Protocol for the Examination of Specimens From Patients With Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and Rectum

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 large bowel and rectum. 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 colon of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.Colon and Rectum: Resection, Including Transanal Disk Excision of Rectal Neoplasms (note A)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)Procedure*Specimen Size (applicable to transanal disk excision)Tumor Site (select all that apply) (note B)Tumor Size (note C)Tumor FocalityHistologic Type (note D)*Alternative Histologic Classification (note E)*Histologic Grade (note E)aa For poorly differentiated neuroendocrine carcinomas, the College of American Pathologists (CAP) checklist for carcinoma of the colon and rectum1 should be used.Mitotic RateMicroscopic Tumor ExtensionMarginsProximal MarginDistal MarginCircumferential (Radial) Margin (note F)Other Margin(s) (specify): ____________________________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) (notes E and H)*Additional Pathologic Findings (select all that apply) (note I)*Comment(s): ______________________________________This protocol applies to low- and intermediate-grade neuroendocrine neoplasms (carcinoid tumors) of the colon and rectum. 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.2Rectal neuroendocrine tumors are common and constitute approximately a quarter of GI neuroendocrine tumors.3 They are usually small, solitary, and clinically silent, most commonly occurring 4 to 13 cm from the anal verge. Mitotically inactive rectal neuroendocrine tumors or those smaller than 2.0 cm are almost always clinically benign.4 Metastases and carcinoid syndrome are very rare. Large intestinal neuroendocrine tumors outside the ileocecal region and rectum are extremely rare; most reported tumors have been large (average size, 5.0 cm) and high grade, with a poor prognosis. Many low-grade neuroendocrine tumors involving the ileocecal valve represent tumors arising in the terminal ileum rather than in the large bowel.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. Rectal carcinoids smaller than 1.0 cm are almost always clinically benign, and local excision is generally considered sufficient for tumors 1.0 cm or smaller, as well as many tumors between 1.0 and 2.0 cm. More extensive procedures (eg, right hemicolectomy and abdominoperineal resection) are usually reserved for patients with tumors larger than 2.0 cm.The World Health Organization (WHO) classifies neuroendocrine neoplasms as well-differentiated neuroendocrine tumors, well-differentiated neuroendocrine carcinomas, and poorly differentiated neuroendocrine carcinomas.5–8 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.All colonic neuroendocrine tumors are considered potentially malignant; none are classified as benign or low-malignant-potential neuroendocrine tumors. Most are large, bulky, high grade, highly invasive tumors that are metastatic at presentation. Two-thirds arise within the cecum or right colon.Rectal neuroendocrine tumors, in contrast to colonic neuroendocrine tumors, are relatively common and generally behave in a benign fashion.Well-Differentiated Neuroendocrine TumorNonfunctioning cytologically bland tumors confined to mucosa or submucosa, with no angioinvasion, and measuring not more than 2 cm in greatest dimension.Nonfunctioning cytologically bland tumors confined to mucosa or submucosa, with angioinvasion, less than 2 cm in size.Well-Differentiated Neuroendocrine CarcinomaNonfunctioning tumors that are larger than 2 cm, or invade the muscularis propria or beyond, or are metastatic. Functional tumors associated with carcinoid syndrome 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,4 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, a grading system based on mitotic activity has been proposed for neuroendocrine tumors of the ileum, appendix, colon, and rectum9: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 checklist for carcinomas of the colon and rectum1 should be used for poorly differentiated neuroendocrine carcinomas arising in these sites).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 the 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, transverse colon) (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 colon and rectum of the AJCC and the UICC is recommended.11By 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 of the colon and rectum are 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. It should be noted that hindgut neuroendocrine tumors often do not express appreciable amounts of chromogranin A. Rectal neuroendocrine tumors express prostatic acid phosphatase, a potential diagnostic pitfall for tumors arising in male patients.12Immunohistochemistry 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.Coagulative tumor necrosis, usually punctate, may indicate more aggressive behavior10 and should be reported.The authors have no relevant financial interest in the products or companies described in this article.