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Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the appendix.

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 APPENDIX

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.

SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST)

Appendix: Excision (Appendectomy) or 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)

--Appendix

--Cecum

--Right colon

--Terminal ileum

--Other (specify):--

--Not specified

Procedure

-- Appendectomy

*Length: -- cm

-- Appendectomy and right colectomy

*Length of appendix: -- cm

*Length of colonic segment: -- cm

-- Other (specify): --

Specimen Integrity

--Intact

--Fragmented

*Number of pieces in fragmented specimens: Other (specify): --

*Specimen Size (if applicable)

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

Tumor Site

--Proximal half of appendix

--Distal half of appendix

--Diffusely involving appendix

--Appendix, not otherwise specified

--Unknown

Other (specify): --

Tumor Size (note B)

Greatest dimension: -- cm

*Additional dimensions: -- X -- cm --Cannot be determined (see Comment)

Histologic Type (note C)

--Carcinoid

--Atypical carcinoid

--Other (specify): --

*Alternative Histologic Classification (note C)

*--Well-differentiated endocrine tumor, benign behavior

*--Well-differentiated endocrine tumor, uncertain behavior

*-- Well-differentiated endocrine carcinoma

*Histologic Grade (note D) (a)

*--Not applicable

*--GX: Cannot be assessed

*--G1: Low grade

*--G2: Intermediate grade

*--Other (specify): --

(a) For poorly differentiated neuroendocrine carcinomas, the College of American Pathologists (CAP) checklist for carcinoma of the appendix1 should be used.

Mitotic Rate (note D)

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

--Cannot be determined

Microscopic Tumor Extension

--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 extends into mesoappendix

--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: )

Margins (note E)

Proximal Margin

--Cannot be assessed

--Uninvolved by tumor

--Involved by tumor

Distal Margin (not applicable for appendectomy specimens)

--Not applicable

--Cannot be assessed

--Uninvolved by tumor

--Involved by tumor

Mesenteric (Mesoappendiceal) Margin

--Cannot be assessed

--Uninvolved by tumor

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

--Involved by tumor

*Circumferential (Radial) Margin

*--Not applicable

*--Cannot be assessed

*--Uninvolved by tumor

* Involved by tumor (tumor present 0 to 1 mm from margin)

If all margins uninvolved by neuroendocrine tumor: Distance of tumor from closest margin: -- mm Specify margin: --

Lymph-Vascular Invasion

--Not identified

--Present

--Indeterminate

*Perineural Invasion

*--Not identified

*--Present

*--Indeterminate

Pathologic Staging (pTNM) (note F)

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 2 cm or less in greatest dimension

--pT1a: Tumor 1 cm or less in greatest dimension

--pT1b: Tumor more than 1 cm but not more than 2cm

--pT2: Tumor more than 2 cm but not more than 4 cm or with extension to the cecum

--pT3: Tumor more than 4 cm or with extension to the ileum

--pT4: Tumor directly invades other adjacent organs or structures (eg, abdominal wall and skeletal muscle)

Regional Lymph Nodes

--Cannot be assessed

--pN0: No regional lymph node metastasis

--pN1: Regional lymph node metastasis Specify:

Number examined: --

Number involved: --

Distant Metastasis

--Not applicable

--pM1: Distant metastasis

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

*Ancillary Studies (select all that apply) (notes D and G)

*--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 H)

*--Tumor necrosis

*--Acute appendicitis

*--Other (specify): --

*Comment(s): --

EXPLANATORY NOTES

A: Application and Tumor Location.--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.

B: Tumor Size.--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 invasion (4) 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.

C: Histologic Type.--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.

Alternative Classification Based Upon WHO Classification: Neuroendocrine Tumors of the Appendix

Well-Differentiated Neuroendocrine Tumor

Benign.--Nonfunctioning cytologically bland tumors measuring not more than 1 cm in greatest dimension, without extension into mesoappendix.

Uncertain Malignant Potential.--Nonfunctioning cytologically bland tumors measuring 1 to 2 cm, with extension into mesoappendix.

Well-Differentiated Neuroendocrine Carcinoma

Low-Grade Malignant Potential.--Nonfunctioning tumors measuring greater than 2 cm and deeply invading the mesoappendix; functioning tumors of any type.

Histologic Patterns

Although 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.

D: Histologic Grade.--Cytologic atypia in low-grade neuroendocrine tumors has no impact on clinical behavior of these tumors. The following grading system is recommended:
Grade   Mitotic Count (per 10 HPFs) (a)  Ki-67 Index, % (b)

G1      <2                               [less than or equal to] 2
G2      2 to 10                          >2 to 20
G3      >10                              >20

(a) Mitotic count should be based upon counting 50
high-power (x40 objective) fields 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.


[ILLUSTRATION OMITTED]

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).

E: Margins.--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.

F: TNM and Anatomic Stage/Prognostic Groupings.--The

TNM staging system for appendiceal NETs of the AJCC and the UICC is recommended. (2)

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.

T Category Considerations

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.

N Category Considerations

The regional lymph nodes for the appendix are the ileocolic lymph nodes.

pTNM Pathologic Classification

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.

pN0.--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.

Histopathologic Grading

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.
TNM Anatomic Stage/Prognostic Groupings

Stage I     T1       N0      M0
Stage II    T2, T3   N0      M0
Stage III   T4       N0      M0
            Any T    N1      M0
Stage IV    Any T    Any N   M1


G: 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. (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. (14)

Immunohistochemistry for Ki-67 may be useful in establishing tumor grade (note D) and prognosis12 but is not currently considered standard of care. (9)

H: Additional Pathologic Findings.--Coagulative tumor necrosis, usually punctate, may indicate more aggressive behavior (13) and should be reported. Appendiceal NETs are often an incidental finding in specimens removed for acute appendicitis.

References

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

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

(3.) Carr NJ, Sobin LH. Neuroendocrine tumors of the appendix. Semin Diagn Pathol. 2004;21(2):108-119.

(4.) Syracuse DC, Perzin KH, Price JB, Wiedel PD, Mesa-Tejada R. Carcinoid tumors of the appendix: mesoappendiceal extension and nodal metastases. Ann Surg. 1979;190(1):58-63.

(5.) Rossi G, Valli R, Bertolini F, etal. Does mesoappendix infiltration predict a worse prognosis in incidental neuroendocrine tumors of the appendix: a clinicopathologic and immunohistochemical study of 15 cases. Am J Clin Pathol. 2003;120(5):706-711.

(6.) 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, and Pancreas. Philadelphia, PA: WB Saunders; 2004: 483504.

(7.) 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.

(8.) Solcia E, Kloppel G, Sobin LH, et al. Histological typing of endocrine tumours. In: Solcia E, Kloppel G, Sobin LH, eds. World Health Organization International Histological Classification of Tumours. 2nd ed. New York, NY: Springer; 2000:61-68.

(9.) Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology. 2007;50(1):30-41.

(10.) 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.

(11.) Iwafuchi M, Watanabe H, Ajioka Y, Shimoda T, Iwashita A, Seiki I. Immunohistochemical and ultrastructural studies of twelve argentaffin and six argyrophil carcinoids of the appendix vermiformis. Hum Pathol. 1990;21(7):773 780.

(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.) Rindi G, Kloppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451(4):757-762.

(14.) Sobin LH, Hjermstad BM, Sesterhenn IA, Helwig EB. Prostatic acid phosphatase activity in carcinoid tumors. Cancer. 1986;58(1):136-138.

(15.) 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(10):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 Kakar, 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 (DrCarter);the Office of Biorepositories and 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 of Pathology, University of California San Francisco and the Veterans Affairs Medical Center, San Francisco, California (Dr Kakar);the Department of Radiation Oncology, University of Chicago, Chicago, Illinois (Dr Minsky);and the Department of Pathology, Mayo Clinic, Jacksonville, Florida (Dr Nakhleh).

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

Reprints: Mary K. Washington, MD, PhD, Department of Pathology, C-3316 MCN, Vanderbilt University Medical Center, Nashville, Tn 37232-2561 (e-mail: kay.washington@vanderbilt.edu).
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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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