PATHOLOGY OF GASTROINTESTINAL NEUROENDOCRINE TUMORS: AN UPDATE Roger K. Moreira, MDa, Kay Washington, MD, PhDb,* KEYWORDS Gastrointestinal Neuroendocrine Carcinoid
G
astrointestinal (GI) neuroendocrine tumors (NETs) are a heterogeneous group of relatively slow-growing neoplasms with marked site-specific differences in hormonal secretion and clinical behavior. Most are sporadic neoplasms, with only 5% to 10% arising in patients with hereditary disorders, most commonly in multiple endocrine neoplasia type 1. Although a uniform terminology is not universally accepted, use of the 4-category World Health Organization classification of these tumors is becoming more widespread, and recommendations for tumor grading and staging have been recently formulated. Most GI NETs are easily recognized on routine histologic examination; rarely, a limited panel of immunohistochemical markers may be useful in establishing the diagnosis. This article describes general and site-specific features of these tumors and outlines potential pitfalls in diagnosis.
GASTROINTESTINAL NEUROENDOCRINE TUMORS OVERVIEW The term gastrointestinal neuroendocrine tumor (GI NET) refers to a low-grade neoplasm arising
from the diffuse neuroendocrine system scattered throughout the mucosa of the gut. Such tumors have historically been called carcinoid tumors, terminology that is recognized as archaic and ambiguous but still widely used in clinical practice and in tumor registries. Although not in universal usage, the term neuroendocrine is preferred rather than the term endocrine because of shared antigens between neural elements and these cells of the diffuse endocrine system in the GI tract, such as neuron-specific enolase, chromogranins, synaptophysin, and protein gene product 9.5.1 The neuroendocrine cells that give rise to GI NETs are epithelial cells derived from the same stem cells as other epithelial cell lineages in the GI tract, such as enterocytes, Paneth cells, and goblet cells; at least 15 morphologically and functionally distinct GI neuroendocrine cell types producing different hormones have been identified.2 In general, the differentiation pattern of GI NETs reflects the profile of neuroendocrine cells normally located in that part of the GI tract. GI NETS arise as a result of molecular events in progenitor cells that are neuroendocrine committed but not necessarily terminally differentiated. This concept helps explain why certain NETs are more homogeneous, with a dominant hormonal secretory pattern reflecting that of normal neuroendocrine cells in the location in
Disclosures: This project was supported by grant number P50CA095103 from National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. a Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY 20032, USA b Department of Pathology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 32732, USA * Corresponding author. E-mail address: [email protected] Surgical Pathology 3 (2010) 327–347 doi:10.1016/j.path.2010.05.003 1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
surgpath.theclinics.com
ABSTRACT
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Key Features GASTROINTESTINAL NEUROENDOCRINE TUMORS 1. The most common sites for GI NETs are stomach, appendix, and rectum. 2. Many NETs are asymptomatic and are discovered incidentally. 3. Clinical behavior of GI NETs varies with tumor site; NETs of the appendix and rectum are usually benign; ileal and colonic NETs behave in a more aggressive fashion. 4. Histologic feature of low-grade GI NETs are similar in all sites, including various growth patterns (insular, trabecular, or solid, often with pseudorosette formation) and characteristic cytologic features (round, uniform nuclei, with salt-and-pepper type chromatin and small inconspicuous nucleoli). Poorly differentiated NETs may be more difficult to recognize as neuroendocrine and histologically resemble a poorly differentiated adenocarcinoma or extrapulmonary small cell adenocarcinoma. 5. Special types of NETs occur most often in the duodenum (periampullary somatostatinoma: prominent glandular formation, intraluminal mucin, psammoma bodies) and appendix (goblet cell carcinoids and tubular carcinoids). 6. Ancillary tests are rarely indicated but a panel of immunohistochemical markers (most commonly synaptophysin and chromogranin) may be useful in select cases.
molecular pathways involved in neuroendocrine neoplasia. For instance, the MEN1 gene is mutated in up to 40% of sporadic GI and pancreatic NETs.4 Molecular events seem to be different in GI NETs arising in different sites, with foregut tumors often showing loss of 11q, the site of MEN1, in contrast to hindgut tumors which often show losses on 18q.5 Progress in understanding the molecular pathways involved has been hindered by the small number of cases studied and the complex and heterogeneous pathobiology of these tumors, but recent work suggests that CpG island methylation is an important pathway in sporadic GI NETs.6
EPIDEMIOLOGY Analysis of more than 13,000 carcinoid tumors reported to the Surveillance, Epidemiology, and End Results (SEER) database from 1950 to 1999 suggests that the incidence of these tumors is increasing in the US population7; however, it is not clear if the marked increase in gastric and rectal carcinoids is related to changes in tumor registry reporting, improvements in diagnosis, or to a true increase in these tumor types. These tumors are relatively rare, with the incidence for all GI NETs estimated as 2.0/100,000 for men and 2.4/100,000 for women.2 Average age for diagnosis for all carcinoid tumors was 61 years in the SEER data set. Rectal carcinoids are more prevalent among black and Asian populations in the United States. Five-year survival rates are best for appendiceal and rectal NETs.
CLINICAL FEATURES which they arise, and others secrete multiple hormones or lack apparent hormonal functionality. For instance, enterochromaffin-like (ECL) cell NETs arise almost exclusively in the stomach, paralleling the normal distribution of ECL cells. Although GI NETs are derived from epithelial stem cells of the gut, investigations of the neoplastic progression for these tumors have shown that they do not share the same molecular alterations as GI adenocarcinomas, and infrequently show microsatellite instability or abnormalities of Wnt signaling.3
MOLECULAR EVENTS Although only 5% to 10% of GI NETs are linked to hereditary syndromes (generally autosomal dominantly inherited syndromes resulting from mutations in tumor suppressor genes, Table 1), such cases have afforded important insights into
The clinical behavior of GI NETs varies with their location in the GI tract. Small non–gastrinsecreting tumors are usually clinically silent and may be discovered only at autopsy or resection for other indications. When symptoms are attributable to GI NETs, they are caused by local tumor effects such as adhesions or abdominal fibrosis giving rise to abdominal pain or small bowel obstruction, or to secretion of bioactive substances such as serotonin, histamine, or gastrin. The carcinoid syndrome (cutaneous flushing of upper chest, neck and face; gut hypermotility with diarrhea) occurs in less than 10% of patients.5 Diagnostic strategies for patients suspected of having GI NETs include biochemical testing for urinary 5-hydroxyindoleacetic acid or serum testing for increased chromogranin A levels, followed by localization of the tumor by octreoscan scintigraphy, positron emission tomography, or other radiographic imaging techniques.5
Table 1 Hereditary syndromes associated with GI NETs Inheritance and Prevalence
Gene
Gene Product and Function
Multiple endocrine neoplasia type 1
Autosomal dominant; w1:20,000 to 1:40,000
MEN; chromosome 11q13
Menin; controls cell growth and differentiation during development
Neurofibromatosis type 1
Autosomal dominant; w1:4500
NF1; chromosome 17q11.2
Neurofibromin; tumor suppressor functions
Von Hippel-Lindau syndrome
Autosomal dominant; w1:36,000
VHL, chromosome 3p25
VHL; multiple functions
Tuberous sclerosis complex
Autosomal dominant; 1:10,000
TSC1, 9q34 TSC2, 16p13.3
Hamartin Tuberin Tumor suppressor functions
GI NETs
Major Tumor Sites
Stomach and duodenum (gastrinomas); associated with Zollinger-Ellison syndrome; pancreas 1% of patients; usually duodenum/ampulla; express somatostatin but not associated with functional syndromes Pancreatic NETs in 5% to 17%, usually nonfunctioning clear cell tumors Pancreatic NETs (rare)
Anterior pituitary, parathyroid, adrenal cortex, lung
Neurofibromas
Renal cell carcinoma, hemangioblastoma, pheochromocytoma Hamartomatous lesions in brain, skin, eye, heart, lung, kidney
Data from Toumpanakis CG, Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol 2008;103(3):729–32.
GI Neuroendocrine Tumors
Syndrome
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Moreira & Washington GI NETs, most commonly ileal tumors, are associated with second primary tumors, usually discovered synchronously, in about 17% of patients. The most common site for second primary tumors is the GI tract, followed by genitourinary tract and lung. These synchronous tumors are generally of higher grade than the GI NET, which may be discovered during staging workup of the associated second primary malignancy.8
TERMINOLOGY There is no single unified terminology for GI NETS. Many pathologists in the United States still use the term carcinoid to describe all low-grade NETs, regardless of tumor site, and some use the term atypical carcinoid to refer to GI NETs with focal necrosis or increased mitotic activity. However, the atypical carcinoid has not been rigorously defined for GI tumors and this nomenclature is not in widespread use. The term carcinoid has fallen out of favor because of its failure to encompass the full biologic spectrum and site-specific heterogeneity of these tumors, as well as the narrow interpretation of this term to mean a serotonin-producing tumor associated with carcinoid syndrome.9 The World Health Organization, although retaining the carcinoid terminology in the 2000 publication on classification of tumors of the digestive system,10 also outlines a 3tier system11 classifying these neoplasms as welldifferentiated NETs of benign or uncertain malignant potential, well-differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine
carcinoma. This system has gained more acceptance among European pathologists and has the advantage of being more biologically oriented than the umbrella term carcinoid, although this terminology can be cumbersome to apply to individual cases.
GROSS FEATURES GI NETs grossly are firm tan to pale yellow nodules located just beneath the mucosal surface. The muscularis propria may be thickened in the area of tumor, perhaps as a result of secretion of trophic factors by the tumor cells (Fig. 1). Dense fibrotic stroma associated with the tumor cells may produce annular strictures, and mesenteric fibrosis may be seen in small bowel NETs. Ischemic injury secondary to vascular sclerosis may also be seen in small bowel tumors (Fig. 2).12 Extensive lymphatic involvement by tumor is manifested as small yellow nodules on the serosal surface. Multicentricity is common and is site-related; gastric and jejunoileal tumors (33%) are more commonly multiple, whereas multiplicity is rare with colonic or appendiceal NETs. Molecular studies have shown that most multiple GI NETs are independent primaries.13
MICROSCOPIC FEATURES Most GI NETs are readily recognizable as lowgrade NETs. They are composed of solid nests, cords, trabeculae, and glands of relatively uniform cells with round to oval nuclei with finely granular Fig. 1. Low-grade neuroendocrine neoplasms of the GI tract grossly appear as yellow plaques; thickening of the bowel wall as a result of fibrosis and smooth muscle hyperplasia may be seen, as in this example of an ileal tumor.
GI Neuroendocrine Tumors Fig. 2. Elastosis of mesenteric vessels, visible as acellular thickening of vessels walls (A) with duplication of the internal elastic lamina and adventitial elastosis on elastin stain (B) may cause bowel ischemia. These mesenteric vascular changes are primarily associated with ileal NETs.
chromatin and inconspicuous nucleoli (Fig. 3). Less commonly, cystic, tubular, or angiomatoid patterns may be seen. The cytoplasm is generally pale, but in some cases fine red granules are detectable (Fig. 4). Cytologic variants include clear cell NETs (generally found in the pancreas in patients with von Hippel-Lindau disease), and oncocytic and rhabdoid appearances. Large areas of tumor necrosis are uncommon and when present signify a higher-grade tumor, but punctate coagulative necrosis may be seen in larger low-grade tumors (Fig. 5). Perineural and lymphovascular invasion are associated with more aggressive behavior14 (see Fig. 5B, C) and are generally not seen in small low-grade tumors.
PRECURSOR LESIONS Endocrine cell hyperplasia is most commonly seen in the GI tract in the stomach in the setting of hypergastrinemia and chronic atrophic gastritis.15 Duodenal gastrin-producing cells undergo a similar hyperplasia in patients with Zollinger-Ellison syndrome caused by multiple endocrine neoplasia (MEN) type 1. Hyperplastic lesions of the GI neuroendocrine system have been divided for research purposes into diffuse, linear, and nodular patterns; the distinction between nodular hyperplasia and dysplasia is made by size, with dysplastic (preinvasive) lesions measuring between 90 and 210 mm. Gastrin or somatostatin-producing lesions in the
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Moreira & Washington Fig. 3. Low-grade GI NETs are composed of cords, trabeculae, and solid nests of relatively uniform cells with oval finely granular chromatin, typical of neuroendocrine differentiation.
duodenum and measuring larger than 210 mm are classified as GI NETs; microinvasion is recognized by the identification of small clusters of neuroendocrine cells localized in the lamina propria between glands and associated with stromal alterations such as thickened collagen.16 Although appendix, ileum, and rectum are common locations for GI NETs, endocrine cell hyperplasia and dysplastic lesions are rarely encountered in these sites, and in general sporadic NETs lack identifiable precursor lesions. Neuroendocrine cell hyperplasia and multiple GI NETs have been reported in the setting of ulcerative colitis17 and Crohn disease, and are associated with epithelial dysplastic changes in some cases.18
markers of neuroendocrine differentiation (Table 2) may be helpful in selected cases. Cytosolic markers such as neuron-specific enolase and CD56 are highly sensitive but relatively nonspecific for neuroendocrine differentiation. Synaptophysin,
Differential Diagnosis OF GI NETS Gastric NETs Type 1 and 2 (ECL) NETs Sporadic (type 3)
DIFFERENTIAL DIAGNOSIS Although most GI NETs do not present a diagnostic problem, tumors with a glandular growth pattern may be erroneously diagnosed as adenocarcinoma. Low-grade GI NETS should not be confused with high-grade neuroendocrine carcinoma or mixed high-grade adenocarcinoma/ neuroendocrine carcinoma, both of which are associated with poor prognosis. In the rectum, locally invasive prostatic adenocarcinoma may be confused with an NET but knowledge of the clinical history and endoscopic appearance are helpful in avoiding this pitfall.
DIAGNOSIS Most GI NETs do not require use of special stains or immunohistochemical studies for diagnosis. However, a panel of immunohistochemical
Type 4 (high-grade carcinoma)
neuroendocrine
Duodenal and ampullary NETs Gastrinoma Somatostatinoma Nonfunctioning NETs Appendiceal NETs Goblet cell carcinoid Tubular carcinoid Adenocarcinoma Ileal NETs Colorectal NETs
GI Neuroendocrine Tumors Fig. 4. Red cytoplasmic granules are prominent in some GI NETs.
a marker associated with small vesicles, has the advantage of higher specificity, although retaining high sensitivity. The secretory granule marker chromogranin A is widely used and is highly specific for neuroendocrine differentiation (Fig. 6), but is not uniformly expressed among the different endocrine cell types, and is often negative in appendiceal and rectal NETs. Highergrade NETs may be negative for chromogranin A expression, or display only focal positivity. Immunohistochemical findings should be interpreted in the context of the overall microscopic appearance of the lesion, and it is advisable to use a panel of markers rather than a single marker. In practice, the most widely used panel is synaptophysin and chromogranin A, although in some instances low-grade NETs are negative for both markers. The pathologist may also be asked to determine likely sites of origin of NET metastatic to the liver; in such cases, octreoscan scintigraphy is superior to histopathologic assessment. However, expression of CDX2 has been reported in up to 80% of GI NETs, more commonly in tumors arising in the ileum and appendix, and seems to be a useful marker for NETs of GI origin,19 although gastric NETs are frequently negative. Neuroendocrine secretory protein-55, a member of the chromogranin family of proteins found in dense core granules, has been reported to be expressed by NETs of the pancreas and adrenal medulla but not NETs of GI and lung origin.20 Cell-specific markers such as gastrin or somatostatin may be useful in subtyping GI NETs, but immunohistochemical expression of such hormones does not determine functional status
of the tumor, which is defined by clinical manifestations. However, subtle clinical signs of overproduction of such hormones may be overlooked in the preoperative setting and only recognized retrospectively on diagnosis of a GI NET.
STAGING AND PROGNOSTIC MARKERS According to the 2000 WHO classification,11 GI NETs are classified into 4 categories, based on a combination of gross, histologic, and immunohistochemical features (Table 3): 1. Well-differentiated NET of probable benign behavior 2. Well-differentiated NET of uncertain malignant behavior 3. Well-differentiated neuroendocrine carcinoma 4. Poorly differentiated neuroendocrine carcinoma. Recently, TNM classification systems for foregut and hindgut NETs have been proposed by the European Neuroendocrine Tumor Society.21,22 For foregut and hindgut NETs, the T category is assigned based on tumor size, depth of penetration into the bowel wall, and invasion of adjacent structures, according to specific tumor site (see Refs.20,21 for details). In situ carcinoma (Tis) is recognized for gastric lesions less than 0.5 cm in this classification system. N and M categories are assigned based on the presence or absence of regional lymph node (N0–N1) or distant (M0– M1) metastases, respectively. A final stage is assigned according to the combination of T, N, and M categories. The European Neuroendocrine Tumor Society21,22 has also proposed a grading system (Table 4), in
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Fig. 5. Focal areas of coagulative necrosis (A), perineural invasion (B), and lymphovascular invasion (C) are associated with more aggressive behavior in GI NETs.
GI Neuroendocrine Tumors which GI NETs are classified in 3 different categories based on mitotic counts and/or Ki-67 tumor labeling index. G1 and G2 tumors usually correspond to welldifferentiated NETs, whereas G3 indicates a poorly differentiated carcinoma. Preliminary validation studies for this proposed staging system23 using a data set of 202 patients have demonstrated prognostic relevance of staging and grading of lesions for foregut and pancreatic tumors. A recently proposed staging system using similar parameters (depth of tumor invasion, tumor size, lymph node metastases, and distant metastases) also seems to provide useful overall survival estimates when applied to a set of 108 GI NETs from all GI sites.24
SITE-SPECIFIC FEATURES Gastric NETs Gastric NETs form a relatively heterogeneous group of neoplasms because of the diverse population of native neuroendocrine cells in this organ. Tumors may arise from these cell types in a variety of clinical settings, and have been classified in 4 subtypes (Table 5). Types 1 and 2 tumors are ECL cell neoplasms that arise in the setting of hypergastrinemia. Type 1 tumors, by far the most common, are seen in patients with body-predominant atrophic gastritis and hypergastrinemia secondary to hypochlorhydria. These patients develop ECL cell
hyperplasia (Fig. 7), which may progress to true NETs, often multifocal (Fig. 8).25 The prognosis of type 1 tumors is usually favorable, and they can safely be resected endoscopically. In rare cases, more aggressive behavior and lymph node metastases are seen, usually associated with tumors larger than 2 cm and with infiltration of the gastric wall.26 Type 2 tumors are seen in patients with hypergastrinemia caused by gastrin-producing tumors at other sites, such as the duodenum, pancreas, or porta hepatis region (gastrinomas), often in association with Zollinger-Ellison syndrome and MEN-1. Through similar mechanisms as for type 1 tumors, these patients will develop ECL cell hyperplasia and neuroendocrine neoplasms. Like type 1 tumors, type 2 neoplasms usually behave in a benign fashion. Metastatic disease occurs in approximately 10% of cases, usually in tumors larger than 2 cm and with invasion of the muscularis propria.26 Type 3 tumors are defined as sporadic ECL cell neoplasms (ie, not associated with hypergastrinemia). As in types 1 and 2, type 3 tumors occur preferentially in the body and fundic regions, but tend to be solitary rather than multiple.25 Type 3 tumors are frequently larger than 2 cm and carry a worse prognosis compared with types 1 and 2, especially if associated with muscularis propria infiltration and vascular invasion, in which case metastases are likely to be present. Type 4 tumors are poorly differentiated neuroendocrine carcinomas. These tumors are distributed throughout the
Table 2 Immunohistochemistry of GI NETs
Site
Immunohistochemistry Chromogranin A Neuron-specific enolase Synaptophysin Serotonin Other immunohistochemical markers
Carcinoid syndrome
Foregut Tumors
Midgut Tumors
Stomach, proximal duodenum
Jejunum, ileum, Distal colon, rectum appendix, proximal colon
86%–100% 1 90%–100% 1 50% 1 33% 1 Rarely, 1 for pancreatic polypeptide, histamine, gastrin, VIP, or corticotropin Rare
82%–92% 1 95%–100% 1 95%–100% 1 86% 1 Prostatic acid phosphatase 1 in 20%–40%
40%–58% 1 80%–87% 1 94%–100% 1 45%–83% 1 Prostatic acid phosphatase 1 in 20%–82%
5%–39%
Rare
Abbreviation: VIP, vasoactive intestinal peptide. Data from Refs.55–61
Hindgut Tumors
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Moreira & Washington Fig. 6. Most low-grade GI NETs are strongly positive for chromogranin A, a component of neurosecretory granules, but roughly 50% of hindgut tumors are negative for this marker of neuroendocrine differentiation.
stomach, are more commonly diagnosed at a more advanced stage (>4 cm), and often present with extensive metastases.2 The prognosis is, therefore, poor, with most patients dying within 1 year of diagnosis.26 Like poorly differentiated neuroendocrine carcinomas elsewhere, type 4 tumors are positive
for synaptophysin but often negative for chromogranin A by immunohistochemistry.
NETs of the Duodenum and Upper Jejunum The percentage of duodenal and upper jejunal NETs in relation to all GI NETs ranges from 3% in
Table 3 WHO criteria for classification and assessment of the biologic behavior of GI NETs
Biologic Behavior Well-differentiated NET, probably benign Well-differentiated NET, uncertain behavior Well-differentiated neuroendocrine carcinoma, lowgrade malignant behavior Poorly differentiated neuroendocrine carcinoma, highgrade malignant behavior
Invasion of Muscularis Histologic Tumor Angio- Ki-67 Hormonal Differentiation Size (cm) Invasion Index (%) Syndrome Metastasis Propria
WD
%1a
2
1
1
1
PD
Any
1
>30
Abbreviations: PD, poorly differentiated; WD, well differentiated. a Exception: malignant duodenal gastrinomas are usually smaller than 1 cm and confined to the submucosa. b Exception: benign neuroendocrine tumors of the appendix usually invade the muscularis propria.
GI Neuroendocrine Tumors
Table 4 Grading of GI NETs
Grade
Mitotic Count (10 hpf)
Ki-67 Index (%)
G1 G2 G3
20
%2 3–20 >20
Data from Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395–401; and Rindi G, Kloppel 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(4):757–62.
studies that included old tumor databases7,27 to 22% in recent series.28 These tumors show a slight male predominance (1.5:1) and usually affect patients in their fifth and sixth decade.26 Five distinct types of NETs are recognized in this location: gastrinomas, which account for approximately two-thirds of all NETs, followed by somatostatinomas, nonfunctioning (nonsyndromic) serotonin- and calcitonin-producing tumors,
poorly differentiated neuroendocrine carcinomas, and gangliocytic paragangliomas.2 Gastrinomas can either occur sporadically (75% of cases) or in association with MEN-1 (25% of cases).29 By definition, gastrinomas are associated with increased serum levels of gastrin, and two-thirds of the patients present with ZollingerEllison syndrome. Although gastrinomas may occur in several different sites, they are usually located in the so-called gastrinoma triangle, and approximately 70% occur in the duodenum. Sporadic tumors are solitary and have no identifiable precursor lesions, whereas tumors arising in the setting of MEN-1 are usually multifocal and are believed to originate from an underlying precursor lesion (ie, G-cell hyperplasia).16 Duodenal gastrinomas are usually small lesions, usually measuring less than 1 cm in diameter and located in the first portion of the duodenum. Histologically, they show a mixture of histologic growth patterns, often with a trabecular and pseudoglandular architecture.26 In spite of their small size and lack of muscularis invasion, gastrinomas often have an aggressive behavior, with early regional lymph node metastases. Therefore, gastrinomas should be considered potentially malignant regardless of other features.
Table 5 Types of gastric NETs Type 1
Type 2
Type 3
Type 4
Frequency Multiplicity Size
70%–80% of cases Multifocal 0.5–1.0 cm
Rare Multifocal w1.5 cm or less
Rare Solitary Large
Location
Corpus
Corpus
10%–15% of cases Solitary Variable; one-third larger than 2 cm Any where in stomach
Associations
Hypergastrinemic Multiple endocrine states; chronic neoplasia type 1, atrophic gastritis, with ZollingerECL hyperplasia Ellison syndrome Usually benign 30% metastasize
Clinical behavior
Demographic 70%–80% are profile female, 500 s-600 s
Sporadic
Anywhere in stomach Sporadic
71% of tumors >2 cm High-grade with muscularis carcinoma; propria and vascular metastases invasion have lymph common; node metastases poor prognosis Equally in men and More common in men, More common women, mean age mean age 55 years in men 50 years
Data from Graeme-Cook F. Neuroendocrine tumors of the GI tract and appendix. In: Odze RD, Goldblum JR, Crawford JM, editors. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia: Saunders; 2004. p. 483–504; and Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology 2007;50(1):30–41.
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Moreira & Washington Fig. 7. ECL cell hyperplasia may be prominent in long-standing chronic atrophic gastritis associated with hypergastrinemia, and is best visualized with synaptophysin (shown) or chromogranin A immunohistochemistry.
Duodenal somatostatinomas represent 15% to 20% of duodenal NETs26,30 and about 1% of all gastroenteropancreatic NETs.31 They are predominantly located in the periampullary region, and are associated with type 1 neurofibromatosis (von Recklinhausen disease) in up to one-third of the cases, as well as with MEN-1.32 Originally named glandular duodenal carcinoids, this tumor shows characteristic histologic findings that include prominent glandular architecture with intraluminal mucinous material, simulating an epithelial tumor, as well as the presence of psammoma bodies in
most cases (Fig. 9). The cytologic features of a NET (ie, round, uniform nuclei, with salt-andpepper chromatin, and abundant cytoplasm) are morphologic clues on sections stained with hematoxylin and eosin. Immunohistochemistry for somatostatin is positive in almost all cases, although associated somatostatin syndrome (diabetes, achlorhydria, cholelithiasis, and diarrhea) is rarely present. Muscularis propria invasion seems to be a poor prognostic feature, associated with lymph node metastasis. Duodenal/periampullary somatostatinomas do not seem to be related
GI Neuroendocrine Tumors Fig. 8. Type 1 gastric NETs arising in hypergastrinemia are usually small (
G
astrointestinal (GI) neuroendocrine tumors (NETs) are a heterogeneous group of relatively slow-growing neoplasms with marked site-specific differences in hormonal secretion and clinical behavior. Most are sporadic neoplasms, with only 5% to 10% arising in patients with hereditary disorders, most commonly in multiple endocrine neoplasia type 1. Although a uniform terminology is not universally accepted, use of the 4-category World Health Organization classification of these tumors is becoming more widespread, and recommendations for tumor grading and staging have been recently formulated. Most GI NETs are easily recognized on routine histologic examination; rarely, a limited panel of immunohistochemical markers may be useful in establishing the diagnosis. This article describes general and site-specific features of these tumors and outlines potential pitfalls in diagnosis.
GASTROINTESTINAL NEUROENDOCRINE TUMORS OVERVIEW The term gastrointestinal neuroendocrine tumor (GI NET) refers to a low-grade neoplasm arising
from the diffuse neuroendocrine system scattered throughout the mucosa of the gut. Such tumors have historically been called carcinoid tumors, terminology that is recognized as archaic and ambiguous but still widely used in clinical practice and in tumor registries. Although not in universal usage, the term neuroendocrine is preferred rather than the term endocrine because of shared antigens between neural elements and these cells of the diffuse endocrine system in the GI tract, such as neuron-specific enolase, chromogranins, synaptophysin, and protein gene product 9.5.1 The neuroendocrine cells that give rise to GI NETs are epithelial cells derived from the same stem cells as other epithelial cell lineages in the GI tract, such as enterocytes, Paneth cells, and goblet cells; at least 15 morphologically and functionally distinct GI neuroendocrine cell types producing different hormones have been identified.2 In general, the differentiation pattern of GI NETs reflects the profile of neuroendocrine cells normally located in that part of the GI tract. GI NETS arise as a result of molecular events in progenitor cells that are neuroendocrine committed but not necessarily terminally differentiated. This concept helps explain why certain NETs are more homogeneous, with a dominant hormonal secretory pattern reflecting that of normal neuroendocrine cells in the location in
Disclosures: This project was supported by grant number P50CA095103 from National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. a Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY 20032, USA b Department of Pathology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 32732, USA * Corresponding author. E-mail address: [email protected] Surgical Pathology 3 (2010) 327–347 doi:10.1016/j.path.2010.05.003 1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
surgpath.theclinics.com
ABSTRACT
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Moreira & Washington
Key Features GASTROINTESTINAL NEUROENDOCRINE TUMORS 1. The most common sites for GI NETs are stomach, appendix, and rectum. 2. Many NETs are asymptomatic and are discovered incidentally. 3. Clinical behavior of GI NETs varies with tumor site; NETs of the appendix and rectum are usually benign; ileal and colonic NETs behave in a more aggressive fashion. 4. Histologic feature of low-grade GI NETs are similar in all sites, including various growth patterns (insular, trabecular, or solid, often with pseudorosette formation) and characteristic cytologic features (round, uniform nuclei, with salt-and-pepper type chromatin and small inconspicuous nucleoli). Poorly differentiated NETs may be more difficult to recognize as neuroendocrine and histologically resemble a poorly differentiated adenocarcinoma or extrapulmonary small cell adenocarcinoma. 5. Special types of NETs occur most often in the duodenum (periampullary somatostatinoma: prominent glandular formation, intraluminal mucin, psammoma bodies) and appendix (goblet cell carcinoids and tubular carcinoids). 6. Ancillary tests are rarely indicated but a panel of immunohistochemical markers (most commonly synaptophysin and chromogranin) may be useful in select cases.
molecular pathways involved in neuroendocrine neoplasia. For instance, the MEN1 gene is mutated in up to 40% of sporadic GI and pancreatic NETs.4 Molecular events seem to be different in GI NETs arising in different sites, with foregut tumors often showing loss of 11q, the site of MEN1, in contrast to hindgut tumors which often show losses on 18q.5 Progress in understanding the molecular pathways involved has been hindered by the small number of cases studied and the complex and heterogeneous pathobiology of these tumors, but recent work suggests that CpG island methylation is an important pathway in sporadic GI NETs.6
EPIDEMIOLOGY Analysis of more than 13,000 carcinoid tumors reported to the Surveillance, Epidemiology, and End Results (SEER) database from 1950 to 1999 suggests that the incidence of these tumors is increasing in the US population7; however, it is not clear if the marked increase in gastric and rectal carcinoids is related to changes in tumor registry reporting, improvements in diagnosis, or to a true increase in these tumor types. These tumors are relatively rare, with the incidence for all GI NETs estimated as 2.0/100,000 for men and 2.4/100,000 for women.2 Average age for diagnosis for all carcinoid tumors was 61 years in the SEER data set. Rectal carcinoids are more prevalent among black and Asian populations in the United States. Five-year survival rates are best for appendiceal and rectal NETs.
CLINICAL FEATURES which they arise, and others secrete multiple hormones or lack apparent hormonal functionality. For instance, enterochromaffin-like (ECL) cell NETs arise almost exclusively in the stomach, paralleling the normal distribution of ECL cells. Although GI NETs are derived from epithelial stem cells of the gut, investigations of the neoplastic progression for these tumors have shown that they do not share the same molecular alterations as GI adenocarcinomas, and infrequently show microsatellite instability or abnormalities of Wnt signaling.3
MOLECULAR EVENTS Although only 5% to 10% of GI NETs are linked to hereditary syndromes (generally autosomal dominantly inherited syndromes resulting from mutations in tumor suppressor genes, Table 1), such cases have afforded important insights into
The clinical behavior of GI NETs varies with their location in the GI tract. Small non–gastrinsecreting tumors are usually clinically silent and may be discovered only at autopsy or resection for other indications. When symptoms are attributable to GI NETs, they are caused by local tumor effects such as adhesions or abdominal fibrosis giving rise to abdominal pain or small bowel obstruction, or to secretion of bioactive substances such as serotonin, histamine, or gastrin. The carcinoid syndrome (cutaneous flushing of upper chest, neck and face; gut hypermotility with diarrhea) occurs in less than 10% of patients.5 Diagnostic strategies for patients suspected of having GI NETs include biochemical testing for urinary 5-hydroxyindoleacetic acid or serum testing for increased chromogranin A levels, followed by localization of the tumor by octreoscan scintigraphy, positron emission tomography, or other radiographic imaging techniques.5
Table 1 Hereditary syndromes associated with GI NETs Inheritance and Prevalence
Gene
Gene Product and Function
Multiple endocrine neoplasia type 1
Autosomal dominant; w1:20,000 to 1:40,000
MEN; chromosome 11q13
Menin; controls cell growth and differentiation during development
Neurofibromatosis type 1
Autosomal dominant; w1:4500
NF1; chromosome 17q11.2
Neurofibromin; tumor suppressor functions
Von Hippel-Lindau syndrome
Autosomal dominant; w1:36,000
VHL, chromosome 3p25
VHL; multiple functions
Tuberous sclerosis complex
Autosomal dominant; 1:10,000
TSC1, 9q34 TSC2, 16p13.3
Hamartin Tuberin Tumor suppressor functions
GI NETs
Major Tumor Sites
Stomach and duodenum (gastrinomas); associated with Zollinger-Ellison syndrome; pancreas 1% of patients; usually duodenum/ampulla; express somatostatin but not associated with functional syndromes Pancreatic NETs in 5% to 17%, usually nonfunctioning clear cell tumors Pancreatic NETs (rare)
Anterior pituitary, parathyroid, adrenal cortex, lung
Neurofibromas
Renal cell carcinoma, hemangioblastoma, pheochromocytoma Hamartomatous lesions in brain, skin, eye, heart, lung, kidney
Data from Toumpanakis CG, Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol 2008;103(3):729–32.
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Syndrome
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Moreira & Washington GI NETs, most commonly ileal tumors, are associated with second primary tumors, usually discovered synchronously, in about 17% of patients. The most common site for second primary tumors is the GI tract, followed by genitourinary tract and lung. These synchronous tumors are generally of higher grade than the GI NET, which may be discovered during staging workup of the associated second primary malignancy.8
TERMINOLOGY There is no single unified terminology for GI NETS. Many pathologists in the United States still use the term carcinoid to describe all low-grade NETs, regardless of tumor site, and some use the term atypical carcinoid to refer to GI NETs with focal necrosis or increased mitotic activity. However, the atypical carcinoid has not been rigorously defined for GI tumors and this nomenclature is not in widespread use. The term carcinoid has fallen out of favor because of its failure to encompass the full biologic spectrum and site-specific heterogeneity of these tumors, as well as the narrow interpretation of this term to mean a serotonin-producing tumor associated with carcinoid syndrome.9 The World Health Organization, although retaining the carcinoid terminology in the 2000 publication on classification of tumors of the digestive system,10 also outlines a 3tier system11 classifying these neoplasms as welldifferentiated NETs of benign or uncertain malignant potential, well-differentiated neuroendocrine carcinoma, and poorly differentiated neuroendocrine
carcinoma. This system has gained more acceptance among European pathologists and has the advantage of being more biologically oriented than the umbrella term carcinoid, although this terminology can be cumbersome to apply to individual cases.
GROSS FEATURES GI NETs grossly are firm tan to pale yellow nodules located just beneath the mucosal surface. The muscularis propria may be thickened in the area of tumor, perhaps as a result of secretion of trophic factors by the tumor cells (Fig. 1). Dense fibrotic stroma associated with the tumor cells may produce annular strictures, and mesenteric fibrosis may be seen in small bowel NETs. Ischemic injury secondary to vascular sclerosis may also be seen in small bowel tumors (Fig. 2).12 Extensive lymphatic involvement by tumor is manifested as small yellow nodules on the serosal surface. Multicentricity is common and is site-related; gastric and jejunoileal tumors (33%) are more commonly multiple, whereas multiplicity is rare with colonic or appendiceal NETs. Molecular studies have shown that most multiple GI NETs are independent primaries.13
MICROSCOPIC FEATURES Most GI NETs are readily recognizable as lowgrade NETs. They are composed of solid nests, cords, trabeculae, and glands of relatively uniform cells with round to oval nuclei with finely granular Fig. 1. Low-grade neuroendocrine neoplasms of the GI tract grossly appear as yellow plaques; thickening of the bowel wall as a result of fibrosis and smooth muscle hyperplasia may be seen, as in this example of an ileal tumor.
GI Neuroendocrine Tumors Fig. 2. Elastosis of mesenteric vessels, visible as acellular thickening of vessels walls (A) with duplication of the internal elastic lamina and adventitial elastosis on elastin stain (B) may cause bowel ischemia. These mesenteric vascular changes are primarily associated with ileal NETs.
chromatin and inconspicuous nucleoli (Fig. 3). Less commonly, cystic, tubular, or angiomatoid patterns may be seen. The cytoplasm is generally pale, but in some cases fine red granules are detectable (Fig. 4). Cytologic variants include clear cell NETs (generally found in the pancreas in patients with von Hippel-Lindau disease), and oncocytic and rhabdoid appearances. Large areas of tumor necrosis are uncommon and when present signify a higher-grade tumor, but punctate coagulative necrosis may be seen in larger low-grade tumors (Fig. 5). Perineural and lymphovascular invasion are associated with more aggressive behavior14 (see Fig. 5B, C) and are generally not seen in small low-grade tumors.
PRECURSOR LESIONS Endocrine cell hyperplasia is most commonly seen in the GI tract in the stomach in the setting of hypergastrinemia and chronic atrophic gastritis.15 Duodenal gastrin-producing cells undergo a similar hyperplasia in patients with Zollinger-Ellison syndrome caused by multiple endocrine neoplasia (MEN) type 1. Hyperplastic lesions of the GI neuroendocrine system have been divided for research purposes into diffuse, linear, and nodular patterns; the distinction between nodular hyperplasia and dysplasia is made by size, with dysplastic (preinvasive) lesions measuring between 90 and 210 mm. Gastrin or somatostatin-producing lesions in the
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Moreira & Washington Fig. 3. Low-grade GI NETs are composed of cords, trabeculae, and solid nests of relatively uniform cells with oval finely granular chromatin, typical of neuroendocrine differentiation.
duodenum and measuring larger than 210 mm are classified as GI NETs; microinvasion is recognized by the identification of small clusters of neuroendocrine cells localized in the lamina propria between glands and associated with stromal alterations such as thickened collagen.16 Although appendix, ileum, and rectum are common locations for GI NETs, endocrine cell hyperplasia and dysplastic lesions are rarely encountered in these sites, and in general sporadic NETs lack identifiable precursor lesions. Neuroendocrine cell hyperplasia and multiple GI NETs have been reported in the setting of ulcerative colitis17 and Crohn disease, and are associated with epithelial dysplastic changes in some cases.18
markers of neuroendocrine differentiation (Table 2) may be helpful in selected cases. Cytosolic markers such as neuron-specific enolase and CD56 are highly sensitive but relatively nonspecific for neuroendocrine differentiation. Synaptophysin,
Differential Diagnosis OF GI NETS Gastric NETs Type 1 and 2 (ECL) NETs Sporadic (type 3)
DIFFERENTIAL DIAGNOSIS Although most GI NETs do not present a diagnostic problem, tumors with a glandular growth pattern may be erroneously diagnosed as adenocarcinoma. Low-grade GI NETS should not be confused with high-grade neuroendocrine carcinoma or mixed high-grade adenocarcinoma/ neuroendocrine carcinoma, both of which are associated with poor prognosis. In the rectum, locally invasive prostatic adenocarcinoma may be confused with an NET but knowledge of the clinical history and endoscopic appearance are helpful in avoiding this pitfall.
DIAGNOSIS Most GI NETs do not require use of special stains or immunohistochemical studies for diagnosis. However, a panel of immunohistochemical
Type 4 (high-grade carcinoma)
neuroendocrine
Duodenal and ampullary NETs Gastrinoma Somatostatinoma Nonfunctioning NETs Appendiceal NETs Goblet cell carcinoid Tubular carcinoid Adenocarcinoma Ileal NETs Colorectal NETs
GI Neuroendocrine Tumors Fig. 4. Red cytoplasmic granules are prominent in some GI NETs.
a marker associated with small vesicles, has the advantage of higher specificity, although retaining high sensitivity. The secretory granule marker chromogranin A is widely used and is highly specific for neuroendocrine differentiation (Fig. 6), but is not uniformly expressed among the different endocrine cell types, and is often negative in appendiceal and rectal NETs. Highergrade NETs may be negative for chromogranin A expression, or display only focal positivity. Immunohistochemical findings should be interpreted in the context of the overall microscopic appearance of the lesion, and it is advisable to use a panel of markers rather than a single marker. In practice, the most widely used panel is synaptophysin and chromogranin A, although in some instances low-grade NETs are negative for both markers. The pathologist may also be asked to determine likely sites of origin of NET metastatic to the liver; in such cases, octreoscan scintigraphy is superior to histopathologic assessment. However, expression of CDX2 has been reported in up to 80% of GI NETs, more commonly in tumors arising in the ileum and appendix, and seems to be a useful marker for NETs of GI origin,19 although gastric NETs are frequently negative. Neuroendocrine secretory protein-55, a member of the chromogranin family of proteins found in dense core granules, has been reported to be expressed by NETs of the pancreas and adrenal medulla but not NETs of GI and lung origin.20 Cell-specific markers such as gastrin or somatostatin may be useful in subtyping GI NETs, but immunohistochemical expression of such hormones does not determine functional status
of the tumor, which is defined by clinical manifestations. However, subtle clinical signs of overproduction of such hormones may be overlooked in the preoperative setting and only recognized retrospectively on diagnosis of a GI NET.
STAGING AND PROGNOSTIC MARKERS According to the 2000 WHO classification,11 GI NETs are classified into 4 categories, based on a combination of gross, histologic, and immunohistochemical features (Table 3): 1. Well-differentiated NET of probable benign behavior 2. Well-differentiated NET of uncertain malignant behavior 3. Well-differentiated neuroendocrine carcinoma 4. Poorly differentiated neuroendocrine carcinoma. Recently, TNM classification systems for foregut and hindgut NETs have been proposed by the European Neuroendocrine Tumor Society.21,22 For foregut and hindgut NETs, the T category is assigned based on tumor size, depth of penetration into the bowel wall, and invasion of adjacent structures, according to specific tumor site (see Refs.20,21 for details). In situ carcinoma (Tis) is recognized for gastric lesions less than 0.5 cm in this classification system. N and M categories are assigned based on the presence or absence of regional lymph node (N0–N1) or distant (M0– M1) metastases, respectively. A final stage is assigned according to the combination of T, N, and M categories. The European Neuroendocrine Tumor Society21,22 has also proposed a grading system (Table 4), in
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Fig. 5. Focal areas of coagulative necrosis (A), perineural invasion (B), and lymphovascular invasion (C) are associated with more aggressive behavior in GI NETs.
GI Neuroendocrine Tumors which GI NETs are classified in 3 different categories based on mitotic counts and/or Ki-67 tumor labeling index. G1 and G2 tumors usually correspond to welldifferentiated NETs, whereas G3 indicates a poorly differentiated carcinoma. Preliminary validation studies for this proposed staging system23 using a data set of 202 patients have demonstrated prognostic relevance of staging and grading of lesions for foregut and pancreatic tumors. A recently proposed staging system using similar parameters (depth of tumor invasion, tumor size, lymph node metastases, and distant metastases) also seems to provide useful overall survival estimates when applied to a set of 108 GI NETs from all GI sites.24
SITE-SPECIFIC FEATURES Gastric NETs Gastric NETs form a relatively heterogeneous group of neoplasms because of the diverse population of native neuroendocrine cells in this organ. Tumors may arise from these cell types in a variety of clinical settings, and have been classified in 4 subtypes (Table 5). Types 1 and 2 tumors are ECL cell neoplasms that arise in the setting of hypergastrinemia. Type 1 tumors, by far the most common, are seen in patients with body-predominant atrophic gastritis and hypergastrinemia secondary to hypochlorhydria. These patients develop ECL cell
hyperplasia (Fig. 7), which may progress to true NETs, often multifocal (Fig. 8).25 The prognosis of type 1 tumors is usually favorable, and they can safely be resected endoscopically. In rare cases, more aggressive behavior and lymph node metastases are seen, usually associated with tumors larger than 2 cm and with infiltration of the gastric wall.26 Type 2 tumors are seen in patients with hypergastrinemia caused by gastrin-producing tumors at other sites, such as the duodenum, pancreas, or porta hepatis region (gastrinomas), often in association with Zollinger-Ellison syndrome and MEN-1. Through similar mechanisms as for type 1 tumors, these patients will develop ECL cell hyperplasia and neuroendocrine neoplasms. Like type 1 tumors, type 2 neoplasms usually behave in a benign fashion. Metastatic disease occurs in approximately 10% of cases, usually in tumors larger than 2 cm and with invasion of the muscularis propria.26 Type 3 tumors are defined as sporadic ECL cell neoplasms (ie, not associated with hypergastrinemia). As in types 1 and 2, type 3 tumors occur preferentially in the body and fundic regions, but tend to be solitary rather than multiple.25 Type 3 tumors are frequently larger than 2 cm and carry a worse prognosis compared with types 1 and 2, especially if associated with muscularis propria infiltration and vascular invasion, in which case metastases are likely to be present. Type 4 tumors are poorly differentiated neuroendocrine carcinomas. These tumors are distributed throughout the
Table 2 Immunohistochemistry of GI NETs
Site
Immunohistochemistry Chromogranin A Neuron-specific enolase Synaptophysin Serotonin Other immunohistochemical markers
Carcinoid syndrome
Foregut Tumors
Midgut Tumors
Stomach, proximal duodenum
Jejunum, ileum, Distal colon, rectum appendix, proximal colon
86%–100% 1 90%–100% 1 50% 1 33% 1 Rarely, 1 for pancreatic polypeptide, histamine, gastrin, VIP, or corticotropin Rare
82%–92% 1 95%–100% 1 95%–100% 1 86% 1 Prostatic acid phosphatase 1 in 20%–40%
40%–58% 1 80%–87% 1 94%–100% 1 45%–83% 1 Prostatic acid phosphatase 1 in 20%–82%
5%–39%
Rare
Abbreviation: VIP, vasoactive intestinal peptide. Data from Refs.55–61
Hindgut Tumors
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Moreira & Washington Fig. 6. Most low-grade GI NETs are strongly positive for chromogranin A, a component of neurosecretory granules, but roughly 50% of hindgut tumors are negative for this marker of neuroendocrine differentiation.
stomach, are more commonly diagnosed at a more advanced stage (>4 cm), and often present with extensive metastases.2 The prognosis is, therefore, poor, with most patients dying within 1 year of diagnosis.26 Like poorly differentiated neuroendocrine carcinomas elsewhere, type 4 tumors are positive
for synaptophysin but often negative for chromogranin A by immunohistochemistry.
NETs of the Duodenum and Upper Jejunum The percentage of duodenal and upper jejunal NETs in relation to all GI NETs ranges from 3% in
Table 3 WHO criteria for classification and assessment of the biologic behavior of GI NETs
Biologic Behavior Well-differentiated NET, probably benign Well-differentiated NET, uncertain behavior Well-differentiated neuroendocrine carcinoma, lowgrade malignant behavior Poorly differentiated neuroendocrine carcinoma, highgrade malignant behavior
Invasion of Muscularis Histologic Tumor Angio- Ki-67 Hormonal Differentiation Size (cm) Invasion Index (%) Syndrome Metastasis Propria
WD
%1a
2
1
1
1
PD
Any
1
>30
Abbreviations: PD, poorly differentiated; WD, well differentiated. a Exception: malignant duodenal gastrinomas are usually smaller than 1 cm and confined to the submucosa. b Exception: benign neuroendocrine tumors of the appendix usually invade the muscularis propria.
GI Neuroendocrine Tumors
Table 4 Grading of GI NETs
Grade
Mitotic Count (10 hpf)
Ki-67 Index (%)
G1 G2 G3
20
%2 3–20 >20
Data from Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395–401; and Rindi G, Kloppel 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(4):757–62.
studies that included old tumor databases7,27 to 22% in recent series.28 These tumors show a slight male predominance (1.5:1) and usually affect patients in their fifth and sixth decade.26 Five distinct types of NETs are recognized in this location: gastrinomas, which account for approximately two-thirds of all NETs, followed by somatostatinomas, nonfunctioning (nonsyndromic) serotonin- and calcitonin-producing tumors,
poorly differentiated neuroendocrine carcinomas, and gangliocytic paragangliomas.2 Gastrinomas can either occur sporadically (75% of cases) or in association with MEN-1 (25% of cases).29 By definition, gastrinomas are associated with increased serum levels of gastrin, and two-thirds of the patients present with ZollingerEllison syndrome. Although gastrinomas may occur in several different sites, they are usually located in the so-called gastrinoma triangle, and approximately 70% occur in the duodenum. Sporadic tumors are solitary and have no identifiable precursor lesions, whereas tumors arising in the setting of MEN-1 are usually multifocal and are believed to originate from an underlying precursor lesion (ie, G-cell hyperplasia).16 Duodenal gastrinomas are usually small lesions, usually measuring less than 1 cm in diameter and located in the first portion of the duodenum. Histologically, they show a mixture of histologic growth patterns, often with a trabecular and pseudoglandular architecture.26 In spite of their small size and lack of muscularis invasion, gastrinomas often have an aggressive behavior, with early regional lymph node metastases. Therefore, gastrinomas should be considered potentially malignant regardless of other features.
Table 5 Types of gastric NETs Type 1
Type 2
Type 3
Type 4
Frequency Multiplicity Size
70%–80% of cases Multifocal 0.5–1.0 cm
Rare Multifocal w1.5 cm or less
Rare Solitary Large
Location
Corpus
Corpus
10%–15% of cases Solitary Variable; one-third larger than 2 cm Any where in stomach
Associations
Hypergastrinemic Multiple endocrine states; chronic neoplasia type 1, atrophic gastritis, with ZollingerECL hyperplasia Ellison syndrome Usually benign 30% metastasize
Clinical behavior
Demographic 70%–80% are profile female, 500 s-600 s
Sporadic
Anywhere in stomach Sporadic
71% of tumors >2 cm High-grade with muscularis carcinoma; propria and vascular metastases invasion have lymph common; node metastases poor prognosis Equally in men and More common in men, More common women, mean age mean age 55 years in men 50 years
Data from Graeme-Cook F. Neuroendocrine tumors of the GI tract and appendix. In: Odze RD, Goldblum JR, Crawford JM, editors. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia: Saunders; 2004. p. 483–504; and Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology 2007;50(1):30–41.
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Moreira & Washington Fig. 7. ECL cell hyperplasia may be prominent in long-standing chronic atrophic gastritis associated with hypergastrinemia, and is best visualized with synaptophysin (shown) or chromogranin A immunohistochemistry.
Duodenal somatostatinomas represent 15% to 20% of duodenal NETs26,30 and about 1% of all gastroenteropancreatic NETs.31 They are predominantly located in the periampullary region, and are associated with type 1 neurofibromatosis (von Recklinhausen disease) in up to one-third of the cases, as well as with MEN-1.32 Originally named glandular duodenal carcinoids, this tumor shows characteristic histologic findings that include prominent glandular architecture with intraluminal mucinous material, simulating an epithelial tumor, as well as the presence of psammoma bodies in
most cases (Fig. 9). The cytologic features of a NET (ie, round, uniform nuclei, with salt-andpepper chromatin, and abundant cytoplasm) are morphologic clues on sections stained with hematoxylin and eosin. Immunohistochemistry for somatostatin is positive in almost all cases, although associated somatostatin syndrome (diabetes, achlorhydria, cholelithiasis, and diarrhea) is rarely present. Muscularis propria invasion seems to be a poor prognostic feature, associated with lymph node metastasis. Duodenal/periampullary somatostatinomas do not seem to be related
GI Neuroendocrine Tumors Fig. 8. Type 1 gastric NETs arising in hypergastrinemia are usually small (
