Protocol for the Examination of Specimens From Patients With

Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and

Rectum
Version: ColonRectum NET 4.0.0.2 Protocol Posting Date: February 2020

CAP Laboratory Accreditation Program Protocol Required Use Date: November 2020

Includes pTNM requirements from the 8th Edition, AJCC Staging Manual

For accreditation purposes, this protocol should be used for the following procedures AND tumor types:
Procedure Description
Resection Includes specimens designated as low anterior resection
and abdominaoperineal resection, total, partial, or segmental
resection
Tumor Type Description
Well-differentiated neuroendocrine tumor

This protocol is NOT required for accreditation purposes for the following:
Procedure
Biopsy
Excision biopsy (transanal disk excision or polypectomy)
Primary resection specimen with no residual cancer (eg, following neoadjuvant therapy)
Recurrent tumor
Cytologic specimens

The following tumor types should NOT be reported using this protocol:
Tumor Type
Poorly-differentiated neuroendocrine carcinoma including small cell and large cell neuroendocrine
carcinoma (consider the Colon and Rectum Carcinoma protocol)
Other epithelial carcinoma of the colon and rectum including mixed neuroendocrine-non-neuroendocrine
neoplasm (consider the Colon and Rectum Carcinoma protocol)
Gastrointestinal stromal tumor (consider the GIST protocol)
Non-GIST sarcoma (consider the Soft Tissue protocol)

Authors
Chanjuan Shi, MD, PhD*; Volkan Adsay, MD; Emily K. Bergsland, MD; Jordan Berlin, MD; Philip A. Branton, MD;
Patrick L. Fitzgibbons, MD; Wendy L. Frankel, MD; Sanjay Kakar, MD; Veronica Klepeis, MD, PhD; David S.
Klimstra, MD; Joseph T. Lewis, MD; Laura H. Tang, MD; Eugene A. Woltering, MD; Mary K. Washington, MD,
PhD

With guidance from the CAP Cancer and CAP Pathology Electronic Reporting Committees.
* Denotes primary author. All other contributing authors are listed alphabetically.

© 2020 College of American Pathologists (CAP). All rights reserved.

For Terms of Use please visit www.cap.org/cancerprotocols.
 Endocrine • Colon and Rectum NET • 4.0.0.2

Accreditation Requirements
This protocol can be utilized for a variety of procedures and tumor types for clinical care purposes. For
accreditation purposes, only the definitive primary cancer resection specimen is required to have the core and
conditional data elements reported in a synoptic format.
• Core data elements are required in reports to adequately describe appropriate malignancies. For
accreditation purposes, essential data elements must be reported in all instances, even if the response is
“not applicable” or “cannot be determined.”
• Conditional data elements are only required to be reported if applicable as delineated in the protocol. For
instance, the total number of lymph nodes examined must be reported, but only if nodes are present in the
specimen.
• Optional data elements are identified with “+” and although not required for CAP accreditation purposes,
may be considered for reporting as determined by local practice standards.
The use of this protocol is not required for recurrent tumors or for metastatic tumors that are resected at a
different time than the primary tumor. Use of this protocol is also not required for pathology reviews performed at
a second institution (ie, secondary consultation, second opinion, or review of outside case at second institution).

Synoptic Reporting
All core and conditionally required data elements outlined on the surgical case summary from this cancer protocol
must be displayed in synoptic report format. Synoptic format is defined as:
• Data element: followed by its answer (response), outline format without the paired "Data element:
Response" format is NOT considered synoptic.
• The data element should be represented in the report as it is listed in the case summary. The response for
any data element may be modified from those listed in the case summary, including “Cannot be
determined” if appropriate.
• Each diagnostic parameter pair (Data element: Response) is listed on a separate line or in a tabular format
to achieve visual separation. The following exceptions are allowed to be listed on one line:
o Anatomic site or specimen, laterality, and procedure
o Pathologic Stage Classification (pTNM) elements
o Negative margins, as long as all negative margins are specifically enumerated where applicable
• The synoptic portion of the report can appear in the diagnosis section of the pathology report, at the end of
the report or in a separate section, but all Data element: Responses must be listed together in one location
Organizations and pathologists may choose to list the required elements in any order, use additional methods in
order to enhance or achieve visual separation, or add optional items within the synoptic report. The report may
have required elements in a summary format elsewhere in the report IN ADDITION TO but not as replacement for
the synoptic report i.e. all required elements must be in the synoptic portion of the report in the format defined
above.

Summary of Changes
Version 4.0.0.2
Background Notes (WHO 2019)

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CAP Approved Endocrine • Colon and Rectum NET • 4.0.0.2

Surgical Pathology Cancer Case Summary

Protocol posting date: February 2020

COLON AND RECTUM:

Note: This case summary is recommended for reporting local excision and polypectomy specimens, but
is not required for accreditation purposes.

Select a single response unless otherwise indicated.

Procedure (Note A)
___ Right hemicolectomy
___ Transverse colectomy
___ Left hemicolectomy
___ Sigmoidectomy
___ Low anterior resection
___ Total abdominal colectomy
___ Abdominoperineal resection
___ Transanal disk excision (local excision)
___ Polypectomy
___ Other (specify): ____________________________
___ Not specified

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

___ Cecum
___ Right (ascending) colon
___ Hepatic flexure
___ Transverse colon
___ Splenic flexure
___ Left (descending) colon
___ Sigmoid colon
___ Rectosigmoid junction
___ Rectum
___ Ileocecal valve
___ Colon, not otherwise specified
___ Cannot be determined (explain): _______________________________

Tumor Size (Note C)

Greatest dimension (centimeters): ___ cm (specify size of largest tumor if multiple tumors are present)
+ Additional dimensions (centimeters): ___ x ___ cm
___ Cannot be determined (explain): ____________________________

Tumor Focality
___ Unifocal
___ Multifocal (specify number of tumors): ______
___ Cannot be determined

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 3
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Endocrine • Colon and Rectum NET • 4.0.0.2

Histologic Type and Grade (Notes D and E)

___ G1: Well-differentiated neuroendocrine tumor
___ G2: Well-differentiated neuroendocrine tumor
___ G3: Well-differentiated neuroendocrine tumor
___ Other (specify): _________________________
___ GX: Well-differentiated neuroendocrine tumor, grade cannot be assessed
___ Not applicable
Note: For poorly differentiated neuroendocrine carcinomas, the CAP protocol for carcinoma of the colon and rectum should be
used.1

Mitotic rate and/or Ki67 labeling index is required to determine histologic grade.

Mitotic Rate (Note E)#

___ <2 mitoses/2mm2
___ 2-20 mitoses/2mm2
+Specify mitoses per 2mm2: _____
___ >20 mitoses per 2mm2
+Specify mitoses per 2mm2: _____
___ Cannot be determined (explain): __________________________
___ Not applicable
# Mitotic rate should be reported as number of mitoses per 2 mm2, by evaluating at least 10 mm2 in the most mitotically active
part of the tumor (eg, if using a microscope with a field diameter of 0.55 mm, count 42 high power fields [10 mm2] and divide
the resulting number of mitoses by 5 to determine the number of mitoses per 2 mm2 needed to assign tumor grade).

Ki-67 Labeling Index (Note E)

___ <3%
___ 3% to 20%
+ Specify Ki-67 percentage: ____%
___ >20%
+ Specify Ki-67 percentage: ____%
___ Cannot be determined (explain): __________________________
___ Not applicable

Tumor Extension
___ No evidence of primary tumor
___ Tumor invades the lamina propria
___ Tumor invades the submucosa
___ Tumor invades the muscularis propria
___ Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa
___ Tumor invades the visceral peritoneum (serosa)
___ Tumor invades other organs or adjacent structures (specify): ____________________
___ Cannot be assessed

Margins (Note F)
Note: Use this section only if all margins are uninvolved and all margins can be assessed.
___ All margins are uninvolved by tumor
Margins examined: _______________________
Note: Margins may include proximal, distal, radial or mesenteric, deep, mucosal, and others.
+ Distance of tumor from closest margin (millimeters or centimeters): ___ mm or ___ cm
+ Specify closest margin: __________________________

Individual margin reporting required if any margins are involved or margin involvement cannot be assessed

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 4
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Endocrine • Colon and Rectum NET • 4.0.0.2

For colectomy and rectal resection specimens only

Proximal Margin
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Distal Margin
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Radial or Mesenteric Margin

___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Other Margin(s) (required only if applicable)

Specify margin(s): _____________________________
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

For transanal disk excision or polypectomy specimens only

Deep Margin
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Mucosal Margin
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Other Margin(s) (required only if applicable)

Specify margin(s): _____________________________
___ Cannot be assessed
___ Uninvolved by tumor
___ Involved by tumor

Lymphovascular Invasion
___ Not identified
___ Present
___ Cannot be determined

+ Perineural Invasion
+ ___ Not identified
+ ___ Present
+ ___ Cannot be determined

Regional Lymph Nodes

___ No lymph nodes submitted or found

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 5
clinically important but are not yet validated or regularly used in patient management.
CAP Approved Endocrine • Colon and Rectum NET • 4.0.0.2

Lymph Node Examination (required only if lymph nodes are present in the specimen)

Number of Lymph Nodes Involved: ____

___ Number cannot be determined (explain): ______________________

Number of Lymph Nodes Examined: ____

___ Number cannot be determined (explain): ______________________

Pathologic Stage Classification (pTNM, AJCC 8th Edition) (Note G)

Note: Reporting of pT, pN, and (when applicable) pM categories is based on information available to the pathologist at the time
the report is issued. Only the applicable T, N, or M category is required for reporting; their definitions need not be included in
the report. The categories (with modifiers when applicable) can be listed on 1 line or more than 1 line.

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 the lamina propria or submucosa and is ≤2 cm
___ pT1a: Tumor <1 cm in greatest dimension
___ pT1b: Tumor 1-2 cm in greatest dimension
___ pT2: Tumor invades the muscularis propria or is >2 cm with invasion of the lamina propria or submucosa
___ pT3: Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying
serosa
___ pT4: Tumor invades visceral peritoneum (serosa) or other organs or other adjacent structures
#Note: For any T, add “(m)” for multiple tumors [TX(#) or TX(m), where X = 1–4 and # = number of primary tumors identified##];
for multiple tumors with different T, use the highest.
##Example: If there are two primary tumors, only one of which invades through the muscularis propria into the subserosal

tissue without penetration of the overlying serosa, we define the primary tumor as either T3(2) or T3(m) .

Regional Lymph Nodes (pN)

___ pNX: Regional lymph nodes cannot be assessed
___ pN0: No regional lymph node metastasis has occurred
___ pN1: Regional lymph node metastasis

Distant Metastasis (pM) (required only if confirmed pathologically in this case)

___ pM1: Distant metastasis
___ pM1a: Metastasis confined to liver
___ pM1b: Metastasis in at least one extrahepatic site (eg, lung, ovary, nonregional lymph node, peritoneum,
bone)
Specify site(s), if known: __________________________
___ pM1c: Both hepatic and extrahepatic metastases
Specify site(s), if known: __________________________

+ Additional Pathologic Findings (select all that apply) (Note H)

+ ___ None identified
+ ___ Tumor necrosis
+ ___ Other (specify): __________________________

+ Comment(s)

+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be 6
clinically important but are not yet validated or regularly used in patient management.
Background Documentation Endocrine • Colon and Rectum NET • 4.0.0.2

Explanatory Notes

A. Application and Tumor Location

This protocol applies to well-differentiated neuroendocrine tumors (carcinoid tumors) of the colon and rectum.
Poorly differentiated neuroendocrine carcinomas (including small cell carcinomas and large cell neuroendocrine
carcinomas) and tumors with mixed glandular/neuroendocrine differentiation are not included1.

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 1). 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.2

Table 1. Site of Origin of Gastrointestinal Neuroendocrine Tumors

Foregut Tumors Midgut Tumors Hindgut Tumors
Site Stomach, Proximal Jejunum, Ileum, Distal Colon,
Duodenum Appendix, Rectum
Proximal Colon
Immunohistochemistry
Chromogranin A 86%-100% + 82%-92% + 40%-58% +
Synaptophysin 50% + 95%-100% + 94%-100% +
Serotonin 33% + 3 86% + 3 45%-83% + 3-7
Other Rarely, + for pancreatic Prostatic acid Prostatic acid
Immunohistochemical polypeptide, histamine, gastrin, phosphatase + in phosphatase + in
Markers vasoactive intestinal peptide 20%-40% 8,9 20%-82% 3-9
(VIP), or adrenocorticotropic
hormone (ACTH)
Carcinoid syndrome Rare 5%-39% 10,11 Rare

References
1. Kakar S, Shi C, Berho ME, et al. Protocol for the Examination of Specimens From Patients With Primary
Carcinoma of the Colon and Rectum. 2017. Available at www.cap.org/cancerprotocols.
2. Rorstad O. Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg
Oncol. 2005;89(3):151-160.
3. Eckhauser FE, Argenta LC, Strodel WE, et al. Mesenteric angiopathy, intestinal gangrene, and midgut
carcinoids. Surgery. 1981;90(4):720-728.
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, and Pancreas. Philadelphia, PA: Saunders;
2004: 483-504.
6. Anlauf M, Garbrecht N, Henopp T, et al. Sporadic versus hereditary gastrinomas of the duodenum and
pancreas: distinct clinico-p
7. Eckhauser FE, Argenta LC, Strodel WE, et al. Mesenteric angiopathy, intestinal gangrene, and midgut
carcinoids. Surgery. 1981;90(4):720-728.
8. Kimura N, Sasano N. Prostate-specific acid phosphatase in carcinoid tumors. Virchows Arch A Pathol Anat
Histopathol. 1986;410(3):247-251.
9. 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 J
Clin Pathol. 1986;86(2):415-422.
10. Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology. 2007;50(1):30-
41.

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Background Documentation Endocrine • Colon and Rectum NET • 4.0.0.2

11. 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.

B. Site-Specific Features
Rectal neuroendocrine tumors are not uncommon, constitute approximately one-quarter of GI neuroendocrine
tumors.1 They are usually small, solitary, and clinically silent, most commonly occurring 4 cm to 13 cm from the
anal verge. Mitotically inactive rectal neuroendocrine tumors or those smaller than 2.0 cm are almost always
clinically indolent.2 Metastases and carcinoid syndrome are very rare. L-cell NETs are usually seen in the rectum.
Colonic neuroendocrine tumors outside the ileocecal region and rectum are extremely rare; most are large, bulky,
highly invasive tumors that are metastatic at presentation. Two-thirds of them arise within the cecum or right
colon. Many well-differentiated neuroendocrine tumors involving the ileocecal valve represent tumors arising in
the terminal ileum, rather than in the large bowel.

References
1. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97(4):934-959.
2. 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.

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. Rectal carcinoids smaller than 1.0 cm are almost always clinically indolent,
and local excision is generally considered sufficient for tumors 1.0 cm or smaller, as well as many tumors
between 1.0 cm and 2.0 cm. More extensive procedures (eg, right hemicolectomy and abdominoperineal
resection) are usually reserved for patients with rectal tumors larger than 2.0 cm, rectal tumors with regional
metastasis, and most colonic neuroendocrine tumors.

D. Histologic Type
The World Health Organization (WHO) classifies neuroendocrine neoplasms as well-differentiated
neuroendocrine tumors (either the primary tumor or metastasis) and poorly differentiated neuroendocrine
carcinomas.1-4 Historically, well-differentiated neuroendocrine tumors 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. The use of the term “carcinoid” for neuroendocrine tumor
reporting is therefore discouraged for these reasons.

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.

Although specific histologic patterns in well-differentiated neuroendocrine tumors, such as trabecular, insular, and
glandular, roughly correlate with tumor location,5 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.
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, synaptophysin, and CD56.3 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.6

References
1. 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: Saunders;
2004:483-504.
2. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International
Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1).

8
Background Documentation Endocrine • Colon and Rectum NET • 4.0.0.2

3. Williams GT. Endocrine tumours of the gastrointestinal tract: selected topics. Histopathology. 2007;50(1):30-
41.
4. 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.
5. 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.
6. Sobin LH, Hjermstad BM, Sesterhenn IA, Helwig EB. Prostatic acid phosphatases activity in carcinoid tumors.
Cancer. 1986;58(1):136-138.

E. Histologic Grade
Cytologic atypia in well-differentiated neuroendocrine tumors has no impact on clinical behavior of these tumors.
The WHO classification1 and others2 use mitotic rate and/or Ki-67 index as one of the criteria for potential for
aggressive behavior. Mitotic rate should be reported as number of mitoses per 2 mm2, by evaluating at least 10
mm2 in the most mitotically active part of the tumor. Only clearly identifiable mitotic figures should be counted;
hyperchromatic, karyorrhectic, or apoptotic nuclei are excluded. Because of variations in field size, the number of
high-power fields (HPF) (at 40X magnification) for 10 mm2 (thereby 2 mm2) must be determined for each
microscope (Table 2). For example, if using a microscope with a field diameter of 0.55 mm, count 42 HPF and
divide the resulting number of mitoses by 5 to determine the number of mitoses per 2 mm2 needed to assign
tumor grade.

Table 2. Number of HPF Required for 10 mm2 Using Microscopes With Different Field Diameter
Field Diameter (mm) Area (mm2) Number of HPF for 10 mm2
0.40 0.125 80
0.41 0.132 75
0.42 0.139 70
0.43 0.145 69
0.44 0.152 65
0.45 0.159 63
0.46 0.166 60
0.47 0.173 58
0.48 0.181 55
0.49 0.189 53
0.50 0.196 50
0.51 0.204 49
0.52 0.212 47
0.53 0.221 45
0.54 0.229 44
0.55 0.238 42
0.56 0.246 41
0.57 0.255 39
0.58 0.264 38
0.59 0.273 37
0.60 0.283 35
0.61 0.292 34
0.62 0.302 33

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Background Documentation Endocrine • Colon and Rectum NET • 4.0.0.2

0.63 0.312 32
0.64 0.322 31
0.65 0.332 30
0.66 0.342 29
0.67 0.353 28
0.68 0.363 28
0.69 0.374 28

Ki-67 index is reported as percent positive tumor cells in area of highest nuclear labeling (“hot spot”), although the
precise method of assessment has not been standardized. A number of methods have used to assess Ki-67
index, including automatic counting and “eyeballing”.3,4 Automated counting is not widely available and requires
careful modification of the software to circumvent the inaccuracies.11 Eye-balling can be used for most tumors;
however, for tumors with Ki-67 index close to grade cut-offs, it is recommended to perform the manual count on
the print of camera-captured image of the hot spot. It has been recommended that a minimum of 500 tumor cells
be counted to determine the Ki-67 index and a notation is made if less cells are available. Grade assigned based
on Ki-67 index is typically higher than that based on mitotic count, and the case is assigned to the higher of the 2
if both methods are performed.1

It is important to note that there are a small group of well-differentiated neuroendocrine tumors with a Ki-67 index
>20% and a mitotic rate usually <20 per 10 HPF. In WHO-2010, these tumors were considered as G3 poorly
differentiated neuroendocrine carcinomas. However, they have typical morphology of well-differentiated tumors.
Previous studies (most on pancreatic neuroendocrine tumors) have demonstrated that these tumors have a worse
prognosis than grade 2 (Ki-67=3-20 % and mitosis <20/10 HPF) neuroendocrine tumors, but they are not as
aggressive as poorly differentiated neuroendocrine carcinomas.5 In addition, these tumors do not have the genetic
abnormalities seen in poorly differentiated neuroendocrine carcinomas.6 Furthermore, unlike poorly differentiated
neuroendocrine carcinomas, they are less responsive to platinum-based chemotherapy.7 In WHO-2019 blue book
of digestive system tumors and AJCC 8th edition, those with typical morphology of well-differentiated tumors are
classified as “well differentiated neuroendocrine tumor” but as grade 3 (Table 3).1,8

Table 3
Recommended Grading System for Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors.
Grade Mitotic Rate (per 2mm2) Ki-67 index (%)
Well-differentiated neuroendocrine tumor, G1 <2 <3
Well-differentiated neuroendocrine tumor, G2 2-20 3-20
Well-differentiated neuroendocrine tumor, G3 >20 >20

References
1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International
Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol. 1).
2. 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.
3. Tang LH, Gonen M, Hedvat C, Modlin I, Klimstra DS. Objective quantification of the Ki67 proliferative index in
neuroendocrine tumors of gastroenteropancreatic system: a comparison of digital image analysis with manual
methods. Am J Surg Pathol. 2012;36(12):1761-1770.
4. Reid MD, Bagci P, Ohike N, et al. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a
comparative analysis of four counting methodologies. Mod Pathol. 2016;29(1):93.
5. Shi C, Klimstra DS. Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Semin
Diagn Pathol. 2014;31(6):498-511.
6. Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas
are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg
Pathol. 2012;36(2):173-84.

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Background Documentation Endocrine • Colon and Rectum NET • 4.0.0.2

7. Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine
carcinoma. Cancer. 2014;120(18):2814-2823.
8. Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer;
2017.

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, if applicable. The circumferential (radial) margin is considered positive if the tumor is present at 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.

A, Mesenteric margin in viscus completely encased by peritoneum (dotted line). B, Circumferential (radial) margin (dotted line)
in viscus incompletely encased by peritoneum. C, Circumferential (radial) margin (dotted line) in viscus completely unencased
by peritoneum.

G. Pathologic Stage Classification

The TNM staging system for neuroendocrine tumors of the colon and rectum of the American Joint Committee on
Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.1

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.

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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 following 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 prior to
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 of the colon and rectum are as follows:
Cecum: Pericolic, anterior cecal, posterior cecal, ileocolic, right colic
Ascending colon: Pericolic, ileocolic, right colic, middle colic
Hepatic flexure: Pericolic, middle colic, right colic
Transverse colon: Pericolic, middle colic
Splenic flexure: Pericolic, middle colic, left colic, inferior mesenteric
Descending colon: Pericolic, left colic, inferior mesenteric, sigmoid
Sigmoid colon: Pericolic, inferior mesenteric, superior rectal (hemorrhoidal), sigmoidal, sigmoid mesenteric
Rectosigmoid: Pericolic, perirectal, left colic, sigmoid mesenteric, sigmoidal, inferior mesenteric, superior rectal
(hemorrhoidal), middle rectal (hemorrhoidal)
Rectum: Perirectal, sigmoid mesenteric, inferior mesenteric, lateral sacral, presacral, internal iliac, sacral
promontory (Gerota’s), internal iliac, superior rectal (hemorrhoidal), middle rectal (hemorrhoidal), inferior
rectal (hemorrhoidal)

References
1. Shi C, Klimstra DS. Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. Semin
Diagn Pathol. 2014;31(6):498-511.

H. Additional Pathologic Findings

Coagulative tumor necrosis, usually punctate, may indicate more aggressive behavior1 and should be reported.

References
1. 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.

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