Protocol for the Examination of Specimens From Patients With Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix

Abstract

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 appendix. Goblet cell carcinoids, poorly differentiated carcinomas with neuroendocrine features, and small cell carcinomas are not included. The 7th edition TNM staging system for neuroendocrine tumors of the appendix 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)ProcedureSpecimen Integrity*Specimen Size (if applicable)Tumor SiteTumor Size (note B)Histologic Type (note C)*Alternative Histologic Classification (note C)*Histologic Grade (note D)aa For poorly differentiated neuroendocrine carcinomas, the College of American Pathologists (CAP) checklist for carcinoma of the appendix1 should be used.Mitotic Rate (note D)Microscopic Tumor ExtensionMargins (note E)Proximal MarginDistal Margin (not applicable for appendectomy specimens)Mesenteric (Mesoappendiceal) Margin*Circumferential (Radial) MarginIf all margins uninvolved by neuroendocrine tumor:Lymph-Vascular Invasion*Perineural InvasionPathologic Staging (pTNM) (note F)TNM Descriptors (required only if applicable) (select all that apply)Primary Tumor (pT)Regional Lymph NodesDistant Metastasis*Ancillary Studies (select all that apply) (notes D and G)*Additional Pathologic Findings (select all that apply) (note H)*Comment(s): ______________________________________This protocol applies to well-differentiated neuroendocrine neoplasms (carcinoid tumors) of the appendix. Poorly differentiated neuroendocrine carcinomas, small cell carcinomas, and goblet cell carcinoids are not included.The appendix is a common site of gastrointestinal neuroendocrine tumors, usually presenting as small solitary lesions incidentally discovered after appendectomy. A separate staging system for appendiceal neuroendocrine tumors (NETs) is included in the AJCC Cancer Staging Manual2 because of the substantial differences in behavior between appendiceal carcinomas and NETs and between appendiceal NETs and other gastrointestinal NETs. Neuroendocrine tumors arising in the appendix have no in situ state and arise in the deep mucosa or submucosa. Unlike adenocarcinomas, for appendiceal NETs, tumor size is a more important predictor of patient outcome than depth of tumor invasion.Appendiceal neuroendocrine tumors smaller than 1.0 cm do not recur or metastasize, whereas those between 1.0 and 2.0 cm rarely do.3 Tumor size greater than 2.0 cm and mesoappendiceal invasion4 have been correlated with nodal metastasis, but not with poor outcome.5 For these reasons, appendectomy is 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) are usually reserved for patients with tumors larger than 2.0 cm or with invasion beyond the muscularis propria.Most appendiceal NETs are low grade, with few mitoses and no necrosis, and have traditionally been classified as “carcinoids.” While the term atypical carcinoid is not well defined for gastrointestinal NETs, the AJCC Cancer Staging Manual2 recommends using this term for appendiceal NETs with a mitotic count of 2 to 10 mitoses per 10 HPFs and/or focal necrosis. Although the term carcinoid tumor remains in widespread use, this term may cause confusion for clinicians, who might view a carcinoid tumor as a serotonin-producing tumor associated with functional manifestations of carcinoid syndrome.Alternative classification schemes based upon the World Health Organization (WHO) classification categorize neuroendocrine neoplasms as well-differentiated neuroendocrine tumors, well-differentiated neuroendocrine carcinomas, and poorly differentiated neuroendocrine carcinomas.6–9 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 measuring not more than 1 cm in greatest dimension, without extension into mesoappendix.Nonfunctioning cytologically bland tumors measuring 1 to 2 cm, with extension into mesoappendix.Well-Differentiated Neuroendocrine CarcinomaNonfunctioning tumors measuring greater than 2 cm and deeply invading the mesoappendix; functioning tumors of any type.Histologic PatternsAlthough specific histologic patterns in well-differentiated neuroendocrine neoplasms, such as trabecular, insular, and glandular, roughly correlate with tumor location,10 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.Most appendiceal neuroendocrine tumors are derived from enterochromaffin cells. Rarely, L-cell neuroendocrine tumors of the appendix are encountered; because of their distinctive growth pattern of teardrop-shaped tubules embedded in a fibrous stroma,11 these lesions are sometimes called tubular neuroendocrine tumors. It should be noted that these tumors are negative for chromogranin A but express enteroglucagon, peptide YY, and pancreatic polypeptide. Tubular neuroendocrine tumors are usually small lesions confined to the appendix and are found in female patients. These lesions exhibit benign behavior and should not be confused with adenocarcinoma.Cytologic atypia in low-grade neuroendocrine tumors has no impact on clinical behavior of these tumors. The following grading system is recommended:This grading system, while based upon that proposed by Rindi and colleagues,13 differs from their system in the designation of G2 tumors as showing mitotic counts of up to 10 per 10 HPFs, rather than 20 per 10 HPFs, in order to harmonize criteria for “atypical carcinoid” tumors, as proposed in the 7th edition of the AJCC TNM Cancer Staging Manual,2 with criteria for G2 designation.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 appendiceal carcinoma1 should be used for poorly differentiated neuroendocrine carcinomas of appendix).Margins in a simple appendectomy specimen include the proximal and mesenteric or radial margin. It is recommended that the proximal margin on a simple appendectomy specimen be taken en face to evaluate the entire appendiceal mucosa and muscularis circumferentially. In most cases, the appendix is entirely peritonealized, and the closest distance between the invasive carcinoma and the mesenteric resection margin represents the radial margin and should be measured. Even retrocecal appendices are usually invested by peritoneum but have adhered to the posterior cecum, either because of inflammation or tumor. Exceptionally, a retrocecal appendix may be retroperitoneal, in which case the distance between the tumor and the nonperitonealized radial resection margin is the “surgical clearance” and should be measured.In general, the circumferential (radial) margin must be assessed for any segment of gastrointestinal tract either incompletely encased or unencased by peritoneum (Figure, B and C). The posterior surface of the ascending colon portion of a right hemicolectomy specimen lacks a peritoneal covering and thus constitutes a circumferential margin, which in rare cases may be relevant in right hemicolectomy specimens resected for treatment of appendiceal neuroendocrine tumors. The circumferential (radial) 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, if applicable. 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, appendix and cecum) (Figure, A). Involvement of this margin should be reported even if tumor does not penetrate the serosal surface.The TNM staging system for appendiceal NETs of the AJCC and the UICC is recommended.2By 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.Tumor that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumor is present in the adhesion, microscopically the classification should be pT1 to pT3.The regional lymph nodes for the appendix are the ileocolic lymph nodes.The pT, pN, and pM categories correspond to the T, N, and M categories except that pM0 (no distant metastasis) does not exist as a category.Histologic examination of a regional lymphadenectomy specimen will ordinarily include 12 or more lymph nodes. If the lymph node results are negative, but the number ordinarily examined is not met, classify as pN0.Histologic grading is not required for carcinoid tumors, but a mitotic count of 2 to 10 per 10 HPFs and/or focal necrosis are features of atypical carcinoids (well-differentiated neuroendocrine carcinomas), a type seen much more commonly in the lung than in the appendix.Goblet cell carcinoids are classified according to the carcinoma scheme.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 CD56.9 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.14Immunohistochemistry for Ki-67 may be useful in establishing tumor grade (note D) and prognosis12 but is not currently considered standard of care.9Coagulative tumor necrosis, usually punctate, may indicate more aggressive behavior13 and should be reported. Appendiceal NETs are often an incidental finding in specimens removed for acute appendicitis.The authors have no relevant financial interest in the products or companies described in this article.