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

This protocol applies to well-differentiated neuroendocrine tumors of the stomach. 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 stomach of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.

Stomach: Endoscopic Resection, Gastrectomy (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)

1. ___ Stomach

2. ___ Portion of stomach

   1. ___ Gastric body

   2. ___ Gastric antrum

   3. ___ Not specified

3. ___ Distal esophagus

4. ___ Proximal duodenum

5. ___ Other (specify): _______________________________

6. ___ Not specified

Procedure

1. ___ Endoscopic resection

2. ___ Partial gastrectomy, proximal

3. ___ Partial gastrectomy, distal

4. ___ Partial gastrectomy, other (specify): ____________

5. ___ Total gastrectomy

6. ___ Other (specify): _______________________________

7. ___ Not specified

*Specimen Size (if applicable)

1. *Specify: ___ (length) × ___ × ___ cm

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

1. ___ Gastric cardia

2. ___ Gastric fundus

3. ___ Gastric body

4. ___ Gastric antrum

5. ___ Other (specify): _______________________________

6. ___ Not specified

Tumor Size (note C)

1. Greatest dimension: ___ cm (specify size of largest tumor if multiple tumors are present)

2. *Additional dimensions: ___ × ___ cm

3. ___ Cannot be determined (see Comment)

Tumor Focality

1. ___ Unifocal

2. ___ Multifocal (specify number of tumors: _____)

3. ___ Cannot be determined

Histologic Type (note D)

1. ___ Carcinoid tumor

2. ___ Other (specify): _______________________________

*Alternative Histologic Classification (note E)

1. *___ Well-differentiated endocrine tumor, benign behavior

2. *___ Well-differentiated endocrine tumor, uncertain behavior

3. *___ Well-differentiated endocrine carcinoma

*Histologic Grade (note E)^a

1. *___ Not applicable

2. *___ GX: Cannot be assessed

3. *___ G1: Low grade

4. *___ G2: Intermediate grade

5. *___ Other (specify): ______________________________

^a For poorly differentiated (high-grade) neuroendocrine carcinomas, the College of American Pathologists (CAP) checklist for carcinoma of the stomach1 should be used.

Mitotic Rate (note E)

1. Specify: ___/10 high-power fields (HPFs)

2. ___ Cannot be determined

Microscopic Tumor Extension

1. ___ Cannot be assessed

2. ___ No evidence of primary tumor

3. ___ Tumor invades lamina propria

4. ___ Tumor invades into but not through muscularis mucosae

5. ___ Tumor invades submucosa

6. ___ Tumor invades muscularis propria

7. ___ Tumor invades subserosal tissue without involvement of visceral peritoneum

8. ___ Tumor penetrates serosa (visceral peritoneum)

9. ___ Tumor directly invades adjacent structures (specify: _________________ )

10. ___ Tumor penetrates to the surface of the visceral peritoneum (serosa) and directly invades adjacent structures (specify: _________________ )

Margins (select all that apply)

Proximal Margin

1. ___ Cannot be assessed

2. ___ Uninvolved by neuroendocrine tumor

3. ___ Involved by neuroendocrine tumor

4. *___ Involved by neuroendocrine cell hyperplasia/dysplasia

Distal Margin

1. ___ Cannot be assessed

2. ___ Uninvolved by neuroendocrine tumor

3. ___ Involved by neuroendocrine tumor

4. *___ Involved by neuroendocrine cell hyperplasia/dysplasia

Omental (Radial) Margin (note F)

1. ___ Cannot be assessed

2. ___ Uninvolved by neuroendocrine tumor

3. ___ Involved by neuroendocrine tumor

Other Margin(s) (specify): _________________________

1. ___ Not applicable

2. ___ Cannot be assessed

3. ___ Uninvolved by neuroendocrine tumor

4. ___ Involved by neuroendocrine tumor

5. *___ Involved by neuroendocrine cell hyperplasia/dysplasia

If all margins uninvolved by neuroendocrine tumor:

1.  Distance of tumor from closest margin: ___ mm or ___ cm

2.  Specify margin: ________________________________

Lymph-Vascular Invasion

1. ___ Not identified

2. ___ Present

3. ___ Indeterminate

*Perineural Invasion

1. *___ Not identified

2. *___ Present

3. *___ Indeterminate

Pathologic Staging (pTNM) (note G)

TNM Descriptors (required only if applicable) (select all that apply)

1. ___ m (multiple primary tumors)

2. ___ r (recurrent)

3. ___ y (posttreatment)

Primary Tumor (pT)

1. ___ pTX: Primary tumor cannot be assessed

2. ___ pT0: No evidence of primary tumor

3. ___ pTis: Carcinoma in situ/dysplasia (tumor size less than 0.5 mm), confined to mucosa

4. ___ pT1: Tumor invades lamina propria or submucosa and 1 cm or less in size

5. ___ pT2: Tumor invades muscularis propria or more than 1 cm in size

6. ___ pT3: Tumor penetrates subserosa

7. ___ pT4: Tumor invades visceral peritoneum (serosal) or other organs or adjacent structures

Regional Lymph Nodes (pN)

1. ___ Cannot be assessed

2. ___ pN0: No regional lymph node metastasis

3. ___ pN1: Metastasis in regional lymph nodes

   1.  Specify:

      1. Number examined: ___

      2. Number involved: ___

Distant Metastasis (pM)

1. ___ Not applicable

2. ___ pM1: Distant metastasis

   1. *Specify site(s), if known: _____________________

*Ancillary Studies (select all that apply) (notes E and H)

1. *___ Ki-67 index

   1. *___ ≤2%

   2. *___ >2% to 20%

   3. *___ >20%

2. *___ Other (specify): ______________________________

3. *___ Not performed

Additional Pathologic Findings (select all that apply) (note I)

1. *___ Atrophic gastritis

2. *___ Intestinal metaplasia of gastric mucosa

3. *___ Glandular dysplasia of gastric mucosa

4. *___ Endocrine cell hyperplasia

5. *___ Absence of parietal cells

6. *___ Tumor necrosis

7. *___ Other (specify): ______________________________

*Comment(s): ______________________________________

This protocol applies to well-differentiated neuroendocrine neoplasms (carcinoid tumors) of the stomach. 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 1). In general, the distribution pattern along the gastrointestinal tract parallels that of the progenitor cell type, and the anatomic site of origin of gastrointestinal neuroendocrine tumors is an important predictor of clinical behavior.2 

Gastric neuroendocrine tumors are divided into 4 types.3 Type 1 tumors arising in the setting of atrophic gastritis with associated hypergastrinemia are the most common. These lesions are composed of enterochromaffin-like cells and are usually found as multiple small nodules in the body of the stomach and limited to mucosa and submucosa. Type 1 lesions are generally benign and may regress following antrectomy; lymph node metastases are very rare and occur only when the tumors are large (greater than 2 cm) and infiltrate the muscularis propria.

Type 2 gastric neuroendocrine tumors are rare. These multifocal small tumors, which are associated with multiple endocrine neoplasia type 1 with Zollinger-Ellison syndrome, develop in the body of the stomach, are usually smaller than 1.5 cm, and are confined to the mucosa or submucosa. However, in contrast to type 1 tumors, 30% metastasize. Tumors greater than 2 cm and invading the muscularis propria and exhibiting vascular invasion are more likely to metastasize.

Type 3 gastric neuroendocrine tumors, the second most common neuroendocrine tumor in the stomach, are sporadic solitary tumors that are unassociated with atrophic gastritis or endocrine cell hyperplasia. These tumors may occur anywhere in the stomach. Metastasis is associated with larger mean size, angioinvasion, and invasion of muscularis propria. Surgical resection is usually advised for solitary gastric carcinoid tumors, particularly those larger than 2.0 cm, but tumors smaller than 1.0 cm have been rarely reported to metastasize.4 

Type 4 gastric neuroendocrine tumors are rare, high-grade neuroendocrine carcinomas that are usually bulky tumors with metastases at diagnosis (the CAP cancer checklist for gastric carcinoma1 applies).

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. In the stomach, types 3 and 4 neuroendocrine tumors are significantly larger than type 1 tumors,3 which usually measure 1 cm or less5,6 (Table 2). Tumor size correlates with depth of invasion for gastric neuroendocrine tumors, with larger tumors more likely to be deeply infiltrative and thus at higher risk for metastases. Nodules measuring 0.5 mm or larger are defined as neuroendocrine tumors; lesions measuring less than 0.5 mm are regarded as representing in situ tumor, neuroendocrine cell dysplasia, or hyperplasia.

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.

Well-Differentiated Neuroendocrine Tumor

Nonfunctioning cytologically bland tumors confined to mucosa or submucosa, without angiovascular invasion, and measuring not more than 1 cm in greatest dimension. Nodules of neuroendocrine cells that measure between 0.5 and 1 cm and are confined to the mucosa are classified by some as microneuroendocrine tumors.

Nonfunctioning, cytologically bland tumors confined to mucosa or submucosa, with or without angioinvasion and measuring from 1 to 2 cm.

Well-Differentiated Neuroendocrine Carcinoma

Nonfunctioning tumors that invade the muscularis propria or beyond, or are metastatic, or measure greater than 2 cm; all sporadic gastric neuroendocrine tumors (type 3 tumors) and some type 1 and 2 tumors. All functioning tumors of any type, including gastrinomas.

Histologic Patterns

Although specific histologic patterns in well-differentiated neuroendocrine neoplasms, such as trabecular, insular, and glandular, roughly correlate with tumor location, 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 recommended9:

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 carcinomas of the stomach1 applies).

For surgical resection specimens, margins include the proximal, distal, and radial margins. The radial margins represent the nonperitonealized soft-tissue margins closest to the deepest penetration of tumor. In the stomach, the lesser omental (hepatoduodenal and hepatogastric ligaments) and greater omental resection margins are the only radial margins. For endoscopic resection specimens, margins include mucosal margins and the deep margin of resection. It may be helpful to mark the margin(s) closest to the tumor with ink. Margins marked by ink should be designated in the macroscopic description.

The TNM staging system for gastric neuroendocrine tumors of the AJCC and the UICC is recommended.10 

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.

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 specific nodal areas of the stomach are listed below.10 

1. Greater curvature of stomach: greater curvature, greater omental, gastroduodenal, gastroepiploic, pyloric, and pancreaticoduodenal

2. Pancreatic and splenic area: pancreaticolienal, peripancreatic, splenic

3. Lesser curvature of stomach: lesser curvature, lesser omental, left gastric, cardioesophageal, common hepatic, celiac, and hepatoduodenal

Involvement of other intra-abdominal lymph nodes, such as hepatoduodenal, retropancreatic, mesenteric, and para-aortic, is classified as distant metastasis.10 

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 CD56.6 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 prognosis8 but is not currently considered standard of care.6 

Immunohistochemistry 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.

Most gastric neuroendocrine tumors arise in the setting of chronic atrophic gastritis (see note B). Atrophic gastritis may be associated with glandular dysplasia, and in rare cases, gastric adenocarcinoma. Coagulative tumor necrosis, usually punctate, may indicate more aggressive behavior9 and should be reported.

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