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Available online at www.sciencedirect.com

www.elsevier.com/locate/semdp

Gastroenteropancreatic neuroendocrine neoplasms: Historical context and current issues Zhaohai Yang, MD, PhDa, Laura H. Tang, MD, PhDb, David S. Klimstra, MDb,n a

Department of Pathology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, New York

b

A RT I C L E IN F O

A BS T R A C T The digestive organs contain a large number of neuroendocrine cells as part of the diffuse

Keywords:

neuroendocrine system. Neuroendocrine tumors can occur in every digestive organ. It has

Neuroendocrine tumors

long been recognized that this is a diverse group of tumors with very different clinical

Carcinoid tumor

outcomes; however, well-recognized prognostic parameters had been elusive until

Pancreatic neoplasms

recently. Over the years, there have been several different classification schemes, each

Neoplasm grading

with different strengths and weaknesses. In an effort to standardize the classification and

Neoplasm staging

grading criteria for gastroenteropancreatic neuroendocrine tumors, the current World

Ki67 antigen

Health Organization classification includes a histologic grade based on proliferative rate (mitotic rate and Ki67 index) and a TNM stage that varies from organ to organ. The prognostic value of both the grade and stage has been validated in multiple studies. However, several issues remain, including the lack of standardized methods to assess proliferative rate, potential discrepancies between the mitotic count and the Ki67 index; intratumoral heterogeneity in proliferative rate; and the need for refinement in proliferative cut-points to define the grades. More studies are needed to further improve the classification of neuroendocrine tumors, thus guiding optimal treatment for these tumors. & 2013 Elsevier Inc. All rights reserved.

Introduction The digestive organs, including the stomach, small and large intestines, and pancreas (the gastroenteropancreatic, or GEP, system), contain a large number of neuroendocrine cells, which belong to the diffuse neuroendocrine system. These cells secrete various hormones that regionally or systemically regulate and coordinate the exocrine activity of one or more organs. GEP neuroendocrine neoplasms are generally uncommon but with increasing detection due to enhanced diagnostic capabilities, they recently reached 3.65 cases per 100,000 population per year.1 Despite their rarity, these tumors have attracted enormous interest over the years from almost all medical disciplines, partially due to the various associated neuroendocrine syndromes (e.g., carcinoid syndrome). Most n

Corresponding author. E-mail address: [email protected] (D.S. Klimstra).

0740-2570/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semdp.2013.06.005

such tumors, in particular well-differentiated neuroendocrine tumors (NETs), grow slowly even after the development of distant metastases, and they are thus dubbed “cancers in slow motion.”2 Although many patients may survive for years, cure of metastatic disease is rare, and most patients will ultimately die of disease. Other patients [e.g., those with poorly differentiated neuroendocrine carcinomas (NEC)] have a rapidly progressive clinical course. Various prognostic parameters have been proposed during the past decades, with the hope of guiding patient management and prognostic stratification. These efforts have culminated in the new grading and staging systems by the European Neuroendocrine Tumour Society (ENETS), the American Joint Committee on Cancer (AJCC), and the World Health Organization (WHO). This review will present the evolution of thinking about the

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classification and prognostic stratification of NETs along with the current proposals for proliferative rate-based grading and TNM staging that will hopefully allow a more uniform approach to this diverse group of neoplasms.

The GEP neuroendocrine system In the luminal gastrointestinal (GI) tract, individual neuroendocrine cells, also known as Kulchitsky cells, are scattered in the pits, crypts, or surface epithelium.3 Although the proportion of such cells is small (1% or less of the total epithelial cells), due to its large volume, the GI tract is considered the largest organ in the diffuse neuroendocrine system. Pancreatic neuroendocrine cells are predominantly clustered in the islets of Langerhans, although a few individually arranged neuroendocrine cells are present within larger pancreatic ducts as well. The cells in the diffuse neuroendocrine system were initially thought to be APUD cells (uptake and decarboxylation of amine precursors) of neural crest origin that migrated to various organs during early development.4 They do share some features with neurons, such as containing neurosecretory granules and exhibiting neuron-like process. However, it is now known that these cells arise from endodermally derived pluripotent stem cells.5,6 Thus some authors use the term “endocrine” instead of “neuroendocrine.” Nevertheless, at least some of the GI neuroendocrine cells function as sensory and effector cells for the central nervous system and are the indispensable link in the brain–gut axis.7 In addition, most neuroendocrine cells (as well as their

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neoplastic counterparts) express neuronal markers such as synaptophysin. Furthermore, some tumors such as gangliocytic paraganglioma of the duodenum and NET of the appendix often have a neural component or are closely associated with nerves. Based on these arguments, “neuroendocrine” is the term now favored in the WHO classification. The GEP neuroendocrine cells share some common morphological features, such as relatively small uniform cells, regular round to oval nuclei, granular chromatin with a “saltand-pepper” quality, inconspicuous nucleoli, and moderate clear or finely granular cytoplasm. The cells in the tubular gut are often basally located, presumably facilitating release of peptides into the capillaries or surrounding tissues. These cells may be difficult to distinguish from adjacent exocrine cells on routine H&E staining. Although silver staining techniques and electron microscopy have been utilized in the past, immunohistochemical staining is now the easiest method and has the added advantage of identifying the specific peptides/cell types. Most neuroendocrine cells express one or more general neuroendocrine markers such as chromogranin, synaptophysin, protein gene product 9.5 (PGP 9.5), CD56 (neural cell adhesion molecule), and neuronspecific enolase (NSE). Chromogranin and synaptophysin are considered the most specific, both for normal cells and tumors.8 Synaptophysin appears to be more widely expressed than chromogranin A, especially in the lower GI tract. In the stomach, the fundic and antral glands contain different populations of neuroendocrine cells. Enterochromaffinlike (ECL) cells, the predominant neuroendocrine population in the fundus, are few in number, and are located in the deep glands along the basal lamina, in close apposition to the

Fig. 1 – Normal neuroendocrine cells in selected GEP organs: (A) gastric body (arrow); (B) gastric antrum (arrow); (C) small intestine (arrow: neuroendocrine cells and asterisk: Paneth cells); and (D) islet of Langerhans in the pancreas (asterisk). (H&E staining, original magnification  400.)

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parietal and chief cells (Fig. 1A).9 ECL cells secrete histamine, which then stimulates parietal cells to secrete hydrochloric acid. Immunohistochemical staining for histamine and histidine decarboxylase is difficult,10 but vesicular monoamine transporter 2 (VMAT-2) has been successfully used as a specific immunohistochemical marker of ECL cells,11 as has in situ hybridization for histidine decarboxylase.12 ECL cell changes including hyperplasia, dysplasia, and neoplasia have been described in response to hypergastrinemia, since gastrin provides both secretory and trophic stimulation to these cells.13,14 The most abundant neuroendocrine cell in the gastric antrum is the gastrin-secreting G cell, which is located in the neck portion of the pyloric glands. G cells are more abundant than ECL cells (Fig. 1B). G cell secretes gastrin in response to increased pH, which then stimulates the ECL cells to secrete histamine. The gastric fundus generally lacks G cells; thus, a negative gastrin stain is useful to confirm the corpus/fundus origin of a gastric biopsy that lacks distinguishing histologic features. There are at least 15 different types of neuroendocrine cells in the intestines, and the morphology and distribution vary depending on the cell type. Many are seen in the basolateral portion of crypts and are flask-shaped, with dark red basally located secretory granules (Fig. 1C). Serotonin and substance P-producing enterochromaffin (EC) cells are most frequent and are distributed throughout the intestines. L cells, which secrete glucagon-like peptide and pancreatic peptide/peptide YY, are also seen in most portions of the intestines, especially in the distal large bowel. Somatostatin-secreting D cells are

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fairly constant throughout the intestinal tract, while G cells are predominantly located in the proximal duodenum.15 In the pancreas, the neuroendocrine cells in the islets of Langerhans are closely admixed with a delicate capillary network that forms a miniature portal system within each islet (Fig. 1D).16 There are two different types of islets in the pancreas, reflecting their different embryologic origins. The head (including the uncinate process) is largely derived from the ventral bud and mainly contains diffuse islets, which have a trabecular architecture interposing between nests of acinar cells. Diffuse islets are rich in pancreatic polypeptidesecreting PP cells and β cells; α cells are sparse. The pancreatic body and tail, from the dorsal bud, contain more spherical compact islets, which secrete mainly insulin (β cells) and glucagon (α cells), with lesser numbers of somatostatin (δ cells) and pancreatic polypeptide (PP cells). The β cells are concentrated in the center of the islets, while α cells are at the periphery. Normal islet cells are positive for chromogranin with varying intensity (α cells stronger than β cells), in contrast to the uniform staining pattern typically seen in neoplastic conditions.

Terminology for GEP NETs The term “carcinoid” (carcinoma-like) was first introduced in 1907 by Oberndorfer,17 who initially believed that these tumors were benign but later acknowledged that some showed malignant behavior (Fig. 2A). The same term was

Fig. 2 – Examples of well-differentiated NET and poorly differentiated NEC. (A) Well-differentiated NET of the terminal ileum with solid tumor nest and no mitotic figures (previously known as midgut carcinoid tumor, EC cell carcinoid, or type A tumor). (B) Well-differentiated NET of the pancreas with trabecular/ribbon-like growth pattern and no mitotic figures (previously known as islet cell tumor or type B tumor). (C) Poorly differentiated NEC of the ampulla of Vater, resembles small cell carcinoma. (D) Poorly differentiated NEC of the stomach, resembles large cell NEC. (H&E staining, original magnification  400.)

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accepted in the first WHO classification in 1980, except for in the pancreas, where “islet cell tumor” (Fig. 2B) was used.18 Now it is well accepted that all neuroendocrine tumors, with the possible exception of the microadenoma in the pancreas and minute, gastrin-driven type 3 carcinoid tumors in the stomach, are best considered at least low-grade malignant tumors. The terms “carcinoid” and “islet cell tumor” have been criticized as not fully reflecting the malignant behavior of many GEP NETs. Further confusion came from the perception that carcinoid tumors should produce the carcinoid syndrome, which is, for the most part, restricted to a small portion of metastatic serotonin-secreting EC cell tumors. In 1995, Capella et al.8 proposed the more general term, “neuroendocrine tumor,” for less aggressive tumors and “neuroendocrine carcinoma” for tumors showing metastases or gross local invasion. This system was adopted in the revised WHO classification of tumors in 2000 and 2004, except “endocrine” was used instead of “neuroendocrine.”19,20 NET and NEC were kept in the most recent WHO classification in 2010, although the meanings are slightly different. Currently NET is used to describe the well-differentiated tumors, whether or not they exhibit obvious evidence of malignant behavior; while NEC is intended as a synonym for the poorly differentiated neuroendocrine carcinomas related to small cell carcinoma or large cell neuroendocrine carcinoma as defined in the lung.21 It should be pointed out that in the lung and thymus, carcinoid tumor and atypical carcinoid tumor are still the official terms.22

Classification of GEP NETs Historical note In 1963, Williams and Sandler23 proposed a classification scheme based on the embryonic segments: foregut (respiratory tract, thymus, stomach, duodenum, upper jejunum, biliary tract, and pancreas), midgut [lower jejunum and ileum (Fig. 2A), appendix, cecum, and proximal colon] and hindgut (distal colon and rectum). This classification pointed out some clinicopathologic differences depending on the anatomic origin, but the foregut tumors in particular were too heterogeneous to be considered as one entity, which severely limited its practical value.18 Nonetheless, in recent years it has been recognized that NETs of the tubular GI tract are heterogeneous and perhaps should not all be lumped together; perhaps some of the original distinguishing features based on anatomic origin will re-emerge as relevant. In 1971, Soga and Tazawa24 introduced an architectural classification: type A [nodular/solid nest (Fig. 2A)], type B [trabecular/ribbon-like (Fig. 2B)], type C (tubular/acinar/glandular), type D (lower/atypical differentiation), and mixed type. The presence of mixed patterns in many NETs along with the variability in patterns found within individual organs limited the use of this system. In 1980, the WHO published its first classification of NETs. The then-called carcinoid tumors were separated into EC cell carcinoid (Fig. 2A), gastrin cell carcinoid, and other carcinoids.18 Again, those categories were too limited and the classification had no prognostic relevance.

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To overcome the shortcomings of older classifications, Capella et al. proposed a new scheme in 1995. The tumors were separated into four categories based on a number of prognostic factors such as tumor size, angioinvasion, and functioning status: Group 1: well-differentiated NET, benign; Group 2: well-differentiated NET, benign or low-grade malignant; Group 3: well-differentiated NEC, low-grade malignant; and Group 4: poorly differentiated NEC, high-grade malignant.8 The revised WHO classification for luminal GI tumors (2000) and pancreatic tumors (2004) adopted the Capella classification with some modifications. This classification has proven prognostic value in multiple studies.25–28 It should be pointed out that although the terms were similar and the principles were the same between the Capella and WHO 2000/2004 classifications, only the Capella and WHO 2004 classification for pancreatic tumors had clearly defined categories. Furthermore, these classification schemes were hybrid systems which used a combination of grading (proliferation rate) and staging parameters (size, extent of invasion, and metastasis). Follow-up studies of the “uncertain behavior” category of pancreatic NETs revealed a very high rate of disease recurrence, inconsistent with the “uncertain” descriptor. Also, the nomenclature was confusing, since a well-differentiated NET that was localized at presentation would be designated “tumor,” whereas the same tumor would be termed “carcinoma” if it were to metastasize later —a very common occurrence. Lastly, the classification did not provide prognostic stratification for metastatic disease, which clearly varies among patients. To overcome those problems, the European Neuroendocrine Tumor Society (ENETS) proposed a uniform classification scheme for all GEP NETs in 200629 and 2007.30 In this system, all NETs are classified as either well-differentiated NET or poorly differentiated NEC. The former is further graded as low-grade (G1) or intermediate-grade (G2) based on mitotic count and Ki67 labeling index (see below), and the latter corresponds to high-grade (G3), which includes small cell carcinoma and large cell neuroendocrine carcinoma (Fig. 2). A separate TNM staging system was also proposed for each organ. The ENETS grading system was entirely accepted by the AJCC31 and new WHO classification in 201021; while the staging systems were adopted with some modification (see Tables 1 and 2 for examples).

Histologic grading Histologic grading reflects the inherent degree of aggressiveness of a given tumor. Although various systems have been proposed over the years, some of which are organ-specific, all include the proliferative rate as the major component of grading. Proliferative rate is assessed by counting mitotic figures or calculating the proportion of cells by immunolabeling for the proliferation marker Ki67 (the Ki67 index) using the MIB1 antibody. The tumor nuclei in most NETs are fairly uniform, although the NETs may be clinically aggressive; conversely, some very indolent tumors show prominent nuclear pleomorphism (endocrine atypia). Thus, nuclear morphology does not factor into grading of NETs. A grading system using proliferative rate (mitotic count) and necrosis was developed first for pulmonary and thymic

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Table 1 – Comparison of different classification schemes of gastric neuroendocrine neoplasms. Capella (1995)8 (nonfunctional)

WHO (2000)41

ENETS (2006)29 and WHO (2010)21 (grading)

ENETS (2006)29 (T stage)

AJCC (2010)31 (T stage)

Benign Nonfunctioning Up to submucosa No angioinvasion, and ≤ 1 cm

Well-differentiated endocrine neoplasm, benign behavior Nonfunctioning Up to submucosa No angioinvasion o 1 cm, and Types 1 or 2

Well-differentiated NET, G1 or G2

Tis (in situ tumor/ dysplasia) Limited to mucosa, and o 0.5 cm T1 Up to submucosa, and ≤ 1 cm

Tis (in situ tumor/ dysplasia) Limited to mucosa, and o 0.5 cm T1 Up to submucosa, and ≤ 1 cm

Benign or low-grade malignant Nonfunctioning Up to submucosa No angioinvasion, and 1–2 cm, or Angioinvasive and o2 cm

Well-differentiated endocrine neoplasm, aggressive behavior Functioning Beyond submucosa Angioinvasive 4 1 cm, or Type 3

Well-differentiated NET, G1 or G2

T1 T2 Invades muscularis Invades muscularis propria, Invades subserosa, or 4 1 cm

T1 T2 Invades muscularis propria, or Invades muscularis propria, or 4 1 cm

Well-differentiated NET, G1 or G2

T2 T3 (penetrates serosa) T4 (invades adjacent structures)

T2 T3 (invades subserosa) T4 (perforate serosa or other organs/adjacent structures)

Poorly differentiated NEC, G3

Stage as NET

Stage as adenocarcinoma

Low-grade malignant Nonfunctioning Beyond submucosa, or 4 2 cm Functioning High-grade malignant Poorly differentiated

Poorly differentiated NEC High-grade malignant

Note: Due to the different parameters used in different classifications, it is often difficult to find the exact match of categories between them. Thus, the corresponding category listed in the table should be considered as approximate at best.

carcinoid tumors.22,32,33 In pancreatic nonfunctioning NETs, a mitotic count ≥2/10 HPF (high power fields) was found to predict a worse outcome.34 Likewise, the Ki67 index was also associated with prognosis in pancreatic NETs, although the cutoff value to separate low and intermediate grades has varied in different studies from 2%,34 2.5%,35 and 2.6%,36 to 5%.37,38 Hochwald et al.40 proposed a grading scheme for pancreatic NETs using mitotic count (a rate of 2 per 50 HPF to separate low- from intermediate-grade) and necrosis in 2002, which was found to correlate strongly with survival for both primary and metastatic tumors.39 Although the proliferation rate was also mentioned to have prognostic value for some NETs of the tubular GI tract in the 2000 WHO classification, it failed to be included as a grading parameter for welldifferentiated tumors.41 In the 2004 WHO classification of pancreatic NETs, both mitotic count and Ki67 labeling index were used as criteria to distinguish tumors with benign and uncertain behaviors, along with staging parameters (Table 2).20 The unifying grading scheme proposed by ENETS in 2006 and 2007 is based on the proliferative rate (mitoses and Ki67 index) only and applies to all GEP NETs as follows: low-grade or G1 (mitoses ≤2/10 HPF, AND Ki67 index ≤2%); intermediate-grade or G2 (mitoses 2–20/10 HPF, OR Ki67 index 3–20%); and high-grade or G3 (mitoses 420/HPF, OR Ki67 index 420%) (Table 3 and Fig. 3).29,30 When using fractional Ki67 indices, a rate of o3% is regarded as G1. Mitoses should be counted in 40–50 high power fields to ensure accuracy, and

the Ki67 index is to be based on counting 500–2000 cells in the highest labeling regions within the tumor (“hot spots”) identified by scanning at low power. If the two proliferation indices point to different grades, the higher grade should be assigned. The prognostic value of this grading scheme was validated in both primary and metastatic GI tract and pancreatic NETs,42–47 and it was adopted by the AJCC and WHO in 2009 and 2010, respectively. Notably, the category of poorly differentiated NEC (high-grade, G3) corresponds to the highgrade tumor in the earlier classifications, but the proliferation cutoffs are different (Table 3). Necrosis, a prognostic factor in many NETs, is not included in the ENETS/WHO grading scheme. Despite their significantly different prognosis, G1 and G2 NETs are distinguished based on subtle differences in mitosis count and Ki67 index. Thus, it is crucial to accurately determine the mitotic count and Ki67 index, a determination viewed as burdensome and fraught with ambiguity.48 For mitotic counting, 10 HPFs corresponds to an area of 2 mm2 in older models of microscopes. In the newer models (such as Olympus BX40 with a standard 10  / 22 eyepiece), 8.3 HPFs roughly equals 2 mm2. In addition, there is great variability in the size of the tumor cells as well as the amount of stroma; thus, a certain area does not contain the same number of tumor cells in every NET, which may affect the accuracy of mitotic count.49 To date, there have been no studies that express mitotic count as a

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Table 2 – Comparison of different classification schemes of pancreatic neuroendocrine neoplasms. Capella (1995)8 (nonfunctional)

WHO (2004)20

ENETS (2006)29 and WHO (2010)21 (grading)

ENETS (2006)29 (T stage)

AJCC (2010)31 (T stage)

Benign o 2 cm, and No angioinvasion

Well-differentiated NET, benign behavior Confined to pancreas No angioinvasion o 2 cm ≤ 2 mitoses/10 HPF, and ≤ 2% Ki67 index

Well-differentiated NET, G1

T1 Limited to pancreas, and o 2 cm

T1 Limited to pancreas, and ≤ 2 cm

Benign or low-grade malignant 2–3 cm, and No angioinvasion

Well-differentiated NET, uncertain behavior Confined to pancreas, and Angioinvasion, Perineural invasion ≥ 2 cm, 2–10 mitoses/10 HPF, or 4 2% Ki67 index

Well-differentiated NET, G1 or G2

T2 limited to pancreas, and 2–4 cm

T2 Limited to pancreas, and 4 2 cm

Low-grade malignant 4 3 cm, or Angioinvasion

Well-differentiated NET, uncertain behavior

Well-differentiated NET, G1 or G2

T1a, T2 T3 limited to pancreas, and 4 4 cm, or Invades duodenum/bile duct

T1a, T2, or T3 (beyond pancreas)

Well-differentiated NEC Gross local invasion, or Metastasis

Well-differentiated NET, G1 or G2

T1a T2a T3, or T4 [invading adjacent organs (stomach, spleen, colon, and adrenal gland), or large vessel wall]

T1a T2a T3, or T4 (involving celiac axis or superior mesenteric artery)

Poorly differentiated NEC High-grade malignant 4 10 mitoses/10 HPF

Poorly differentiated NEC, G3

Stage as NET

Stage as NET/ adenocarcinoma

High-grade malignant Poorly differentiated

Note: Due to the different parameters used in different classifications, it is often difficult to find the exact match of categories between them. Thus, the corresponding category listed in the table should be considered as approximate at best. a Theoretically, a low T-stage tumor may show angioinvasion and thus would be considered low-grade malignant in the earlier classification, although in practice this is rare.

percentage of the tumor cells (similar to the Ki67 index), rather than a rate per unit area, but intuitively this method would be more reproducible in tumors. Thus, some authors suggest that the Ki67 index is more reliable than mitotic counting.38 Determining the Ki67 index is also problematic, however. Many pathologists employ casual visual inspection (“eyeballing”) rather than rigorous counting of individual cells.48 Eyeballing may be sufficient to separate G1/G2 from obvious G3 tumors (Fig. 3), but it has been criticized as lacking accuracy and reproducibility, especially when dealing with G1 and G2 tumors that differ by only a few percentage points.50 In a study determining the interobserver variability of eyeballing (using a 2000-cell count as the gold standard), the intra-class correlation coefficient for eyeballing was only 0.13 among different observers, and the Kappa statistic was 0.24, indicating only low to moderate agreement.50 Digital image analysis can also be used to more accurately and

objectively determine the Ki67 index, but this technique in not widely available and also has a set of technical issues for optimal implementation.46,49,50 The mitotic count and Ki67 index generally correlate well.35,45 However, in some cases there is a discrepancy between mitotic count and Ki67 index sufficient to change the grade.38,51 In such cases, it is recommended that the higher grade should be applied.21 Recent work has revealed that grade-discordant NETs indeed behave more like the higher grade, which is usually that defined by the Ki67 index rather than the mitotic rate. In one study of pancreatic NETs, the cases with a mitotic rate in the G1 range but a Ki67 index in the G2 range had an outcome similar to those with both indices indicating G2.51 Not only can there be grade discordance between the mitotic rate and the Ki67 index in G1 and G2 NETs, but there are occasionally cases in which the mitotic rate points to a well-differentiated (G1 or G2) NET, but the Ki67 index is over

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Table 3 – Comparison of different criteria proposed for histologic grading of neuroendocrine neoplasms. WHO (2004)22

Moran (2000)33

Hochwald (2002)40

WHO (2004)18

ENETS (2006/2007),29,30 AJCC, (2010)31 and WHO (2010)21 GI, Pancreas

Lung, Thymus

Thymus

Pancreas

Pancreas

G1 MR: o2/10 HPF No necrosis

MR: o3/10 HPF No necrosis

MR: o2/50 HPF No necrosis

MR: o2/10 HPF Ki67: o2% AND othersa

MR: o2/10 HPF Ki67: ≤2% (o3%)

G2 MR: 2–10/10 HPF, or Necrosis

MR: 4–9/10 HPF or Necrosis

MR: 42/50 HPF or Necrosis

MR: 2–10/10 HPF Ki67: 42% OR othersa

MR: 2–20/10 HPF Ki67: 3–20%

G3 MR: 410/10 HPF

MR: 410/10 HPF

NA

MR: 410/10 HPF

MR: 420/10 HPF Ki67: 420%

MR, mitotic rate; NA, not applicable; G1, low-grade, benign behavior, or typical carcinoid (lung); G2, intermediate-grade, uncertain behavior, or atypical carcinoid (lung); G3, high-grade, poorly differentiated NEC. The 2000 WHO classification for GI tract NET consisted mostly of staging parameters thus is not listed in the table (see text). a The 2004 WHO classification for pancreatic NET was a grading/staging hybrid system for which only the grading parameters are listed (see text).

20%, in the range of high-grade neuroendocrine carcinomas (G3).52 In general, such cases retain the cytoarchitectural features of well-differentiated NETs, and the Ki67 is in the 20–50% range, lower than for true poorly differentiated neuroendocrine carcinomas. Follow-up data on these cases reveals

a worse outcome than G2-concordant NETs, but they are not as aggressive as poorly differentiated neuroendocrine carcinomas such as small cell carcinoma and large cell neuroendocrine carcinoma.52 Treatment response data also suggest that this group of NETs with a Ki67 index in the lower end of

Fig. 3 – Neuroendocrine neoplasms of different histologic grades based on 2010 WHO criteria. (A and D) Low-grade (G1) NET with low mitotic rate (0.6/10 HPF) and Ki67 index (0.8%). (B and E) Intermediate-grade (G2) NET with moderate mitotic rate (3.5/ 10 HPF) and Ki67 index (9.6%). (C and F) High-grade NEC (G3) with high mitotic rate (64/10 HPF) and Ki67 index (38%). [(A–C) H&E staining, original magnification  400; (D–F) immunohistochemical staining for Ki67, original magnification  200.]

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the G3 range behave more like well-differentiated NETs. In one study, only neuroendocrine carcinomas with a Ki67 index greater than 55% responded to platinum-based chemotherapy, whereas the tumors in the 20–55% range did not respond.53 These findings raise the possibility that the cutoff points proposed in the ENETS/WHO classification to separate the grades may need to be re-addressed. But before new grading cut-points are introduced, rigorous data must be collected to determine which proliferative rates best separate neuroendocrine neoplasms into clinically relevant groups for prognosis and treatment responsiveness. Furthermore, it is important to record in pathology reports the specific proliferation indices, not simply the grade, so that retrospective reassessment of grades can be more readily performed. Another issue that complicates grading is that the proliferative rate within an individual NET (or among topographically or temporally different sites of disease) may not be uniform. This heterogeneity may manifest only as proliferation “hot spots” that can be found on Ki67 stains, or occasionally there may be corresponding cytologic changes suggesting progression to a more aggressive neoplasm. Variations in the Ki67 index may be sufficient to change the tumor grade in nearly half of well-differentiated NETs (Fig. 4).54 Although both ENETS and WHO recommend that the areas with high Ki67 labeling should be used to determine the grade, supporting data exist but are sparse.46 An additional issue is that biopsy sampling (of a metastatic focus, for example) has the potential to miss higher-grade foci. When

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biopsies were taken from resected hepatic metastases of well-differentiated NETs, it was determined that G2 NETs (based on Ki67 staining of the entire resected tumor) would be misclassified as G1 in 65% of cases if only one biopsy was taken, and in 52% of cases if three biopsies were taken.46 These discrepancies did not affect the accuracy of prognostic stratification for the entire study population, but if treatment decisions for the individual patient are to be made based on the grading of biopsy samples, the issue of heterogeneity of proliferation must be considered.

Staging Despite the obvious importance of stage for prognosis of NETs, formal TNM staging systems did not exist for NETs prior to 2006–2007, when the ENETS proposed staging criteria for NETs of the GI tract and pancreas. Analogous to the staging of carcinomas of the same sites, the parameters used to designate a T stage generally consist of tumor size, depth of invasion, and extent of local invasion. Any number of positive lymph node metastasis is considered N1. Distant metastasis is M1.29,30 A similar (although not identical) system was adopted by the AJCC/UICC in the 2010 staging manual for GI tract NETs (Tables 1, 2, and 4).31 Differences in T-stage parameters between the ENETS and AJCC/UICC systems are most significant for NETs of the appendix and pancreas. Both staging systems have been generally validated in multiple reports,25,35,42,43,55–57 but early comparative

Fig. 4 – Intratumoral heterogeneity in a metastatic well-differentiated pancreatic NET. (A) A high power field shows no mitotic figures; (B) a high power field from another area of the same tumor shows four mitotic figures (H&E staining, original magnification  400). (C) Ki67 staining in the same area as “A” shows a labeling index of o1% (G1); (D) Ki67 staining in the same area as “B” shows a labeling index of 3.4% (G2) (original magnification  200) (Reproduced with permission from Klimstra and Yang49).

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Table 4 – Comparison of selected TNM staging schemes in the ENETS and AJCC systems. Stomach/small intestine

Pancreas

ENETS29,a

AJCC31,b

Stage 0e Stage I

Tis N0 M0 T1 N0 M0

Tis N0 M0 T1 N0 M0

Stage Stage Stage Stage Stage

T2 N0 M0 T3 N0 M0 T4 N0 M0 T1–4 N1 M0 M1

T2 N0 M0 T3 N0 M0 T4 N0 M0 T1–4 N1 M0 M1

IIa IIb IIIa IIIb IV

ENETS29,c Stage Stage Stage Stage Stage Stage Stage Stage

0 Ia Ib IIa IIb IIIa IIIb IV

T1 N0 M0 T2 N0 M0 T3 N0 M0 T4 N0 M0 T1–4 N1 M0 M1

AJCC31,d Tis N0 M0 T1 N0 M0 T2 N0 M0 T3 N0 M0 T1–3 N1 M0 T4 N0/1 M0 M1

a

Similar ENETS staging scheme also applies to pancreas (see right column) and appendix. Similar AJCC staging scheme also applies to colon/rectum. c The ENETS staging scheme does not separate Ia from Ib, and there is no Tis in pancreas. d The AJCC staging scheme for pancreatic NETs is the same as pancreatic adenocarcinoma, and there is no further stratification in stage III. e Stage 0 (Tis) in the luminal GI tract only applies to stomach. b

studies suggest that the ENETS system may more accurately stratify prognosis.58,59

Poorly differentiated neuroendocrine carcinomas Poorly differentiated NECs include small cell carcinoma and large cell neuroendocrine carcinoma, and the ENETS/WHO grading systems implies these are synonymous with G3 neuroendocrine neoplasms. Gastrointestinal and pancreatic NECs are much less common than NETs. Currently, poorly differentiated NECs are defined to have either 420 mitoses/10 HPF or a Ki67 index 420%, although as mentioned above, some morphologically well-differentiated NETs may have a Ki67 index in the low end of this range. Most bona fide poorly differentiated NECs have a proliferative rate based on both mitoses and Ki67 well in excess of these minimal thresholds. They often also show numerous apoptotic bodies and extensive necrosis (Fig. 3C). NECs are very aggressive, frequently showing lymph node and distant metastases at diagnosis and having a dismal prognosis. A review of the GI small cell carcinomas revealed a median survival of 6–12 months60; a more recent series of NEC showed a combined 2-year survival of 25%, with median survival of 15.7 months.61 Morphologically, poorly differentiated NECs of the GI tract and pancreas resemble small cell carcinoma or large cell neuroendocrine carcinoma of the lung. Small cell carcinoma often arises in organs lined by squamous epithelium (esophagus and anorectum), whereas large cell NEC tends to occur in organs with glandular mucosa, frequently associated with adenocarcinoma components.61 Small cell carcinoma is composed of oval or fusiform cells with very high nuclear to cytoplasmic ratio and indistinct cell borders. The nuclei are hyperchromatic, and the chromatin has a finely granular appearance, with inconspicuous nucleoli (Fig. 2C). Large cell NECs often show a nested growth pattern, with round to oval cells containing moderate cytoplasm. The nuclei are much larger, granular, or vesicular, and may contain prominent nucleoli (Fig. 2D). Demonstration of the expression of chromogranin or synaptophysin is required for a diagnosis of large cell NEC.61 Small cell carcinoma is traditionally treated

with platinum-based chemotherapy. Now, the National Comprehensive Cancer Network (NCCN) recommends the same treatment regimen be applied to large cell NEC,62 making the distinction between the two less important. The possibility of progression from a well-differentiated NET to poorly differentiated NEC is still controversial. Although cases with morphological features of a welldifferentiated NET may show regions with a G3 proliferation rate, most retain the cytomorphology of a well-differentiated NET in the more highly proliferative regions, and the proliferation rates are usually in the low end of the G3 range.63 The prognosis and appropriate treatment for such neoplasms is still being determined.

Summary It has been more than 100 years since the first description of carcinoid tumor. Tremendous progress has been made in understanding the clinicopathologic aspects of these tumors, which are accompanied by much confusion, as reflected by diverse terminology and classification schemes. The recent introduction of a separate grading and staging systems provides a standard platform for treatment selection and prognostic stratification, although issues remain. Our understanding of the molecular pathogenesis of NET is just beginning; identification of additional therapeutic targets is expected to guide more sophisticated therapy in the era of precision medicine.

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Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues.

The digestive organs contain a large number of neuroendocrine cells as part of the diffuse neuroendocrine system. Neuroendocrine tumors can occur in e...
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