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Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the small intestine and ampulla.

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the "Surgical Pathology Cancer Case Summary (Checklist)" portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.

The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1,2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.

PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH NEUROENDOCRINE TUMORS (CARCINOID TUMORS) OF THE SMALL INTESTINE AND AMPULLA

This protocol applies to well-differentiated neuroendocrine tumors of the duodenum, ampulla, jejunum, and ileum. Carcinomas with mixed endocrine/glandular differentiation, poorly differentiated carcinomas with neuroendocrine features, and small cell carcinomas are not included. The 7th edition TNM staging system for neuroendocrine tumors of the small intestine and ampulla of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.

SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST)

Small Intestine and Ampulla: Segmental Resection, Ampullectomy, Pancreaticoduodenectomy (Whipple Resection)

Select a Single Response Unless Otherwise Indicated

* Data elements with asterisks are not required. However, these elements may be clinically important but are not yet validated or regularly used in patient management.

Specimen (select all that apply) (note A)

--Duodenum

--Ampulla of Vater

--Small intestine

*--Jejunum

*--Ileum

*--Unknown

Other organs received:

--Stomach

--Head of pancreas

--Common bile duct

--Gallbladder

--Cecum

--Right colon

--Appendix

--Other (specify): --

--Not specified

Procedure

--Segmental resection

--Ampullectomy

--Pancreaticoduodenectomy (Whipple resection)

--Other (specify): --

--Not specified

* Specimen Size (if applicable)

* Specify: --(length) X--X--cm

Tumor Site (select all that apply) (note B)

--Duodenum

--Ampulla

--Small bowel

*--Jejunum

*--Ileum

--Other (specify): --

--Not specified

Tumor Size (note C)

Greatest dimension: --cm (specify size of largest tumor if multiple tumors are present)

*Additional dimensions: --X --cm

--Cannot be determined (see Comment)

Tumor Focality

--Unifocal

--Multifocal (specify number of tumors: --)

--Cannot be determined

Histologic Type (note D)

--Carcinoid tumor (low-grade neuroendocrine neoplasm)

*--Somatostatinoma

*--Gastrinoma

*--Gangliocytic paraganglioma

*--Other (specify): --

*Alternative Histologic Classification (note D)

*--Well-differentiated endocrine tumor, benign behavior

*--Well-differentiated endocrine tumor, uncertain behavior

*--Well-differentiated endocrine carcinoma

Histologic Grade (note E) (a)

--Not applicable

--GX: Cannot be assessed

--G1: Low grade

--G2: Intermediate grade

--Other (specify): --

(a) For poorly differentiated neuroendocrine carcinomas arising in the small intestine or ampulla, the College of American Pathologists (CAP) checklists for carcinomas of those organ sites (1,2) should be used.

Mitotic Rate

Specify: --/10 high-power fields (HPFs)

--Cannot be determined

Microscopic Tumor Extension: Small Intestine

--Cannot be assessed

--No evidence of primary tumor

--Tumor invades lamina propria

--Tumor invades submucosa

--Tumor invades muscularis propria

--Tumor invades subserosal tissue without involvement of visceral peritoneum

--Tumor penetrates serosa (visceral peritoneum)

--Tumor directly invades adjacent structures (specify: --)

--Tumor penetrates to the surface of the visceral peritoneum (serosa) and directly invades adjacent structures (specify: --)

Microscopic Tumor Extension: Ampulla

--Cannot be assessed

--No evidence of primary tumor

--Tumor limited to ampulla of Vater or sphincter of Oddi

--Tumor invades duodenal wall

--Tumor invades pancreas

--Tumor invades peripancreatic soft tissues

--Tumor invades common bile duct

--Tumor invades other adjacent organs or structures (specify): --

Margins

Small-Intestine Resection Specimen

Proximal Margin

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor

Distal Margin

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor

Mesenteric (Radial) Margin (note F)

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor

Other Margin(s) (specify): --

--Not applicable

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor

Ampullectomy Specimen

--Margins cannot be assessed

--Margins uninvolved by neuroendocrine tumor Distance of neuroendocrine tumor from closest margin: --mm or --cm Specify margin (if possible): --

--Margin(s) involved by neuroendocrine tumor Specify margin(s) (if possible):

--Not applicable

Pancreaticoduodenal Resection Specimen (for ampullary tumors)

Proximal Mucosal Margin (Gastric or Duodenal)

--Cannot be assessed

--Uninvolved neuroendocrine tumor

--Involved by neuroendocrine tumor

Distal Margin (Distal Duodenal or Jejunal)

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor

Pancreatic Retroperitoneal (Uncinate) Margin

--Not applicable

--Cannot be assessed

--Uninvolved by neuroendocrine tumor

--Involved by neuroendocrine tumor (present 0-1 mm from margin)

Bile Duct Margin

--Not applicable

--Cannot be assessed

--Margin uninvolved by neuroendocrine tumor

--Margin involved by neuroendocrine tumor

Distal Pancreatic Resection Margin

--Not applicable

--Cannot be assessed

--Margin uninvolved by neuroendocrine tumor

--Margin involved by neuroendocrine tumor

If all margins uninvolved by neuroendocrine tumor:

Distance of tumor from closest margin: --mm or --cm

Specify margin: --

Lymph-Vascular Invasion

--Not identified

--Present

--Indeterminate

*Perineural Invasion

*--Not identified

*--Present

*--Indeterminate

Pathologic Staging (pTNM) (note G)

TNM Descriptors (required only if applicable) (select all that apply)

--m (multiple primary tumors)

--r (recurrent)

--y (posttreatment)

Primary Tumor (pT)

--pTX: Primary tumor cannot be assessed

--pT0: No evidence of primary tumor

--pT1: Tumor invades lamina propria or submu cosa and size 1 cm or less (small intestinal tumors); tumor 1 cm or less (ampullary tumors)

--pT2: Tumor invades muscularis propria or tumor size greater than 1 cm (small intestinal tumors); tumor size greater than 1 cm (ampullary tumors)

--pT3: Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa (jejunal or ileal tumors) or invades pancreas or retroperitoneum (ampullary or duodenal tumors) or into nonperitonealized tissues

--pT4: Tumor penetrates visceral peritoneum (serosa) or invades other organs

Regional Lymph Nodes (pN)

--Cannot be assessed

--pN0: No regional lymph node metastasis

--pN1: Regional lymph node metastasis

Specify:

Number examined: --

Number involved: --

Distant Metastasis (pM)

--Not applicable

--pM1: Distant metastasis

*Specify site(s), if known: --

*Ancillary Studies (select all that apply) (note H)

*--Ki-67 index

*-- [less than or equal to] #2%

*--.2% to 20%

*--.20%

*--Other (specify): --

*--Not performed

*Additional Pathologic Findings (select all that apply) (note I)

*--Endocrine cell hyperplasia

*--Tumor necrosis

*--Psammoma bodies

*--Mesenteric vascular elastosis

*--Other (specify): --

*Comment(s): --

EXPLANATORY NOTES

A: Application and Tumor Location.--This protocol applies to well-differentiated neuroendocrine neoplasms (carcinoid tumors) of the small intestine and ampulla of Vater. Poorly differentiated neuroendocrine carcinomas, small cell carcinomas, and tumors with mixed glandular/ neuroendocrine differentiation are not included.

Because of site-specific similarities in histology, immunohistochemistry, and histochemistry, neuroendocrine tumors of the digestive tract have traditionally been subdivided into those of foregut, midgut, and hindgut origin (Table). In general, the distribution pattern along the gastrointestinal (GI) tract parallels that of the progenitor cell type, and the anatomic site of origin of GI neuroendocrine tumors is an important predictor of clinical behavior. (3)

B: Site Specific Features.--Duodenal neuroendocrine tumors (NETs) are relatively uncommon, accounting for roughly 4% of GI NETs. (4) The most common subtype is the gastrin-secreting NET, or gastrinoma, associated with Zollinger-Ellison syndrome in one-third of cases. (5) These gastrin-secreting tumors are often associated with multiple endocrine neoplasia type 1 (MEN1) syndrome, but sporadic tumors also occur. (6) Duodenal somatostatin-producing tumors (somatostatinomas) are less common, accounting for about 1% of GI NETs, and are seldom associated with the functional syndrome of mild diabetes mellitus, cholelithiasis, and steatorrhea. These tumors often have a pure glandular growth pattern with scattered psammoma bodies and may be confused with conventional adenocarcinomas. (7) They arise almost exclusively in the ampulla or periampullary duodenum and are often associated with MEN1 and with neurofibromatosis type 1. (8)

Most small-bowel neuroendocrine tumors occur in the distal ileum. Multiple tumors are found in 25% to 40% of cases and may be associated with a worse outcome. (9) Metastatic risk is increased by tumor size greater than 2 cm, involvement of the muscularis propria, and mitotic activity. (3)

C: Tumor Size.--For neuroendocrine tumors in any part of the gastrointestinal tract, size greater than 2.0 cm is associated with a higher risk of lymph node metastasis. For jejunoileal tumors, nodal metastases occur in about 12% of patients with tumors smaller than 1.0 cm and in most patients with tumors larger than 1.0 cm. (3) Thus, treatment for small-bowel carcinoid tumor includes complete resection with regional lymphadenectomy.

D: Histologic Type.--The World Health Organization (WHO) classifies neuroendocrine neoplasms as well-differentiated neuroendocrine tumors, well-differentiated neuroendocrine carcinomas, and poorly differentiated neuroendocrine carcinomas. (5,7,10) Historically, well-differentiated neuroendocrine neoplasms have been referred to as carcinoid tumors, a term which may cause confusion because clinically a carcinoid tumor is a serotonin-producing tumor associated with functional manifestations of carcinoid syndrome.

Classification of neuroendocrine tumors is based upon size, functionality, site, and invasion. Functioning tumors are those associated with clinical manifestations of hormone production or secretion of measurable amounts of active hormone; immunohistochemical demonstration of hormone production is not equivalent to clinically apparent functionality.

Neuroendocrine Tumors of the Small Bowel

Well-Differentiated Neuroendocrine Tumor

Benign.--Nonfunctioning cytologically bland tumors confined to mucosa or submucosa, with no angioinvasion, and measuring not more than 1 cm in greatest dimension.

Uncertain Malignant Potential.--Nonfunctioning cytologically bland tumors confined to mucosa or submucosa, with or without angioinvasion, or greater than 1 cm in size. All gangliocytic paragangliomas without metastases are included in this category.

Well-Differentiated Neuroendocrine Carcinoma

Low-Grade Malignant Potential.--Nonfunctioning tumors that are larger than 2 cm or invade the muscularis propria or beyond or are metastatic. All functional tumors, such as small gastrinomas, are included in this category.

Histologic Patterns

Although specific histologic patterns in well-differentiated neuroendocrine neoplasms, such as trabecular, insular, and glandular, roughly correlate with tumor location, (11) these patterns have not been clearly shown independently to predict response to therapy or risk of nodal metastasis and are rarely reported in clinical practice.

E: Histologic Grade.--Cytologic atypia in low-grade neuroendocrine tumors has no impact on clinical behavior of these tumors. However, grading systems based on mitotic activity have been shown to have utility for foregut tumors. The following grading system is recommended (12):
Grade Mitotic Count (per 10 HPFs) (a) Ki-67 Index, % (b)

G1  <2 #2       [less than or equal to]2
G2  2 to 20     >2 to 20
G3  >20         >20

(a) Mitotic count should be based upon counting 50
high-power (X 40 objective) fields and in the area of
highest mitotic activity and reported as number of
mitoses per 10 HPFs.

(b) Ki-67 index is reported as percentage of positive
tumor cells in area of highest nuclear labeling. It has
been recommended that 2000 tumor cells be counted
to determine the Ki-67 index (12); however, this practice
may not be practical for routine clinical purposes,
and it is acceptable to estimate the labeling index.


G1 and G2 are well-differentiated tumors with diffuse intense chromogranin/synaptophysin positivity. Punctate necrosis is more typical of G2 tumors. G3 tumors are high-grade neuroendocrine carcinomas (the CAP carcinoma checklist for the appropriate organ system should be used for poorly differentiated neuroendocrine carcinomas of the small intestine1 and ampulla (2)).

F: Circumferential (Radial or Mesenteric) Margin.--In addition to addressing the proximal and distal margins, assessment of the circumferential (radial) margin is necessary for any segment of gastrointestinal tract, either unencased (Figure, C) or incompletely encased by peritoneum (Figure, B). The circumferential margin represents the adventitial soft-tissue margin closest to the deepest penetration of tumor and is created surgically by blunt or sharp dissection of the retroperitoneal or subperitoneal aspect, respectively. The distance between the tumor and circumferential (radial) margin should be reported. The circumferential (radial) margin is considered negative if the tumor is more than 1 mm from the inked nonperitonealized surface but should be recorded as positive if tumor is located 1 mm or less from the nonperitonealized surface. This assessment includes tumor within a lymph node as well as direct tumor extension, but if circumferential (radial) margin positivity is based solely on intranodal tumor, this should be so stated.

[ILLUSTRATION OMITTED]

The mesenteric resection margin is the only relevant circumferential margin in segments completely encased by peritoneum (eg, jejunum and ileum) (Figure, A). Involvement of this margin should be reported even if tumor does not penetrate the serosal surface.

G: TNM and Stage Groupings.--The TNM staging system for neuroendocrine tumors of the duodenum, ampulla, and small bowel of the AJCC and the UICC is recommended.13

By AJCC/UICC convention, the designation "T" refers to a primary tumor that has not been previously treated. The symbol "p" refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.

Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.

TNM Descriptors

For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.

The "m" suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.

The "y" prefix indicates those cases in which classification is performed during or after initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The "y" categorization is not an estimate of tumor before multimodality therapy (ie, before initiation of neoadjuvant therapy).

The "r" prefix indicates a recurrent tumor when staged after a documented disease-free interval and is identified by the "r" prefix: rTNM.

The "a" prefix designates the stage determined at autopsy: aTNM.

N Category Considerations

The regional lymph nodes for the small intestine vary with site. For duodenal tumors, the regional lymph nodes are duodenal, hepatic, pancreaticoduodenal, infrapyloric, gastroduodenal, pyloric, superior mesenteric, and pericholedochal nodes. For ileal and jejunal tumors, the regional lymph nodes are the cecal (for tumors arising in the terminal ileum), superior mesenteric, and mesenteric nodes. Metastases to celiac nodes are considered distant metastases.

The regional nodes for the ampulla may be subdivided as follows.

1. Superior: lymph nodes superior to head and body of pancreas

2. Inferior: lymph nodes inferior to head and body of pancreas

3. Anterior: anterior pancreaticoduodenal, pyloric, and proximal mesenteric lymph nodes

4. Posterior: posterior pancreaticoduodenal, common bile duct or pericholedochal, and proximal mesenteric nodes

H: Ancillary Studies.--Immunohistochemistry and other ancillary techniques are generally not required to diagnose well-differentiated neuroendocrine tumors. Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, neuron-specific enolase, synaptophysin, and CD56.7 Because of their relative sensitivity and specificity, chromogranin A and synaptophysin are recommended.

Immunohistochemistry for Ki-67 may be useful in establishing tumor grade (note E) and prognosis12 but is not currently considered standard of care.7

Immunohistochemistry for specific hormone products, such as glucagon, gastrin, and somatostatin, may be of interest in some cases. However, immunohistochemical demonstration of hormone production does not equate with clinical functionality of the tumor.

I: Additional Pathologic Findings.--Psammoma Bodies.-- Commonly found in duodenal neuroendocrine tumors, especially periampullary tumors14 expressing somatostatin and associated with von Recklinhausen disease.5

Mesenteric Vascular Changes (Elastic Vascular Sclerosis).-- Associated with midgut carcinoids, may produce arterial luminal narrowing due to concentric accumulation of elastic tissue in the adventitia. These vascular changes may lead to intestinal ischemia and frank necrosis.15

References

1. Washington K, Berlin J, Branton P, et al. Protocol for the examination of specimens from patients with carcinoma of the small intestine. In: Reporting on Cancer Specimens: Case Summaries and Background Documentation. Northfield, IL: College of American Pathologists; 2009.

2. Washington K, Berlin J, Branton P, et al. Protocol for the examination of specimens from patients with carcinoma of the ampulla of Vater. In: Reporting on Cancer Specimens: Case Summaries and Background Documentation. Northfield, IL; College of American Pathologists: 2009.

3. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors ofthe gastrointestinal tract. J Surg Oncol. 2005;89(3):151-160.

4. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid

tumors. Cancer. 2003;97(4):934 959.

5. Graeme-Cook F. Neuroendocrine tumors of the GI tract and appendix. In: Odze RD, Goldblum JR, Crawford JM, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, andPancreas. Philadelphia, PA: WB Saunders; 2004:483 504.

6. Anlauf M, Garbrecht N, Henopp T, et al. Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. WorldJGastroenterol. 2006;12(34):5440 5446.

7. Williams GT. Endocrine tumours of the gastrointestinal tract: selected

topics. Histopathology. 2007;50(1):30 41.

8. Garbrecht N, Anlauf M, Schmitt A, et al. Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional

activity. Endocr Rel Cancer. 2008;15(1):229 241.

9. Yantiss RK, Odze RD, Farraye FA, Rosenberg AE. Solitary versus multiple carcinoid tumors ofthe ileum: aclinicaland pathologic reviewof69 cases. Am J

SurgPathol. 2003;27(6):811 817.

10. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci.

2004;1014:13 27.

11. Soga J. Carcinoids of the colon and ileocecal region: a statistical evaluation of 363 cases collected from the literature. J Exp Clin Cancer Res. 1998;17(2):139-148.

12. Rindi G, Kloppel G, Alhman H, et al; and all other Frascati Consensus Conference participants; European Neuroendocrine Tumor Society (ENETS). TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449(4):395 401.

13. Edge SB, Byrd DR, Carducci MA, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009.

14. Burke AP, Sobin LH, FederspielBH, ShekiTkta KM, Helwig EB. Carcinoid

tumors of the duodenum: a clinicopathologic study of 99 cases. Arch Pathol Lab

Med. 1990;114(7):700 704.

15. Eckhauser FE, Argenta LC, Strodel WE, et al. Mesenteric angiopathy, intestinal gangrene, and midgut carcinoids. Surgery. 1981;90(4):720 728.

16. Kimura N, Sasano N. Prostate-specific acid phosphatase in carcinoid

tumors. Virchows Arch A Pathol Anat Histopathol. 1986;410(3):247 251.

17. Nash SV, Said JW. Gastroenteropancreatic neuroendocrine tumors: a histochemical and immunohistochemical study of epithelial (keratin proteins, carcinoembryonic antigen) and neuroendocrine (neuron-specific enolase, bombesin and chromogranin) markers in foregut, midgut, and hindgut tumors.

Am JClin Pathol. 1986;86(2):415 422.

18. Washington MK, Berlin J, Branton PA, et al. Protocol for the examination of specimens from patients with primary carcinomas of the colon and rectum.

Arch Pathol Lab Med. 2009;133(9):1539 1551.

Mary Kay Washington, MD, PhD; Laura H. Tang, MD, PhD; Jordan Berlin, MD; Philip A. Branton, MD; Lawrence J. Burgart, MD; David K. Carter, MD; Carolyn C. Compton, MD, PhD; Patrick L. Fitzgibbons, MD; Wendy L. Frankel, MD; J. Milburn Jessup, MD; Sanjay Ka

kar, MD; Bruce Minsky, MD; Raouf E. Nakhleh, MD; for the Members of the Cancer Committee, College of American Pathologists

Accepted for publication October 14, 2009.

From the Departments of Pathology (Dr Washington) and Medicine (Dr Berlin), Vanderbilt University Medical Center, Nashville, Tennessee; the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Inova Fairfax Hospital, Falls Church, Virginia (Dr Branton);Allina Laboratories, Abbott Northwestern Hospital, Minneapolis, Minnesota (Dr Burgart); Department of Pathology, St Mary's/Duluth Clinic Health System, Duluth, Minnesota (Dr Carter); theOfficeofBiorepositoriesand Biospecimen Research (Dr Compton) and the Division of Cancer Treatment and Diagnosis (Dr Jessup), National Cancer Institute, Bethesda, Maryland; the Department of Pathology, St Jude Medical Center, Fullerton, California (Dr Fitzgibbons); the Department of Pathology, Ohio State University Medical Center, Columbus, Ohio (Dr Frankel); the Department ofPathology, University of California San Francisco and the Veterans Affairs Medical Center, San Francisco, California (Dr Kakar); the Department of Radiation Oncology, UniversityofChicago, Chicago, Illinois (Dr Minsky); and theDepartmentof Pathology, Mayo Clinic, Jacksonville, Florida (Dr Nakhleh).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: MaryKayWashington, MD, PhD, DepartmentofPathology, C-3316 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2561 (e-mail: kay.washington@vanderbilt.edu).
Site of Origin of Gastrointestinal Neuroendocrine Tumors

Site
                                       Foregut Tumors

                                 Stomach, proximal duodenum

Immunohistochemistry, % +
  Chromogranin A             86-100
  NSE                        90-100
  Synaptophysin              50
  Serotonin                  33 (16,17)
Other immunohistochemical    Rarely, + for pancreatic
  markers                      polypeptide, histamine,
                               gastrin, VIP, or ACTH
Carcinoid syndrome, %        Rare

Site                                  Midgut Tumors

                                 Jejunum, leum, appendix,
                                      proximal colon

Immunohistochemistry, % +
  Chromogranin A             2-92
  NSE                        95-100
  Synaptophysin              95-100
  Serotonin                  86 (16,17)
Other immunohistochemical    Prostatic acid phosphatase + in
  markers                      20%-40% of cases (16,17)

Carcinoid syndrome, %        5-39 (7,8)

Site
                                      Hindgut Tumors

                                   Distal colon, rectum

Immunohistochemistry, % +
  Chromogranin A             40-58
  NSE                        80-87
  Synaptophysin              94-100
  Serotonin                  45-83 (4 6,17)
Other immunohistochemical    Prostatic acid phosphatase + in
  markers                      20% 82% of cases (4-6,17)

Carcinoid syndrome, %        Rare

Abbreviations: ACTH, adrenocorticotropic hormone; NSE, neuron-specific
enolase; VIP, vasoactive intestinal peptide; +, positive.

TNM Anatomic Stage/Prognostic Groupings

Stage I      T1      N0      M0 (a)
Stage IIA    T2      N0      M0
Stage IIB    T3      N0      M0
Stage IIIA   T4      N0      M0
Stage IIIB   Any T   N1      M0
Stage IV     Any T   Any N   M1

(a) M0 is defined as no distant metastasis.
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Author:Washington, Mary Kay; Tang, Laura H.; Berlin, Jordan; Branton, Philip A.; Burgart, Lawrence J.; Cart
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Feb 1, 2010
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