) that sharply delineates these two neoplasms. Both poorly differentiated NECs and well-differentiated NET G3 and are classified as high-grade (grade 3) tumors, either with a high mitotic rate (greater than 2 per 2 mm2) and/or high Ki-67 proliferative index (greater than 20 per 2 mm2). Although a Ki-67 proliferative rate between 20 to 55 percent can be seen with either a G3 NET or poorly differentiated NEC, an extremely high Ki-67 proliferative index (>70 percent) usually indicates a poorly differentiated NEC (figure 2). A mitotic rate greater than 20 per 2 mm2 also usually indicates a NEC, since most NET G3 cases fall into the high-grade range solely based on their Ki-67 index.

In general, tumors that are classified as well-differentiated NET G3 but have a Ki-67 index greater than 55 percent should be re-evaluated by a pathologist for the possibility that the tumor is a poorly differentiated NEC. Likewise, tumors classified as a poorly differentiated NEC with a Ki-67 less than 55 percent should re-evaluated by a pathologist for the possibility that the tumor is a NET G3. (See 'Assessing tumor grade' below.)

Other factors – A prior diagnosis of well-differentiated NET or a focal area of well-differentiated NET elsewhere within a neoplasm supports a diagnosis of NET G3, while a history of or combination with adenocarcinoma or, rarely, squamous cell carcinoma, supports a diagnosis of NEC. In difficult cases, immunohistochemical staining may be helpful for differentiating NEC from NET G3. For example, pancreatic NET G3 shows loss of DAXX or ATRX in roughly one-half of cases, similar to pancreatic NET G1 and G2, whereas loss of Rb or abnormality in p53 expression supports a diagnosis of NEC [20].

An important consideration is that chemotherapy can induce treatment-related changes in NECs, including a reduction in the Ki-67 index. In some cases, a Ki-67 index less than 10 percent may be observed, either focally or diffusely [21]. The reduction in proliferative rate following treatment is of uncertain clinical significance but should not be taken as evidence of a lower grade (NET) component of the neoplasm.

Mixed neuroendocrine/non-neuroendocrine neoplasms — In approximately 40 percent of cases, poorly differentiated NECs contain non-neuroendocrine components, including adenocarcinoma and squamous cell carcinoma. If the neoplasm consists of a neuroendocrine component (most commonly poorly differentiated) and a gland-forming component, both exceeding 30 percent, the WHO classification places it in the conceptual category of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) (table 1) [22,23]. The origin of these mixed tumors is thought to be a totipotent stem cell present in the submucosa that can differentiate into various cell lines [24-26]. These carcinomas are treated similarly to pure NECs. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

NEN of unknown primary — NENs of unknown primary, especially the well-differentiated ones, often present initially with liver metastases, and most of these represent GEP NETs. Thus, the WHO grading scheme also applies to this category unless a different primary site is found. In this setting, histologic grade is particularly important since NENs of unknown primary are, by definition, metastatic disease and therefore are considered stage IV in all TNM staging systems. Histologic grade may be the only prognostic parameter available for this group of tumors and may be the basis for the choice of treatment. (See 'Staging system' below and "Neuroendocrine neoplasms of unknown primary site".)

Assessing tumor grade — The WHO classification for GEP NENs relies entirely on proliferative rate to separate low-grade, intermediate-grade, and high-grade tumors, and the definitions are the same for NETs of the tubular gastrointestinal tract, pancreas, and hepatobiliary tract (table 1) [2]. Proliferative rate can be assessed using either mitotic counts or Ki-67 labeling index.

Assessment of mitotic activity — In all grading schemes that rely on mitotic count, the difference between low and intermediate grade is subtle and may hinge on only 1 mitotic figure per 10 high-powered fields (HPF); thus, it is very important to count the mitoses accurately. It is recommended that only clear-cut mitotic figures be counted, excluding degenerating dark-stained nuclei and apoptotic bodies.

In addition, the size of the microscopic field matters tremendously; the size of 10 HPF is set to 2 mm2 for standardization. For the microscopes used in earlier studies, the size of 10 HPF (using a 40x objective) roughly equals 2 mm2; however, the size of the fields has not been standardized between different brands of microscopes, a fact that has not been considered in some studies and can lead to variability in mitotic rate determination.

Other factors that add variability to mitotic counting include variable section thickness, variability in tumor cellularity/stromal ratio, and variations in tumor cell size. For these reasons, simply counting 10 HPFs or 2 mm2 does not mean we are evaluating the same number of tumor cells.

Furthermore, the total number of tumor cells in 10 HPFs or 2 mm2 is different for different tumors, but this has not been considered in any of the grading schemes.

Assessment of Ki-67 labeling index — The optimal cutoff values for the Ki-67 labeling index to distinguish low-, intermediate-, and high-grade GEP NENs have not been conclusively established and may vary depending on the primary site of the neoplasm. However, the ENETS, the AJCC, and the WHO classifications include a uniform Ki-67 labeling cutoff of <3 percent to define low-grade, 3 to 20 percent for intermediate-grade, and >20 percent for high-grade NENs of the tubular gastrointestinal tract, pancreas, and hepatobiliary sites (table 1) [2]. Assignment of grade based on these Ki-67 cutoffs has been shown to correlate with patient survival independent of tumor stage in both primary and metastatic GEP NETs [27-32].

As with mitotic index, determining optimal cutoffs has plagued efforts to standardize grading using Ki-67. The choice of cutoff may be influenced by the measures of patient outcome (dead versus alive, recurrence versus no recurrence, disease-specific survival, disease-free survival [33], etc) and the investigator's interpretation of its clinical significance. As such, a range of values, instead of a single value, may provide similar prognostic significance. Although various investigators have proposed different Ki-67 cutoff values for grading, it is increasingly recognized that both Ki-67 and mitotic rate are continuous variables, at least within the low- and intermediate-grade ranges, so it may not be practical to define the "absolute" values that separate grades. Rather, proliferative rates can be used to define prognosis based upon the absolute values of Ki-67 and mitotic rate, with increasing values predicting increasingly aggressive clinical behavior. This underscores the importance of recording the actual proliferation values in pathology reports, rather than simply reporting the grade [34]. It is also increasingly recognized that the intent to grade all GEP NETs using a single system may obscure the inherent biologic variability that likely exists among various primary sites.

To establish the percent of positive cells (the Ki-67 labeling index), manual counting of a certain number of nuclei (eg, 2000 as previously recommended by the WHO [35], although an acceptable grade may be obtained with as few as 500 cells) is used. This method has been considered overly burdensome and not practical [34]. Alternatively, some pathologists choose to estimate the labeling index by scanning the slide or "eyeballing." Eyeballing may be sufficient to separate low- to intermediate-grade from high-grade tumors (ie, Ki-67 1 to 20 versus >50 percent), but this approach has been criticized due to a lack of precision and reproducibility [34].

When either manual counting or eyeballing is used for research studies, issues of intraobserver and/or interobserver variability necessitate some sort of statistical confirmation (eg, the Bland-Altman approach [36]) to ensure that intraobserver variability is within an acceptable range. Digital image analysis has been validated for the assessment of nuclear markers, with much less variability than manual counting or eyeballing [32,37-39], thus avoiding the need for complicated statistical analyses for reproducibility. However, this technique is not yet in widespread use and also has technical limitations. Studies assessing the time required to calculate an accurate Ki-67 index have concluded that with currently available morphometric algorithms, the optimal method is to print a photograph of the hot spot region and manually count the Ki-67 positive cells, using the photograph to tick off each cell as it is counted [40].

Choice of method — The best method (mitotic counting versus Ki-67 labeling index) to establish the proliferative rate is not established. The WHO/AJCC classification system provides criteria for both mitotic rate counting and Ki-67 labeling as an assessment of proliferative rate, without a preference for one method over the other.

Although mitotic counting can be performed without immunohistochemical staining, Ki-67 labeling index offers several advantages:

Ki-67 labeling index is based on the percentage of positive cells, which is not affected by the size of the microscopic field or the number of neoplastic cells in a given area of the tumor.

In most tumors, there are many more Ki-67-labeled cells than there are cells in mitosis. In a limited specimen, such as liver biopsy, gastrointestinal biopsy, or fine needle aspiration of the pancreas, there may be only a few HPFs available, much less than the 40 to 50 HPFs required for accurate mitotic counting, and accurate determination of mitotic rate is difficult in those cases. However, 500 to 2000 cells are generally present even in those limited specimens, from which a Ki-67 index can be comfortably obtained.

With the advent of the digital era, especially artificial intelligence, Ki-67 labeling index has the potential of at least partial automation, thus eliminating the tedious work of counting a certain number of cells or HPFs.

Additionally, for NET G3, it is often only the Ki-67 index above 20 percent that allows recognition of the high-grade nature of the neoplasm (table 1) [2].

Previously, a common practice was to use mitotic counting for grading in resection specimens and to use the Ki-67 labeling index for more limited material, but this approach does not allow formal grading based on the WHO and AJCC criteria. Including the mitotic count can be helpful to distinguish poorly differentiated NECs from high-grade well-differentiated NETs since the latter rarely have a mitotic rate in the high-grade range (ie, they are grade discordant). For optimal grading and better guidance for chemotherapy, it may be necessary to do both.

The Ki-67 labeling index generally correlates with the mitotic count [31,41]; however, there may be discrepancies. The Ki-67 protein has a short half-life, and its amount and localization change with the cell cycle, which may explain the discrepancies observed by some authors. In cases with discordance between these two measures of proliferation, the WHO classification recommends using the higher grade [2], which was validated in a study of discordant low-grade/intermediate-grade pancreatic NETs [42]. As noted above, the WHO "NET G3" category of digestive tract NENs is also grade discordant in most, if not all, cases (table 1). (See 'WHO classification system' above.)

Impact of intratumoral heterogeneity — Heterogeneity of the proliferative rate within a tumor (or among different sites of disease if metastases are present) is a common finding in NETs. Even on a single slide, there may be great variability in terms of mitotic count and Ki-67 labeling index (picture 4). Within the ENETS/WHO classification system, it is recommended that at least 40 HPFs should be counted for mitoses and that areas of highest labeling ("hot spots") should be used to determine the Ki-67 labeling index [13,14,43].

If Ki-67 staining is performed on a large specimen, such as a resection, it is relatively simple to scan the tumor at low power to identify the hot spots of greatest labeling. However, within a limited specimen (eg, core needle biopsy), the Ki-67 index may not be representative. Furthermore, there are few data addressing whether the proliferative rate within hot spot areas more accurately predicts prognosis than, for example, the average proliferative rate in the entire tumor [32,36].

In one analysis of Ki-67 labeling indices in simulated biopsies of metastatic well-differentiated NETs, nearly one-half of the tumors showed intratumoral heterogeneity that was sufficient to change the grade from low to intermediate [32]. Histologic grade based upon either the average or highest Ki-67 index demonstrated a statistically significant correlation with patient survival (figure 3). However, for overall survival, grade according to the highest Ki-67 index resulted in better separation of the two prognostically different groups than did grade as assessed using the average Ki-67 index.

These data support counting hot spots to assess Ki-67 index in heterogeneous tumors. In such cases, a low grade based upon a small, randomly directed biopsy may not represent the true grade of the tumor. In order to better predict patient outcome, multiple biopsies would be needed, although the optimal number has not been determined.

Other parameters and markers for histologic grading — Some prognostic parameters used in the earlier classifications, such as tumor size and the presence of metastasis, are incorporated into the AJCC staging system and are no longer included in the WHO classification system [2]. (See 'Classification and terminology' above.)

Tumor necrosis is one of the criteria for intermediate grade in the WHO classification of lung [44] and thymic NENs, and it was used in the Hochwald and Armed Forces Institute of Pathology classifications of pancreatic NETs [45,46]. However, necrosis is not a component of the WHO classifications for GEP NETs [2]. Similarly, lymphovascular and perineural invasion are not part of the grading criteria, although they should be recorded as prognostic factors.

Several other markers have been reported to have prognostic value in certain NETs. Cytokeratin 19 (CK19) is a marker of pancreatic ductal epithelium but is also transiently expressed in islet cells. Its expression has been shown to correlate with worse survival in pancreatic NETs [47]. A classification scheme based upon expression of CK19 and CD117 (KIT) has been proposed, with CK19 and CD117 positive pancreatic NETs having the shortest survival [48]. Those markers may be useful in primary NETs, but they do not appear to have any prognostic significance in metastatic disease, unlike Ki-67 labeling index [31,32]. Mutations in DAXX or ATRX are considered adverse prognostic factors in pancreatic NETs [49,50]. Emerging data suggest that programmed cell death ligand 1 (PD-L1) may be a biomarker for high-grade GEP NENs, but confirmatory studies are needed [51].

The potential prognostic significance of other markers such as p27Kip1, CD99, and PAX8 is controversial even in primary tumors. The fact that some of the putative markers are also lineage specific may have limited their value as a general prognostic marker for NETs. To date, none of these prognostic markers has achieved widespread use, and none is currently proposed as a basis for treatment stratification.

Tumor functionality — Tumor functionality also impacts the nomenclature of well-differentiated NET. Functioning NETs are defined based upon the presence of clinical symptoms due to excess hormone secretion by the tumor. Functioning (hormone-secreting) pancreatic NETs are classified according to the predominant hormone they secrete and the resulting clinical syndrome (eg, insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma) (table 2). Immunohistochemical staining is not a defining criterion for tumor classification. For example, if a tumor stains for gastrin but does not produce symptoms of Zollinger-Ellison syndrome, it should not be considered a gastrinoma. (See "Clinical features of carcinoid syndrome" and "Insulinoma" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Glucagonoma and the glucagonoma syndrome" and "Clinical presentation, diagnosis, and management of VIPoma" and "Somatostatinoma: Clinical manifestations, diagnosis, and management".)

Although functionality may impact prognosis (eg, insulinomas are generally indolent tumors), the biologic behavior of most functioning NETs is defined by the grade and stage of the tumor. Thus, the pathologic diagnosis of a functioning pancreatic NET should be the same as for a nonfunctioning NET, with the descriptive functional designation appended to the diagnosis when there is knowledge of a clinical syndrome. NETs of the tubular gastrointestinal tract are classified similarly whether they produce symptoms of carcinoid syndrome or not. (See "Clinical features of carcinoid syndrome" and "Diagnosis of carcinoid syndrome and tumor localization".)

STAGING SYSTEM — 

The American Joint Committee on Cancer (AJCC) has endorsed staging neuroendocrine carcinomas (NECs) using the same tumor, node, metastasis (TNM) staging system for adenocarcinoma of the respective digestive organs, while creating separate organ-specific TNM staging systems for well-differentiated neuroendocrine tumors (NETs). The T category for NET is mostly based on the size of tumor and/or depth/extent of invasion. The ninth version of the AJCC staging system features slight modifications to the prognostic stage groups but still maintains separate TNM staging systems for well-differentiated NETs of the following primary tumor sites:

Appendix (table 3) – (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Staging and prognosis'.)

Stomach (table 4) – (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Stomach'.)

Colon and rectum (table 5) – (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Rectum' and "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Colon'.)

Duodenum and ampulla of Vater (table 6) – (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Ampulla of Vater'.)

Jejunum and ileum (table 7) – For these tumors, the nodal category (N2) remains for cases with bulky (>2 cm) or extensive (12 or more positive nodes) mesenteric disease, which is a common scenario in this anatomic location. However, the prognostic value of bulky (mesenteric tumor mass >2 cm) in jejunoileal NETs has been questioned [52]. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Jejunum/ileum'.)

Pancreas (table 8) – (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'.)

There are some differences between the original European Neuroendocrine Tumour Society (ENETS) proposal and the TNM classification of the AJCC/Union for International Cancer Control (UICC), including the following:

The ENETS proposal stages poorly differentiated NECs in the same way as well-differentiated NETs, while AJCC stages poorly differentiated NECs similarly to adenocarcinomas.

The T stage definitions for pancreatic NET are in alignment with the ENETS system. However, for well-differentiated NETs at other sites, there remain some differences in the T stage definitions of the TNM staging system and that of ENETS. For small bowel primaries, the separate N2 category for mesenteric masses >2 cm and/or extensive nodal deposits (12 or greater), especially those that encase the superior mesenteric vessels did not exist in the ENETS staging system.

It is unclear which staging system provides better separation of the prognostically different groups; many reports suggest that both the AJCC/UICC (at least the 2010 seventh edition) and ENETS classifications are similarly prognostic for progression-free and overall survival [53,54]; however, one analysis using a large international cohort study concluded that for pancreatic NENs the ENETS staging system provided superior prognostic stratification of the four distinct stages with smaller 95 percent confidence intervals [27]. Nevertheless, at least in the United States, the majority of pathologists must use the AJCC/UICC TNM staging system if the department has accreditation from College of American Pathologists (CAP).

The prognostic validity of both TNM stage and proliferative rate for GEP NENs is supported by several studies using the previous grading/staging schemes [28-32,55-58]. As an example, in one series of 425 patients with pancreatic NENs, five-year survival rates for G1, G2, and G3 (poorly differentiated) neoplasms were 75, 62, and 7 percent, respectively [56]. Using the seventh edition AJCC/UICC classification, five-year overall survival rates for stage I, II, III, and IV tumors were 92, 84, 81, and 57 percent, respectively [56]. The aforementioned large international cohort study also validated the prognostic value of the UICC/AJCC/World Health Organization (WHO) 2010 TNM staging system (though with large 95 percent confidence intervals and poor separation between stages II and III), with hazard ratios of death of 9.57, 9.32, and 30.84 for stages II, III, and IV, respectively, when compared with stage I disease. Multivariable modeling indicated curative surgery, TNM staging, and histologic grade were effective predictors of death, and histologic grade was the second best independent predictor of survival in the absence of staging information [27].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)

SUMMARY AND RECOMMENDATIONS

Definition – Neuroendocrine neoplasms (NENs), which are defined as epithelial neoplasms with predominant neuroendocrine differentiation, can arise in most organs. Gastroenteropancreatic (GEP) NENs can arise either in the tubular gastrointestinal tract or the pancreas. (See 'Introduction' above.)

General principles of classification – GEP NENs are classified by tumor differentiation status and tumor grade. Tumor differentiation refers to the resemblance of the tumor histology to its normal counterparts, whereas tumor grade describes the proliferative activity of the tumor, as measured by mitotic rate or Ki-67 proliferative index. The terminology of GEP NENs has evolved to reflect a separation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) (table 1). (See 'General principles' above.)

Well-differentiated GEP NET

Histopathology and immunohistochemistry – Well-differentiated GEP NET have characteristic "organoid" arrangements of tumor cells, with solid/nesting, trabecular, gyriform, or sometimes, glandular patterns (picture 1). On morphology, the cells are relatively uniform, and they have round to oval nuclei, coarsely stippled chromatin, and finely granular cytoplasm. The cells produce abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin (figure 2). (See 'Histopathology and immunohistochemistry' above.)

Classification system – The World Health Organization (WHO) and the American Joint Committee on Cancer (AJCC) classifies well-differentiated GEP NETs into low (G1), intermediate (G2), and high (G3) grade based on the tumor proliferative rate (table 1). (See 'WHO classification system' above and 'Well-differentiated low- (G1) and intermediate- (G2) grade NET' above and 'Well-differentiated high-grade (G3) NET' above.)

Assessing tumor grade – Well-differentiated GEP NETs are not a homogeneous group, and there is a spectrum of aggressiveness. The biologic behavior of well-differentiated NETs cannot be predicted based on morphology alone. Proliferative rate, as assessed by mitotic count and Ki-67 labeling index, is of prognostic significance, independent of tumor stage. (See 'Assessing tumor grade' above.)

Tumor functionality – Tumor functionality impacts the nomenclature of well-differentiated NET. Functioning NETs are defined based on the presence of clinical symptoms due to excess hormone secretion by the tumor. Functioning (hormone-secreting) pancreatic NETs are classified according to the predominant hormone they secrete and the resulting clinical syndrome (eg, insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma) (table 2). Immunohistochemical staining is not a defining criterion for tumor classification. (See 'Tumor functionality' above.)

Poorly differentiated GEP NEC

Classification system – The WHO classification system distinguishes between well-differentiated GEP NET and poorly differentiated GEP NEC (table 1). Poorly differentiated GEP NEC are further subclassified into small cell type NEC and large cell type NEC. (See 'Poorly differentiated NEC' above.)

Histopathology and immunohistochemistry – Poorly differentiated GEP NECs less closely resemble nonneoplastic neuroendocrine cells on morphology and have a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity. Immunohistochemical expression of neuroendocrine markers is generally more limited in extent and intensity. (See 'Histopathology and immunohistochemistry' above.)

Assessing tumor grade – Poorly differentiated GEP NECs are no longer formally graded, but are considered high grade by default. They are aggressive tumors with a rapidly progressive clinical course. (See 'Poorly differentiated NEC' above and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)

Distinguishing between NET G3 and NEC – Distinguishing a well-differentiated NET G3 from a poorly differentiated NEC can be challenging in many cases, even among pathology experts. (See 'How to distinguish between NET G3 and NEC' above.)

Morphologic features may not always be reliable.

There is no specific Ki-67 index cutoff that sharply delineates these two neoplasms. An extremely high Ki-67 proliferative index (>70 percent) usually indicates a NEC (figure 2). A mitotic rate greater than 20 per 2 mm2 also usually indicates a NEC, since most NET G3 cases fall into the high-grade range solely based on their Ki-67 index.

In general, tumors that are classified as well-differentiated G3 NETs but have a Ki-67 index greater than 55 percent should be re-evaluated by a pathologist for the possibility that the tumor is a poorly differentiated NEC. Likewise, tumors classified as a poorly differentiated NEC with a Ki-67 less than 55 percent should re-evaluated for the possibility that the tumor is a NET G3.

Staging – Both well-differentiated GEP NETs and poorly differentiated GEP NECs are staged using the AJCC tumor, node, metastasis (TNM) staging system. (See 'Staging system' above.)

GEP NEC – GEP NECs follow the same AJCC TNM staging system for adenocarcinoma of the respective digestive organ.

Well-differentiated GEP NET – Well-differentiated GEP NET are staged using the ninth version of the AJCC TNM staging system for well-differentiated NETs of the appendix (table 3), stomach (table 4), colon and rectum (table 5), duodenum and ampulla of Vater (table 6), jejunum and ileum (table 7), and pancreas (table 8). (See 'Staging system' above.)

ACKNOWLEDGMENT — 

The editorial staff at UpToDate would like to acknowledge David S Klimstra, MD, who contributed to an earlier version of this topic review.

  1. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 2018; 31:1770.
  2. WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 10). https://publications.iarc.fr. (Accessed on May 30, 2024).
  3. College of American Pathologists, Cancer Protocol Templates. Available at: https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates (Accessed on April 29, 2021).
  4. Zhang Q, Huang J, He Y, et al. Insulinoma-associated protein 1(INSM1) is a superior marker for the diagnosis of gastroenteropancreatic neuroendoerine neoplasms: a meta-analysis. Endocrine 2021; 74:61.
  5. La Rosa S, Sessa F. High-grade poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: from morphology to proliferation and back. Endocr Pathol 2014; 25:193.
  6. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014; 38:437.
  7. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
  8. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24:152.
  9. Ishida M, Sekine S, Fukagawa T, et al. Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis. Am J Surg Pathol 2013; 37:949.
  10. Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2015; 22:657.
  11. Wick MR. Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol 2000; 17:194.
  12. Rindi G, Mete O, Uccella S, et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol 2022; 33:115.
  13. Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006; 449:395.
  14. Rindi G, Klöppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007; 451:757.
  15. Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015; 39:683.
  16. Coriat R, Walter T, Terris B, et al. Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. Oncologist 2016; 21:1191.
  17. Tang LH, Untch BR, Reidy DL, et al. Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas. Clin Cancer Res 2016; 22:1011.
  18. Shia J, Tang LH, Weiser MR, et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol 2008; 32:719.
  19. Elvebakken H, Perren A, Scoazec JY, et al. A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations. Neuroendocrinology 2021; 111:883.
  20. Tang LH, Basturk O, Sue JJ, Klimstra DS. A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas. Am J Surg Pathol 2016; 40:1192.
  21. Vyas M, Tang LH, Rekhtman N, Klimstra DS. Alterations in Ki67 Labeling Following Treatment of Poorly Differentiated Neuroendocrine Carcinomas: A Potential Diagnostic Pitfall. Am J Surg Pathol 2021; 45:25.
  22. La Rosa S, Sessa F, Uccella S. Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms. Endocr Pathol 2016; 27:284.
  23. La Rosa S, Klimstra DS. Pancreatic MiNENs. In: WHO Classification of Tumours: Digestive System Tumours, 5th ed, WHO Classification of Tumours Editorial Board (Ed), International Agency for Research on Cancer, Lyon 2019. p.370.
  24. Casas F, Ferrer F, Farrús B, et al. Primary small cell carcinoma of the esophagus: a review of the literature with emphasis on therapy and prognosis. Cancer 1997; 80:1366.
  25. Ho KJ, Herrera GA, Jones JM, Alexander CB. Small cell carcinoma of the esophagus: evidence for a unified histogenesis. Hum Pathol 1984; 15:460.
  26. Sidhu GS. The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature. Am J Pathol 1979; 96:5.
  27. Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 2012; 104:764.
  28. Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. Cancer 2011; 117:3332.
  29. La Rosa S, Inzani F, Vanoli A, et al. Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 2011; 42:1373.
  30. Pape UF, Jann H, Müller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008; 113:256.
  31. Strosberg J, Nasir A, Coppola D, et al. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol 2009; 40:1262.
  32. Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol 2011; 35:853.
  33. Voss SM, Riley MP, Lokhandwala PM, et al. Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improves interobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas. Am J Surg Pathol 2015; 39:13.
  34. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010; 34:300.
  35. Klimstra DS, Kloppell G, La Rosa S, Rindi G. Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours: Digestive System Tumours, 5th ed, WHO Classification of Tumours Editorial Board (Ed), International Agency for Research on Cancer, Lyon 2019. p.16.
  36. Couvelard A, Deschamps L, Ravaud P, et al. Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 2009; 22:273.
  37. Lejeune M, Jaén J, Pons L, et al. Quantification of diverse subcellular immunohistochemical markers with clinicobiological relevancies: validation of a new computer-assisted image analysis procedure. J Anat 2008; 212:868.
  38. López C, Lejeune M, Salvadó MT, et al. Automated quantification of nuclear immunohistochemical markers with different complexity. Histochem Cell Biol 2008; 129:379.
  39. Tang LH, Gonen M, Hedvat C, et al. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol 2012; 36:1761.
  40. Reid MD, Bagci P, Ohike N, et al. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. Mod Pathol 2015; 28:686.
  41. La Rosa S, Klersy C, Uccella S, et al. Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 2009; 40:30.
  42. McCall CM, Shi C, Cornish TC, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 2013; 37:1671.
  43. American Joint Committee on Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010.
  44. Travis WD. Lung neuroendocrine neoplasms. In: WHO classification of Tumours series, 5th ed: Thoracic tumors, WHO Classification of Tumours Editorial Board (Ed), IARC Press, Lyon, France 2021.
  45. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol 2002; 20:2633.
  46. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas, ARP/AFIP, Washington, DC 2007. p.422.
  47. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 2004; 28:1145.
  48. Zhang L, Smyrk TC, Oliveira AM, et al. KIT is an independent prognostic marker for pancreatic endocrine tumors: a finding derived from analysis of islet cell differentiation markers. Am J Surg Pathol 2009; 33:1562.
  49. Pea A, Yu J, Marchionni L, et al. Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases. Ann Surg 2020; 271:566.
  50. Roy S, LaFramboise WA, Liu TC, et al. Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times. Gastroenterology 2018; 154:2060.
  51. Cavalcanti E, Armentano R, Valentini AM, et al. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis 2017; 8:e3004.
  52. Gonzalez RS, Cates JMM, Shi C. Number, not size, of mesenteric tumor deposits affects prognosis of small intestinal well-differentiated neuroendocrine tumors. Mod Pathol 2018; 31:1560.
  53. Cho JH, Ryu JK, Song SY, et al. Prognostic Validity of the American Joint Committee on Cancer and the European Neuroendocrine Tumors Staging Classifications for Pancreatic Neuroendocrine Tumors: A Retrospective Nationwide Multicenter Study in South Korea. Pancreas 2016; 45:941.
  54. Strosberg JR, Cheema A, Weber J, Kvols LK. Prognostic relevance of a novel AJCC staging classification for neuroendocrine tumors of the pancreas. J Clin Oncol 2011; 29:177.
  55. Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. J Clin Oncol 2011; 29:2372.
  56. Strosberg JR, Cheema A, Weber J, et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol 2011; 29:3044.
  57. Dolcetta-Capuzzo A, Villa V, Albarello L, et al. Gastroenteric neuroendocrine neoplasms classification: comparison of prognostic models. Cancer 2013; 119:36.
  58. Strosberg JR, Weber JM, Feldman M, et al. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol 2013; 31:420.
Topic 14247 Version 28.0

References