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.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.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)Other organs received:Procedure*Specimen Size (if applicable)Tumor Site (select all that apply) (note B)Tumor Size (note C)Tumor FocalityHistologic Type (note D)*Alternative Histologic Classification (note D)Histologic Grade (note E)aa For poorly differentiated neuroendocrine carcinomas arising in the small intestine or ampulla, the College of American Pathologists (CAP) checklists for carcinomas of those organ sites1,2 should be used.Mitotic RateMicroscopic Tumor Extension: Small IntestineMicroscopic Tumor Extension: AmpullaMarginsSmall-Intestine Resection SpecimenProximal MarginDistal MarginMesenteric (Radial) Margin (note F)Other Margin(s) (specify):___________________________Ampullectomy SpecimenPancreaticoduodenal Resection Specimen (for ampullary tumors)Proximal Mucosal Margin (Gastric or Duodenal)Distal Margin (Distal Duodenal or Jejunal)Pancreatic Retroperitoneal (Uncinate) MarginBile Duct MarginDistal Pancreatic Resection Margin If all margins uninvolved by neuroendocrine tumor:Lymph-Vascular Invasion*Perineural InvasionPathologic Staging (pTNM) (note G)TNM Descriptors (required only if applicable) (select all that apply)Primary Tumor (pT)Regional Lymph Nodes (pN)Distant Metastasis (pM)*Ancillary Studies (select all that apply) (note H)*Additional Pathologic Findings (select all that apply) (note I)*Comment(s): ______________________________________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.3Duodenal 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 1.8Most 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.3For 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.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.Well-Differentiated Neuroendocrine TumorNonfunctioning cytologically bland tumors confined to mucosa or submucosa, with no angioinvasion, and measuring not more than 1 cm in greatest dimension.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 CarcinomaNonfunctioning 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 PatternsAlthough 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.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 recommended12: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 ampulla2).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.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.The TNM staging system for neuroendocrine tumors of the duodenum, ampulla, and small bowel of the AJCC and the UICC is recommended.13By 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.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.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.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.7Immunohistochemistry 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.Commonly found in duodenal neuroendocrine tumors, especially periampullary tumors14 expressing somatostatin and associated with von Recklinhausen disease.5Associated 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.15The authors have no relevant financial interest in the products or companies described in this article.
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Washington et al. (2010) studied this question.