Carcinoid Tumors of the Gastrointestinal Tract

Background

Carcinoid and neuroendocrine tumors are uncommon neoplasms of the gastrointestinal tract. The most frequent site for carcinoids is the gastrointestinal tract (73.7%), with the appendix accounting for 18.9% of the cases.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

ACHLORHYDRIA

Achlorhydria, parietal cell hyperplasia, and multiple gastric carcinoids: a new disorder.

Abraham SC, Carney JA, Ooi A, Choti MA, Argani P.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Am J Surg Pathol. 2005 Jul;29(7):969-75. Abstract quote

We describe a 54-year-old woman who had multiple gastric carcinoid tumors arising in the setting of marked hypergastrinemia associated with a lack of acid production by hypertrophic parietal cells.

The serum gastrin level was 1,400 pg/mL, and investigation revealed no evidence for either of the recognized causes for hypergastrinemia-associated carcinoids, autoimmune gastritis, and Zollinger-Ellision syndrome. Partial gastrectomy was performed.

Pathologic examination showed multiple intramucosal and invasive carcinoid tumors of the body and fundus in a background of marked ECL cell hyperplasia. There were no gastric or duodenal ulcerations. One perigastric lymph node was metastatically involved. The oxyntic mucosa showed marked hyperplasia and hypertrophy of the parietal cells. Some of these cells were vacuolated, and many displayed protrusions of apical cytoplasm into dilated oxyntic glands filled with inspissated eosinophilic material.

Similar findings have occurred in 1 other patient, strongly indicating that the clinicopathologic alterations in the 2 cases are not random but, on the contrary, represent a very rare disorder of gastric carcinoids associated with an intrinsic acid secretion abnormality of the parietal cells.

PATHOGENESIS CHARACTERIZATION

GENERAL

The role of beta-catenin, TGFbeta3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids.

Zhang PJ, Furth EE, Cai X, Goldblum JR, Pasha TL, Min Kw K.

Hum Pathol. 2004 Jun;35(6):670-4. Abstract quote

A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and bowel infarction as a consequence of vascular compression caused by extensive mesenteric sclerosis (MS).

The goal of this study was to determine whether the level of expression of several fibrosing-related growth factors was related to the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS only (group III), were analyzed for immunoexpression of beta-catenin, transforming growth factor-beta 2 (TGFbeta2), nerve growth factor 2 (NGF2), fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections. Standard immunohistochemical technique was used following antigen retrieval. Immunostaining was scored semiquantitively as the product of the percentage and intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200. One-way analysis of variance and Mann-Whitney nonparametric analyses were used for statistical analysis. The mean scores of immunoreactivity of each factor in groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin (cytoplamic reactivity only); 106, 112, and 92 for TGFbeta3; 1.67, 32, and 36 for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52 for BMP4.

There were significant differences in NGF-2 immunoreactivity between groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of membranous beta-catenin, moderate levels of TGFbeta3 and IGFR2, and low levels of FGF-2, with no significant differences seen among the groups. MCs with prominent MS and MA (group I) expressed significantly higher BMP4 than those in groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA.

The level of NGF-2 expression was significantly lower in group I than in group III, possibly indicating abnormal angiogenesis in the formation of angiopathy.

CHROMOSOMAL ABNORMALITIES

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors.

Wang GG, Yao JC, Worah S, White JA, Luna R, Wu TT, Hamilton SR, Rashid A.

1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Mod Pathol. 2005 Aug;18(8):1079-87. Abstract quote

Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations.

We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P=0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P=0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P=0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P=0.02).

Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.

Genetic alterations in goblet cell carcinoids of the vermiform appendix and comparison with gastrointestinal carcinoid tumors.

Stancu M, Wu TT, Wallace C, Houlihan PS, Hamilton SR, Rashid A.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Mod Pathol. 2003 Dec;16(12):1189-98 Abstract quote.

Goblet cell carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis.

We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras, beta-catenin, and DPC4 (SMAD4) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell carcinoids.

We compared the allelic loss in goblet cell carcinoids to those in 18 gastrointestinal carcinoid tumors. For goblet cell carcinoids, appendiceal perforation was the most common (70%, 7/10) clinical presentation. The mean tumor size was 2.0 +/- 1.5 cm (range, 0.4 to 4.5 cm). The tumor invaded to appendiceal serosa in 50% (8/16) of patients, and two patients had metastasis in lymph nodes or adjoining viscera. With mean follow-up of 24 +/- 14 months (median, 23 mo), 1 of 10 patients had died of disease, and 2 others had tumor recurrence. All four patients with metastases, recurrences, and/or death from disease had serosal involvement at presentation (P =.02). Loss of heterozygosity of chromosome 11q was present in 25% of goblet cell carcinoids, 14% of ileal carcinoid tumors, and 9% of nonileal carcinoid tumors; of chromosome 16q in 38%, 29%, and 0 (P =.02); and of chromosome 18q in 56%, 86%, and 9% (P =.002), respectively. No mutations of K-ras, beta-catenin, or DPC4 genes; p53 overexpression; or loss of staining for DPC4 was present in any tumors.

These findings suggest that allelic loss of chromosomes 11q, 16q, and 18q in goblet cell carcinoids and ileal carcinoids may have an important role in the pathogenesis of these tumors.

Different patterns of 11q allelic losses in digestive endocrine tumors.

D'adda T, Pizzi S, Azzoni C, Bottarelli L, Crafa P, Pasquali C, Davoli C, Corleto VD, Fave GD, Bordi C.

Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, University of Parma, Parma, Italy.
Hum Pathol 2002 Mar;33(3):322-9 Abstract quote
Most foregut digestive endocrine neoplasms may be associated with the multiple endocrine type 1 (MEN-1) syndrome. In contrast, midgut/hindgut carcinoids never show such association.

To investigate the pathogenetic involvement of the MEN-1 gene and of putative additional oncosuppressor gene(s) distal to it, a comparative analysis of loss of heterozygosity (LOH) at chromosome 11q13 to 11qter was performed in 27 foregut (pancreatic endocrine tumors [PETs]), 23 midgut (ileal and appendiceal), and 3 hindgut (rectal) endocrine tumors. LOH at the MEN-1 gene locus at 11q13 was observed in 52% of the 23 sporadic and in all 4 MEN-1-associated PETs and was found to consistently and continuously span to the most distal marker investigated at 11qter. In contrast, only occasional, discontinuous, and mostly interstitial LOH for 11q markers was observed in ileal (midgut) carcinoids, whereas no LOH was found in all appendiceal (midgut) and rectal (hindgut) carcinoids.

The consistent extension of LOH from the MEN-1 region to 11qter in sporadic PETs suggests a mechanism of gene inactivation via chromosomal breakage and complete loss of chromosome 11q; furthermore, these results expand beyond the 11q13 region the search for additional oncosuppressor gene(s) potentially involved in the genesis of these neoplasms. The low frequency, limited extension, and discontinuous distribution of 11q deletions in midgut/hindgut carcinoids suggest that MEN-1 gene is not involved in the pathogenesis of these tumors.

CD44 LOSS

Expression of Cell Adhesion Molecules, CD44s and E-Cadherin, and Microvessel Density in Carcinoid Tumors

Xiaoping Sun, M.D., Ph.D., Yun Gong, M.D., Mark S. Talamonti, M.D. and M. Sambasiva Rao, M.D.

Department of Pathology (XS, YG, MSR) and Surgery (MST), Northwestern University Medical School, Chicago, Illinois

Modern Pathology 2002;15:1333-1338 Abstract quote
Although all carcinoids are potentially malignant, their biologic behavior is quite variable. Currently there are no reliable morphological criteria to predict metastatic potential. Cell adhesion molecules, such as CD44 and E-cadherin, are considered important in regulating invasion and metastasis of tumors. Also, angiogenesis has been shown to be associated with tumor growth and progression.

In this study, we examined 51 carcinoids, including 13 carcinoids with known lymph node and/or visceral metastasis, for expression of CD44s (the standard form of CD44) and E-cadherin by immunohistochemistry. We found that 55% and 37% of carcinoids were negative for CD44s and E-cadherin, respectively. Carcinoids with lymph node and/or visceral metastasis were significantly more frequently negative for CD44s than were those without demonstrated metastasis (P = .030). Ten of 11 tumors with lymph node metastasis lacked CD44s (P = .022), whereas E-cadherin was negative in only 3 (P = .975). Additionally, we analyzed microvessel density to evaluate the role of tumor angiogenesis in the tumor behavior.

Carcinoid tumors in general demonstrated high microvessel density (160 ± 82/five 200x fields), irrespective of location and with and without metastasis. These results suggest that loss of CD44s, but not E-cadherin, may be a useful predictor of metastatic potential of carcinoid tumors.

c-KIT

Analysis of protein expression and gene mutation of c-kit in colorectal neuroendocrine carcinomas.

Akintola-Ogunremi O, Pfeifer JD, Tan BR, Yan Y, Zhu X, Hart J, Goldblum JR, Burgart L, Lauwers GY, Montgomery E, Lewin D, Washington K, Bronner M, Xiao SY, Greenson JK, Lamps L, Lazenby A, Wang HL.

Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Am J Surg Pathol. 2003 Dec;27(12):1551-8. Abstract quote

Primary neuroendocrine carcinomas of the colon are rare but highly aggressive malignancies. The recent observations that c-kit protooncogene, a tyrosine kinase, is overexpressed in a subset of small cell lung cancer and that selective kinase inhibitors block the in vitro growth of small cell lung cancer cell lines prompted us to investigate the expression and mutation status of the c-kit gene in colorectal neuroendocrine carcinomas.

Sixty-six cases of primary colorectal neuroendocrine carcinoma were collected from 13 institutions, including 36 small cell carcinomas and 30 moderately differentiated neuroendocrine carcinomas. Immunohistochemical studies using a polyclonal antibody against c-kit protein (CD117) demonstrated a strong and diffuse cytoplasmic staining in 15 cases (23%), which were relatively equally distributed in the small cell and moderately differentiated subgroups. As controls, 25 conventional colorectal adenocarcinomas, 26 colorectal adenomas and 19 colorectal carcinoid tumors were all negative, whereas 15 gastrointestinal stromal tumors were all positive, for kit expression. In contrast to gastrointestinal stromal tumors, kit-overexpressing neuroendocrine carcinomas showed no mutations in the juxtamembrane domain (exon 11) of the c-kit gene as determined by mutational analysis. Kaplan-Meier analysis with the log-rank test revealed that the patients with kit-positive tumors did not differ significantly in survival from those with kit-negative tumors (P = 0.77).

These results indicate that c-kit overexpression observed in a subset of colorectal neuroendocrine carcinomas may not be mediated via activating mutations, and does not appear to be an initiating event during tumorigenesis because of lack of c-kit expression in other types of colorectal epithelial neoplasms. More importantly, our observations may have potential therapeutic implications since specific tyrosine kinase inhibitors have shown promise in the management of patients with kit-expressing malignancies.

p27

p27: A potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior

Gabriella Canavese, MD
Cinzia Azzoni, PhD
Silvia Pizzi, PhD, etal.

Hum Pathol 2001;32:1094-1101. Abstract quote

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53.

p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors.

p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P = .02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases.

Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors.

VASCULAR ENDOTHELIAL GROWTH FACTOR

Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: Correlation with microvessel density and clinicopathologic features.

La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C.

Department of Pathology, Ospedale di Circolo, Varese, Italy and the Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy.

Hum Pathol 2003 Jan;34(1):18-27 Abstract quote
Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone.

The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells.

Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy.

These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

APPENDIX Cancer 1997;79:813�829

After adenocarcinoma, carcinoids are the second most common primary malignant tumor arising in the appendix
The estimated prevalence ranges from 0.32% to 0.8% of patients undergoing appendectomy.

DUODENUM

Sporadic Duodenal Bulb Gastrin-cell Tumors: Association With Helicobacter pylori Gastritis and Long-term Use of Proton Pump Inhibitors.

Merchant SH,

Vanderjagt T,

Lathrop S,

Amin MB.

*Department of Pathology, University of New Mexico daggerDepartment of Pathology, New Mexico VA Health Care System, Albuquerque, NM double daggerDepartment of Pathology, William Beaumont Hospital, Royal Oak, MI.

Am J Surg Pathol. 2006 Dec;30(12):1581-1587. Abstract quote

We reviewed the clinicopathologic profile of a series of recently diagnosed sporadic duodenal gastrin-cell (G-cell) tumors. All cases were discovered incidentally and had a unique clinicopathologic profile: all 18 cases were gastrin-positive tumors located in the duodenal bulb, were small in size (mean size 5.4 mm), demonstrated an insular architectural pattern, and were localized to the lamina propria and submucosa. None of the patients had Zollinger-Ellison or carcinoid syndrome.

The behavior was indolent and there was no evidence of metastasis at diagnosis or during follow-up. In our sampled population, the presence of Helicobacter pylori gastritis and the use of proton pump inhibitors (PPIs) were significantly associated with the presence of G-cell tumors. Both the presence of H. pylori gastritis and use of PPI remained significant in a logistic regression model adjusted for age, race/ethnicity, and sex with P values of 0.0016 (odds ratio=10.1, 95% confidence interval: 2.3 to 42.4) and 0.008 (odds ratio=8.9, 95% confidence interval: 1.76 to 45.4), respectively. Most patients with tumors showed G-cell hyperplasia in the nontumorous regions of the duodenum. The high incidence of sporadic duodenal G-cell tumors in patients with H. pylori gastritis and long-term PPI use suggests an association that needs to be further explored.

Presence of G-cell hyperplasia in the nontumorous duodenal mucosa suggests that these may originate from a proliferative phase, similar to the hyperplasia-dysplasia-neoplasia sequence seen in other endocrine tumors.

Carcinoid tumors of the duodenum and ampulla of vater: A clinicomorphologic, immunohistochemical, and cell kinetic comparison

Leticia Bornstein-Quevedo, MD
Armando Gamboa-Dom�nguez, MD, MSci

Hum Pathol 2001;32:1252-1256. Abstract quote

Carcinoid tumors of the ampulla of Vater (ACs) differ from duodenal carcinoid tumors (DCs). A search for AC and DC was made between 1980 and 2000. The clinicopathologic features and follow-up were assessed.

Immunohistochemistry for panneuroendocrine markers, hormone products, proliferating cell nuclear antigen (PCNA), Ki- 67, p21cip1, and p27kip1 were performed. A blind proliferative index counting 500 cells was made. Differences were contrasted using the Fisher exact and 2-sided Student t test. Five ACs and 8 DCs were identified in 9 women and 4 men with median ages of 59 and 64 years and mean tumor diameters of 1.6 and 1.85 cm, respectively. All patients with AC presented jaundice, and most patients with DC were asymptomatic (P =.047). Metastases were present in 4 ACs and 1 DC (P =.03). Tumor cells expressed synaptophysin and chromogranin in 60% of ACs and in 100% and 87% of DCs. Gastrin was expressed in 75% of DCs and 20% of ACs (P < .05). The mean value for PCNA index was 4.0% in ACs and 3.2% in DCs, and mean values for Ki-67 were 12.2% and 10.2%, respectively (P = NS). Expression of p21cip1 and p27kip1 was observed in 40% of ACs and 37.5% and 12.5% of DCs. Three of 5 patients with AC died of the disease within an average of 11 months, and none of the patients with DC had died at 103 months of follow-up.

The more aggressive behavior of ACs is not associated with higher proliferative indices or with different expression of cell cycle inhibitors.

ESOPHAGUS

Carcinoid tumor of the esophagus: a clinicopathologic study of four cases.

Hoang MP, Hobbs CM, Sobin LH, Albores-Saavedra J.

Division of Anatomic Pathology (M.P.H., J.A.-S.), University of Texas Southwestern Medical Center, Dallas, Texas; and the Department of Hepatic and Gastrointestinal Pathology (C.M.H., L.H.S.), Armed Forces Institute of Pathology, Washington, DC, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):517-22 Abstract quote
Several case reports have emphasized that esophageal carcinoid tumors are associated with a poor prognosis.

To expand our knowledge about the pathology and biologic behavior of these rare tumors, we reviewed the clinicopathologic and immunohistochemical findings of four cases of primary esophageal carcinoid. The age of the patients ranged from 48 to 82 years (mean 63 years; median 61 years). The lower segment of the esophagus was involved in two cases and the mid segment was involved in one case. The sizes of the tumors ranged from 0.3 cm to 3.5 cm. Two tumors were confined to the lamina propria and two invaded into the muscular wall. Two tumors appeared polypoid, whereas the remaining two were incidental findings and associated with adenocarcinoma arising in a background of Barrett esophagus.

The adenocarcinoma was superficially invasive in one case, whereas it penetrated the muscular wall in the other. All four carcinoid tumors were immunoreactive with chromogranin and synaptophysin. There was focal expression of serotonin in two cases, glucagon in one case, and pancreatic polypeptide in one case. Endocrine cell hyperplasia was noted in both the Barrett esophagus and the invasive adenocarcinoma. One patient died secondary to postoperative pneumonia. Three patients are alive and disease free at 1, 6, and 23 years status post therapy. None of the patients had metastatic disease.

These findings show that esophageal carcinoids are associated with a favorable prognosis. They arise in two settings: (1) a single large polypoid tumor or (2) an incidental finding and in association with adenocarcinoma arising in the background of Barrett esophagus. The presence of endocrine cell hyperplasia in the Barrett mucosa and the adenocarcinoma supports the hypothesis that these lesions arise from a common stem cell.

ILEUM

Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases.

Yantiss RK, Odze RD, Farraye FA, Rosenberg AE.

Am J Surg Pathol. 2003 Jun;27(6):811-7. Abstract quote
It is well known that small intestinal carcinoid tumors may occur as solitary or multiple lesions. However, the biologic significance of multiple carcinoid tumors has not been clearly defined.

The purpose of this study was to compare the clinical and pathologic features and prognosis of patients with solitary versus multiple carcinoid tumors of the ileum. Sixty-eight patients, including 50 with solitary and 18 with multiple carcinoid tumors, were included in the study. Hematoxylin and eosin-stained slides from routinely processed tumor resection specimens of the ileum were evaluated for a variety of histologic features such as tumor size, depth of invasion, tumor stage, and venous, perineural, and lymphovascular invasion.

Follow-up and clinical data, such as patient age, gender, presenting complaints, presence of synchronous or metachronous malignancies, and presence of the carcinoid syndrome, were obtained and the results were compared between the two patient groups. Fifty patients with solitary carcinoid tumors (male/female ratio, 27:23) and 18 patients with multiple tumors (male/female ratio, 7:11) were identified. Patients with multiple carcinoid tumors were significantly younger than patients with solitary tumors at the time of diagnosis (55 years vs 63 years, p = 0.006).

There was a high association between multiple carcinoid tumors and the carcinoid syndrome (4 of 18 vs 1 of 50, p = 0.004) as compared with patients with solitary carcinoid tumors. There was also an association between tumor multiplicity and venous invasion, but this relationship was not statistically significant (p = 0.07). The follow-up period was similar for both groups (mean 36 months, median 26 months, range 1-139 months). A significantly higher proportion of patients with multiple carcinoid tumors were either alive with disease or died of disease (56%) compared with those with solitary carcinoid tumors (18%, p = 0.002), and this relationship persisted in multivariate analysis (p = 0.02).

Overall, no significant differences were observed between these two patient groups with respect to other clinicopathologic features such as tumor size, depth of invasion, presence of distant metastases, lymphatic or perineural invasion, or presence of an associated malignancy (p >0.05).

In conclusion, we found that patients with multiple carcinoid tumors are younger, have a significantly greater risk of developing the carcinoid syndrome, and have a poorer prognosis than patients with solitary tumors.

HISTOLOGICAL TYPES CHARACTERIZATION

General

VARIANTS

Goblet Cell Carcinoid (Adenocarcinoid) Tumors of the Appendix
Semin Diagn Pathol 2000;17:91�103
J Gastroenterol 1998;33:582�587
Histopathology 1991;18:61�65

Tumors that had both argentaffin- and mucin-secreting cells

Has been called goblet cell carcinoids, crypt cell carcinoma, mucinous carcinoid, and adenocarcinoid

Tumors infiltrate the submucosa and the muscular wall in a circumferential fashion, sparing the mucosa

In some of our cases, the goblet tumor cells were typically poorly defined among the relatively abundant stroma and/or smooth muscle

The glands lining these compact clusters of cells contained intracytoplasmic mucin and were mucicarmine and Alcian blue positive with no central lumen. No mucinous lakes were seen in any of our cases
Occasional foci of fused goblet cell nests with signet ring cells were also seen

Some cells had PAS diastase�positive eosinophilic granular cytoplasm
The nuclei were crescent-shaped or round and basally oriented, often with a single small nucleolus
Diffuse infiltration into the periappendiceal fat and perineural invasion was seen in most cases

Goblet Cell Carcinoids of the Appendix Immunophenotype and Ultrastructural Study

Arch Pathol Lab Med 125:386�390, 2001

High cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin D1 and p21, and down-regulation of p16.

Although appendiceal carcinoids are potentially lethal neoplasms, tumor eradication is usually feasible and effective

Owing to the pattern of diffuse perineural and appendiceal wall infiltration, a complete removal (with microscopically negative margins) of the goblet cell variety of such carcinoids of the appendix is recommended

Angiogenic Polypoid Proliferation Adjacent to Ileal Carcinoid Tumors: A Nonspecific Finding Related to Mucosal Prolapse

Neil A. Abrahams, M.D., Zissis Vesoulis, M.D. and Robert E. Petras, M.D.

Department of Anatomic Pathology The Cleveland Clinic Foundation (NAA, REP), Cleveland, Ohio; and Department of Anatomic Pathology, Summa Health System (ZV), Akron, Ohio

Mod Pathol 2001;14:821-827 Abstract quote

Case reports have highlighted angiogenic polypoid proliferation in the mucosa adjacent to ileal carcinoid tumors, describing them as granulation tissue polyposis and florid angiogenesis. Some authors have proposed that the ileal carcinoid tumors themselves produce growth factors that cause the change.

The purpose of this study was to determine the frequency of angiogenic polypoid proliferation in a large cohort of resected ileal carcinoid tumors compared with control groups.

Search of the Cleveland Clinic and Summa Health System pathology files (1985 to 1999) yielded 65 resected ileal carcinoid tumors. Mucosal abnormalities adjacent to the ileal carcinoid tumors were graded 0 to 4+. Twenty ileal resection margins from colonic carcinoma cases served as normal controls. Ileal mucosa adjacent to 22 noncarcinoid neoplasms were also examined.

The mucosa adjacent to 54/65 ileal carcinoid tumors (83%) showed mucosal abnormalities (vs. 3/20 normal controls), including mucosal edema, capillary ectasia, muscularis mucosae hypertrophy, fibrosis/smooth muscle proliferation within the lamina propria, club-shaped villi, and intramucosal capillary proliferation. Forty ileal carcinoid tumor cases (61%) showed some degree of angiogenic polypoid proliferation characterized by club-shaped villi and prominent intramucosal capillaries, with 17 (26%) graded as 3+ or 4+. Angiogenic polypoid proliferation was associated with hypertrophy of the muscularis mucosae, lamina proprial fibrosis/smooth muscle proliferation, and capillary ectasia similar to that described with gastrointestinal mucosal trauma/prolapse. This trauma/prolapse change was identified in 45 cases (69%) and was graded 3+ or 4+ in 23 (35%). Seventeen (77%) of the noncarcinoid neoplasms showed trauma/prolapse changes, with 7 (32%) graded as 3+ or 4+. Angiogenic polypoid proliferation also correlated with trauma/prolapse change in the noncarcinoid neoplasm controls. Neither APP (P = .24) nor the prolapse changes (P = .33) were found to be statistically different between the two tumor groups.

Angiogenic polypoid proliferation of the adjacent ileal mucosa is common in patients with ileal carcinoid tumors and with noncarcinoid neoplasms. Angiogenic polypoid proliferation almost invariably coexists with fibromuscular change and capillary ectasia within the lamina propria, suggesting that mucosal trauma/prolapse plays a role in the histogenesis. The association of angiogenic polypoid proliferation with a variety of different neoplasms makes it unlikely that the tumors themselves secrete growth factors.

SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY CHARACTERIZATION

CYTOKERATINS

Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors

Yun-Cai Cai, MD, PhD
Barbara Banner, MD
Jonathan Glickman, MD, PhD
Robert D. Odze, MD, FRCP

Hum Pathol 2001;32:1087-1093. Abstract quote

Expression of cytokeratin (CK) 7 and 20 is commonly used to help distinguish adenocarcinomas from different sites. Thyroid transcription factor 1 (TTF-1) is a 38-kd protein, located primarily in the nucleus of type 2 pneumocytes and clara cells. TTF-1 has been shown to be present in a variety of lung and thyroid tumors and in pulmonary small-cell carcinomas. Carcinoid tumors from the lung and the gastrointestinal (GI) tract are histologically similar and thus are difficult to differentiate from each other based on histologic criteria. Pancreatic endocrine tumors (PET) have a similar histologic appearance to these other tumors.

The purpose of this study was to determine the efficacy of differentiating these 3 groups of tumors by their expression of CK7, CK20, and TTF-1.

Routinely processed paraffin-embedded tissue sections from 62 carcinoid tumors (lung, 16; gastrointestinal [GI] tract, 46) and 12 PETs were immunohistochemically stained for CK7, CK20, and TTF-1. The degree of expression in each tumor was graded as 1+ (1% to 10% of cells positive), 2+ (11% to 25%), 3+ (26% to 50%), and 4+ (>50%). The data were compared between tumor types and between carcinoid tumors from the various locations in the GI tract (stomach, 8; small intestine, 19; large intestine, 17; appendix, 2).

CK7 was expressed in 10 (63%) of 16 pulmonary carcinoid tumors and only 5 (11%) of 46 GI carcinoid tumors (P < .001). Pancreatic endocrine tumors showed CK7 positivity in 6 (50%) of 12 cases, which was similar to the findings in lung carcinoids and significantly higher than in GI carcinoids (P < .01). CK20 was expressed in 0 (0%) of 16 pulmonary carcinoid tumors, in contrast to 24% and 33% of GI carcinoid tumors (P < .05) and PETs (P < .05), respectively. TTF-1 expression was highly specific for pulmonary carcinoid tumors. This peptide was present in 11 (69%) of 16 pulmonary carcinoid tumors and in only 1 (2%) of 46 and 0 (0%) of 12 GI carcinoid tumors (P < .001) and PETs (P < .001), respectively. A CK7+/CK20�/TTF-1+ immunopanel result was moderately sensitive (sensitivity, 50%), and highly specific (specificity, 100%), for a diagnosis of pulmonary carcinoid tumor. CK7, CK20, and TTF-1 did not differ significantly between carcinoid tumors located in different sites of the GI tract. However, a trend was observed toward a lower prevalence of CK20 positivity in gastric tumors (P = .06) than in GI carcinoid tumors from the small intestine, colon, or appendix.

Expression of CK7 and CK20, and particularly TTF-1, may be useful in distinguishing pulmonary from GI carcinoid tumors and PETs, especially when evaluated as a panel of markers. TTF-1 is highly specific for pulmonary carcinoid tumors.

CDX2

Usefulness of CDX2 and TTF-1 in Differentiating Gastrointestinal From Pulmonary Carcinoids.

Saqi A, Alexis D, Remotti F, Bhagat G.

Department of Pathology, Columbia University Medical Center, New York, NY.

Am J Clin Pathol. 2005 Mar;123(3):394-404. Abstract quote

Carcinoids of different organs appear morphologically indistinguishable.

We studied the usefulness of differential expression of CDX2 and thyroid transcription factor-1 (TTF-1) in 78 gastrointestinal and pulmonary carcinoids and their metastases (n = 10). CDX2 staining of gastric biopsy specimens with neuroendocrine hyperplasia (n = 11) and various gastritides (n = 10) was also performed. All ileal (6/6 [100%]), 6 (86%) of 7 appendiceal, 3 (75%) of 4 duodenal, 1 (50%) of 2 ampullary, 12 (33%) of 18 rectal, 6 (30%) of 20 pancreatic, and 1 (17%) of 6 gastric carcinoids expressed CDX2 with variable intensity; none of the pulmonary carcinoids stained.

Of 15 pulmonary carcinoids, 8 (53%) stained with TTF-1, but none of the gastrointestinal carcinoids did. CDX2 and TTF-1 staining profiles of primary and metastatic carcinoids were similar. CDX2+ gastric endocrine cells had a distribution similar to that of gastrin and enterochromaffin cells but not enterochromaffin-like cells.

Our results suggest that CDX2 and TTF-1 have high specificity for gastrointestinal and pulmonary carcinoids, respectively.

EPIDERMAL GROWTH FACTOR RECEPTOR

Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas.

Papouchado B, Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, Lloyd RV.

1Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Mod Pathol. 2005 Oct;18(10):1329-35. Abstract quote

The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of many tumors. To analyze the expression of EGFR and activated EGFR in well-differentiated neuroendocrine carcinomas including primary and metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors (PET), we examined 58 gastrointestinal carcinoid tumors and 48 PET using immunohistochemistry, Western blotting, and RT-PCR. EGFR and activated EGFR (P-EGFR) were expressed by both gastrointestinal carcinoids and PET in primary and metastatic tumors, although a higher percentage of gastrointestinal carcinoid tumors expressed EGFR and activated EGFR. Western blotting detected a 170 kDa band for both EGFR and activated EGFR in three primary carcinoid tumors and two metastatic carcinoid tumors to the liver. RT-PCR analysis confirmed the expression of EGFR mRNA in both primary and metastatic carcinoid tumors.

Patients with activated EGFR expression in their primary PET had a significantly worse prognosis compared to those who did not express activated-EGFR (P=0.043). These results indicate that gastrointestinal carcinoid tumors as well as PET express EGFR and activated EGFR, and that expression is more common in gastrointestinal carcinoid tumors compared to pancreatic endocrine tumors.

These findings implicate the EGFR and P-EGFR signal transduction pathway in the pathogenesis of these neuroendocrine tumors and suggest that targeted therapy directed against the EGFR tyrosine kinase domain may be a useful therapeutic approach in patients with unresectable metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors.

NESP-55

Neuroendocrine Secretory Protein-55 (NESP-55) Expression Discriminates Pancreatic Endocrine Tumors and Pheochromocytomas From Gastrointestinal and Pulmonary Carcinoids.

Srivastava A, Padilla O, Fischer-Colbrie R, Tischler AS, Dayal Y.

*Tufts-New England Medical Center, Boston, MA; and daggerDepartment of Pharmacology, University of Innsbruck, Innsbruck, Austria.

Am J Surg Pathol. 2004 Oct;28(10):1371-1378. Abstract quote

Neuroendocrine secretory protein-55 (NESP-55), the latest addition to the chromogranin family, is a product of a genomically imprinted gene transcribed exclusively from the maternal allele. Initial studies have shown it to have a less widespread distribution than that of chromogranin A in normal tissues. It has also been suggested that NESP-55 may be a marker of neuroendocrine tumors differentiating toward the adrenal chromaffin and pancreatic islet cells. Metastatic gastrointestinal and pulmonary carcinoids may occasionally be difficult to distinguish from pancreatic endocrine tumors (PETs) and pheochromocytomas on morphologic grounds alone.

We studied neuroendocrine tumors from these sites to see if NESP-55 expression could reliably discriminate pulmonary and gastrointestinal carcinoids from neuroendocrine tumors arising in the pancreas or the adrenal medulla. Sixty-three neuroendocrine tumors positive for one or more immunohistochemical marker of neuroendocrine differentiation (chromogranin A, chromogranin B, synaptophysin, secretogranin II, neuron-specific enolase) were selected for the study and consisted of 34 typical carcinoids (15 pulmonary, 11 ileal, 4 gastric, and 4 rectal), 19 PETs, and 10 pheochromocytomas (4 sporadic, 3 MEN-2, 2 neurofibromatosis type 1, and 1 VHL). All cases were stained for NESP-55 after microwave antigen retrieval using a rabbit polyclonal antibody at a dilution of 1:1000. Sections of normal adrenal medulla were used as positive controls for NESP-55 staining. Negative controls consisted of omission of primary antibody and replacement with normal rabbit serum at an equivalent concentration. NESP-55 immunoreactivity was seen as brown finely granular cytoplasmic staining with prominent perinuclear accentuation. All gastric and ileal carcinoids studied were completely negative for NESP-55. One of four rectal and 1 of 15 pulmonary carcinoids showed focal positivity for it in less than 5% of tumor cells.

In contrast, all 10 pheochromocytomas and 14 of 19 PETs showed strong immunohistochemical staining in a variable proportion of tumor cells. Diffuse positivity (>75% of tumor cells) was seen in 6 of 14 PETs and 8 of 10 pheochromocytomas.

Our results indicate that, in contrast to the other granins, NESP-55 reactivity is restricted to endocrine tumors of the pancreas and the adrenal medulla. Immunohistochemical expression of NESP-55 may thus be useful in assigning a pancreatic or adrenal origin to metastatic endocrine tumors of unknown orgin.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Classification of low-grade neuroendocrine tumors of midgut and unknown origin.

Van Eeden S, Quaedvlieg PF, Taal BG, Offerhaus GJ, Lamers CB, Van Velthuysen ML.

Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam Departments of Medical Oncology and Pathology of the Netherlands Cancer Institute, The Netherlands.

Hum Pathol 2002 Nov;33(11):1126-32 Abstract quote
Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course.

Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995.

The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated.

The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance.

We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.

MIB1

Immunohistochemical Staining of Cytologic Smears With MIB-1 Helps Distinguish Low-Grade From High-Grade Neuroendocrine Neoplasms

Oscar Lin, MD, PhD,1 Semra Olgac, MD,1 Ileana Green, MD,2 Maureen F. Zakowski, MD,1 and David S. Klimstra, MD
Am J Clin Pathol 2003;120:209-216 Abstract quote

Neuroendocrine neoplasms (NENs) of the lung and gastrointestinal tract constitute a pathologic and biologic spectrum of tumors. Accurate cytologic diagnosis of a neuroendocrine neoplasm is important since definitive treatment frequently is based on low- and high-grade categories without histologic sampling. In many instances, however, low- and high-grade NENs share cytologic features, hindering a precise classification.

Since the histologic diagnostic criteria for separation of low- from high-grade categories can be based on the proliferation rate, we proposed to evaluate the usefulness of the immunocytochemical stain for the proliferation marker MIB-1 in the grading of NENs. Cytologic preparations of 63 NENs were retrieved from the files of Memorial Sloan-Kettering Cancer Center, New York, NY. One representative alcohol-fixed slide from each case was destained and restained immunocytochemically for MIB-1.

When MIB-1 immunoreactivity was considered, all low-grade NENs showed immunoreactivity in fewer than 25% of the neoplastic cells, and all high-grade NENs demonstrated immunoreactivity in more than 50% of neoplastic cells. Our study demonstrates that MIB-1 dramatically stratifies NENs as low-grade or high-grade. Therefore, the proliferation index also correlates with grade of NEN in cytology specimens.

TREATMENT Surgical removal

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
APPENDIX	Cancer 1997;79:813�829 After adenocarcinoma, carcinoids are the second most common primary malignant tumor arising in the appendix The estimated prevalence ranges from 0.32% to 0.8% of patients undergoing appendectomy.
DUODENUM
Sporadic Duodenal Bulb Gastrin-cell Tumors: Association With Helicobacter pylori Gastritis and Long-term Use of Proton Pump Inhibitors. Merchant SH, Vanderjagt T, Lathrop S, Amin MB. *Department of Pathology, University of New Mexico daggerDepartment of Pathology, New Mexico VA Health Care System, Albuquerque, NM double daggerDepartment of Pathology, William Beaumont Hospital, Royal Oak, MI.	Am J Surg Pathol. 2006 Dec;30(12):1581-1587. Abstract quote We reviewed the clinicopathologic profile of a series of recently diagnosed sporadic duodenal gastrin-cell (G-cell) tumors. All cases were discovered incidentally and had a unique clinicopathologic profile: all 18 cases were gastrin-positive tumors located in the duodenal bulb, were small in size (mean size 5.4 mm), demonstrated an insular architectural pattern, and were localized to the lamina propria and submucosa. None of the patients had Zollinger-Ellison or carcinoid syndrome. The behavior was indolent and there was no evidence of metastasis at diagnosis or during follow-up. In our sampled population, the presence of Helicobacter pylori gastritis and the use of proton pump inhibitors (PPIs) were significantly associated with the presence of G-cell tumors. Both the presence of H. pylori gastritis and use of PPI remained significant in a logistic regression model adjusted for age, race/ethnicity, and sex with P values of 0.0016 (odds ratio=10.1, 95% confidence interval: 2.3 to 42.4) and 0.008 (odds ratio=8.9, 95% confidence interval: 1.76 to 45.4), respectively. Most patients with tumors showed G-cell hyperplasia in the nontumorous regions of the duodenum. The high incidence of sporadic duodenal G-cell tumors in patients with H. pylori gastritis and long-term PPI use suggests an association that needs to be further explored. Presence of G-cell hyperplasia in the nontumorous duodenal mucosa suggests that these may originate from a proliferative phase, similar to the hyperplasia-dysplasia-neoplasia sequence seen in other endocrine tumors.
Carcinoid tumors of the duodenum and ampulla of vater: A clinicomorphologic, immunohistochemical, and cell kinetic comparison Leticia Bornstein-Quevedo, MD Armando Gamboa-Dom�nguez, MD, MSci	Hum Pathol 2001;32:1252-1256. Abstract quote Carcinoid tumors of the ampulla of Vater (ACs) differ from duodenal carcinoid tumors (DCs). A search for AC and DC was made between 1980 and 2000. The clinicopathologic features and follow-up were assessed. Immunohistochemistry for panneuroendocrine markers, hormone products, proliferating cell nuclear antigen (PCNA), Ki- 67, p21cip1, and p27kip1 were performed. A blind proliferative index counting 500 cells was made. Differences were contrasted using the Fisher exact and 2-sided Student t test. Five ACs and 8 DCs were identified in 9 women and 4 men with median ages of 59 and 64 years and mean tumor diameters of 1.6 and 1.85 cm, respectively. All patients with AC presented jaundice, and most patients with DC were asymptomatic (P =.047). Metastases were present in 4 ACs and 1 DC (P =.03). Tumor cells expressed synaptophysin and chromogranin in 60% of ACs and in 100% and 87% of DCs. Gastrin was expressed in 75% of DCs and 20% of ACs (P < .05). The mean value for PCNA index was 4.0% in ACs and 3.2% in DCs, and mean values for Ki-67 were 12.2% and 10.2%, respectively (P = NS). Expression of p21cip1 and p27kip1 was observed in 40% of ACs and 37.5% and 12.5% of DCs. Three of 5 patients with AC died of the disease within an average of 11 months, and none of the patients with DC had died at 103 months of follow-up. The more aggressive behavior of ACs is not associated with higher proliferative indices or with different expression of cell cycle inhibitors.
ESOPHAGUS
Carcinoid tumor of the esophagus: a clinicopathologic study of four cases. Hoang MP, Hobbs CM, Sobin LH, Albores-Saavedra J. Division of Anatomic Pathology (M.P.H., J.A.-S.), University of Texas Southwestern Medical Center, Dallas, Texas; and the Department of Hepatic and Gastrointestinal Pathology (C.M.H., L.H.S.), Armed Forces Institute of Pathology, Washington, DC, U.S.A.	Am J Surg Pathol 2002 Apr;26(4):517-22 Abstract quote Several case reports have emphasized that esophageal carcinoid tumors are associated with a poor prognosis. To expand our knowledge about the pathology and biologic behavior of these rare tumors, we reviewed the clinicopathologic and immunohistochemical findings of four cases of primary esophageal carcinoid. The age of the patients ranged from 48 to 82 years (mean 63 years; median 61 years). The lower segment of the esophagus was involved in two cases and the mid segment was involved in one case. The sizes of the tumors ranged from 0.3 cm to 3.5 cm. Two tumors were confined to the lamina propria and two invaded into the muscular wall. Two tumors appeared polypoid, whereas the remaining two were incidental findings and associated with adenocarcinoma arising in a background of Barrett esophagus. The adenocarcinoma was superficially invasive in one case, whereas it penetrated the muscular wall in the other. All four carcinoid tumors were immunoreactive with chromogranin and synaptophysin. There was focal expression of serotonin in two cases, glucagon in one case, and pancreatic polypeptide in one case. Endocrine cell hyperplasia was noted in both the Barrett esophagus and the invasive adenocarcinoma. One patient died secondary to postoperative pneumonia. Three patients are alive and disease free at 1, 6, and 23 years status post therapy. None of the patients had metastatic disease. These findings show that esophageal carcinoids are associated with a favorable prognosis. They arise in two settings: (1) a single large polypoid tumor or (2) an incidental finding and in association with adenocarcinoma arising in the background of Barrett esophagus. The presence of endocrine cell hyperplasia in the Barrett mucosa and the adenocarcinoma supports the hypothesis that these lesions arise from a common stem cell.
ILEUM
Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases. Yantiss RK, Odze RD, Farraye FA, Rosenberg AE.	Am J Surg Pathol. 2003 Jun;27(6):811-7. Abstract quote It is well known that small intestinal carcinoid tumors may occur as solitary or multiple lesions. However, the biologic significance of multiple carcinoid tumors has not been clearly defined. The purpose of this study was to compare the clinical and pathologic features and prognosis of patients with solitary versus multiple carcinoid tumors of the ileum. Sixty-eight patients, including 50 with solitary and 18 with multiple carcinoid tumors, were included in the study. Hematoxylin and eosin-stained slides from routinely processed tumor resection specimens of the ileum were evaluated for a variety of histologic features such as tumor size, depth of invasion, tumor stage, and venous, perineural, and lymphovascular invasion. Follow-up and clinical data, such as patient age, gender, presenting complaints, presence of synchronous or metachronous malignancies, and presence of the carcinoid syndrome, were obtained and the results were compared between the two patient groups. Fifty patients with solitary carcinoid tumors (male/female ratio, 27:23) and 18 patients with multiple tumors (male/female ratio, 7:11) were identified. Patients with multiple carcinoid tumors were significantly younger than patients with solitary tumors at the time of diagnosis (55 years vs 63 years, p = 0.006). There was a high association between multiple carcinoid tumors and the carcinoid syndrome (4 of 18 vs 1 of 50, p = 0.004) as compared with patients with solitary carcinoid tumors. There was also an association between tumor multiplicity and venous invasion, but this relationship was not statistically significant (p = 0.07). The follow-up period was similar for both groups (mean 36 months, median 26 months, range 1-139 months). A significantly higher proportion of patients with multiple carcinoid tumors were either alive with disease or died of disease (56%) compared with those with solitary carcinoid tumors (18%, p = 0.002), and this relationship persisted in multivariate analysis (p = 0.02). Overall, no significant differences were observed between these two patient groups with respect to other clinicopathologic features such as tumor size, depth of invasion, presence of distant metastases, lymphatic or perineural invasion, or presence of an associated malignancy (p >0.05). In conclusion, we found that patients with multiple carcinoid tumors are younger, have a significantly greater risk of developing the carcinoid syndrome, and have a poorer prognosis than patients with solitary tumors.

Epidemiology
Disease Associations
Pathogenesis
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Gross Appearance and Clinical Variants
Histopathological Features and Variants
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HISTOLOGICAL TYPES	CHARACTERIZATION
General
VARIANTS
Goblet Cell Carcinoid (Adenocarcinoid) Tumors of the Appendix	Semin Diagn Pathol 2000;17:91�103 J Gastroenterol 1998;33:582�587 Histopathology 1991;18:61�65 Tumors that had both argentaffin- and mucin-secreting cells Has been called goblet cell carcinoids, crypt cell carcinoma, mucinous carcinoid, and adenocarcinoid Tumors infiltrate the submucosa and the muscular wall in a circumferential fashion, sparing the mucosa In some of our cases, the goblet tumor cells were typically poorly defined among the relatively abundant stroma and/or smooth muscle The glands lining these compact clusters of cells contained intracytoplasmic mucin and were mucicarmine and Alcian blue positive with no central lumen. No mucinous lakes were seen in any of our cases Occasional foci of fused goblet cell nests with signet ring cells were also seen Some cells had PAS diastase�positive eosinophilic granular cytoplasm The nuclei were crescent-shaped or round and basally oriented, often with a single small nucleolus Diffuse infiltration into the periappendiceal fat and perineural invasion was seen in most cases
Goblet Cell Carcinoids of the Appendix Immunophenotype and Ultrastructural Study	Arch Pathol Lab Med 125:386�390, 2001 High cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin D1 and p21, and down-regulation of p16. Although appendiceal carcinoids are potentially lethal neoplasms, tumor eradication is usually feasible and effective Owing to the pattern of diffuse perineural and appendiceal wall infiltration, a complete removal (with microscopically negative margins) of the goblet cell variety of such carcinoids of the appendix is recommended
Angiogenic Polypoid Proliferation Adjacent to Ileal Carcinoid Tumors: A Nonspecific Finding Related to Mucosal Prolapse Neil A. Abrahams, M.D., Zissis Vesoulis, M.D. and Robert E. Petras, M.D. Department of Anatomic Pathology The Cleveland Clinic Foundation (NAA, REP), Cleveland, Ohio; and Department of Anatomic Pathology, Summa Health System (ZV), Akron, Ohio	Mod Pathol 2001;14:821-827 Abstract quote Case reports have highlighted angiogenic polypoid proliferation in the mucosa adjacent to ileal carcinoid tumors, describing them as granulation tissue polyposis and florid angiogenesis. Some authors have proposed that the ileal carcinoid tumors themselves produce growth factors that cause the change. The purpose of this study was to determine the frequency of angiogenic polypoid proliferation in a large cohort of resected ileal carcinoid tumors compared with control groups. Search of the Cleveland Clinic and Summa Health System pathology files (1985 to 1999) yielded 65 resected ileal carcinoid tumors. Mucosal abnormalities adjacent to the ileal carcinoid tumors were graded 0 to 4+. Twenty ileal resection margins from colonic carcinoma cases served as normal controls. Ileal mucosa adjacent to 22 noncarcinoid neoplasms were also examined. The mucosa adjacent to 54/65 ileal carcinoid tumors (83%) showed mucosal abnormalities (vs. 3/20 normal controls), including mucosal edema, capillary ectasia, muscularis mucosae hypertrophy, fibrosis/smooth muscle proliferation within the lamina propria, club-shaped villi, and intramucosal capillary proliferation. Forty ileal carcinoid tumor cases (61%) showed some degree of angiogenic polypoid proliferation characterized by club-shaped villi and prominent intramucosal capillaries, with 17 (26%) graded as 3+ or 4+. Angiogenic polypoid proliferation was associated with hypertrophy of the muscularis mucosae, lamina proprial fibrosis/smooth muscle proliferation, and capillary ectasia similar to that described with gastrointestinal mucosal trauma/prolapse. This trauma/prolapse change was identified in 45 cases (69%) and was graded 3+ or 4+ in 23 (35%). Seventeen (77%) of the noncarcinoid neoplasms showed trauma/prolapse changes, with 7 (32%) graded as 3+ or 4+. Angiogenic polypoid proliferation also correlated with trauma/prolapse change in the noncarcinoid neoplasm controls. Neither APP (P = .24) nor the prolapse changes (P = .33) were found to be statistically different between the two tumor groups. Angiogenic polypoid proliferation of the adjacent ileal mucosa is common in patients with ileal carcinoid tumors and with noncarcinoid neoplasms. Angiogenic polypoid proliferation almost invariably coexists with fibromuscular change and capillary ectasia within the lamina propria, suggesting that mucosal trauma/prolapse plays a role in the histogenesis. The association of angiogenic polypoid proliferation with a variety of different neoplasms makes it unlikely that the tumors themselves secrete growth factors.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Van Eeden S, Quaedvlieg PF, Taal BG, Offerhaus GJ, Lamers CB, Van Velthuysen ML. Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam Departments of Medical Oncology and Pathology of the Netherlands Cancer Institute, The Netherlands.	Hum Pathol 2002 Nov;33(11):1126-32 Abstract quote Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.
MIB1
Immunohistochemical Staining of Cytologic Smears With MIB-1 Helps Distinguish Low-Grade From High-Grade Neuroendocrine Neoplasms Oscar Lin, MD, PhD,1 Semra Olgac, MD,1 Ileana Green, MD,2 Maureen F. Zakowski, MD,1 and David S. Klimstra, MD	Am J Clin Pathol 2003;120:209-216 Abstract quote Neuroendocrine neoplasms (NENs) of the lung and gastrointestinal tract constitute a pathologic and biologic spectrum of tumors. Accurate cytologic diagnosis of a neuroendocrine neoplasm is important since definitive treatment frequently is based on low- and high-grade categories without histologic sampling. In many instances, however, low- and high-grade NENs share cytologic features, hindering a precise classification. Since the histologic diagnostic criteria for separation of low- from high-grade categories can be based on the proliferation rate, we proposed to evaluate the usefulness of the immunocytochemical stain for the proliferation marker MIB-1 in the grading of NENs. Cytologic preparations of 63 NENs were retrieved from the files of Memorial Sloan-Kettering Cancer Center, New York, NY. One representative alcohol-fixed slide from each case was destained and restained immunocytochemically for MIB-1. When MIB-1 immunoreactivity was considered, all low-grade NENs showed immunoreactivity in fewer than 25% of the neoplastic cells, and all high-grade NENs demonstrated immunoreactivity in more than 50% of neoplastic cells. Our study demonstrates that MIB-1 dramatically stratifies NENs as low-grade or high-grade. Therefore, the proliferation index also correlates with grade of NEN in cytology specimens.
TREATMENT	Surgical removal