Stomach

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2019, Case 33, and is poorly cohesive gastric carcinoma.

Sections consist of a full-thickness portion of stomach. A well-defined mass is not identified, but there are infiltrative lesional cells extending from the submucosa to the subserosa. These neoplastic cells have nuclear hyperchromasia and nuclear pleomorphism and are focally plasmacytoid. Mostly discohesive and often resembling lymphocytes, the tumor cells form glandular structures in rare areas and sometimes occur as larger cells with bizarre nuclei. Lymphovascular and perineural invasion are also present in some sections. The lesional cells are positive for CK7 and negative for CK20, GATA3, TTF1, CD45, CD34, CD117/cKIT, and melanoma markers including S100. The lesion is diagnosed as a poorly cohesive gastric carcinoma (PCC), non-signet-ring cell type.

The World Health Organization 2019 classification groups gastric adenocarcinomas into subtypes based largely on histological parameters. The subtypes include poorly cohesive signet-ring cell carcinoma, mucinous, tubular, parietal cell, micropapillary, papillary, hepatoid, undifferentiated, and other types. Risk factors associated with the development of gastric adenocarcinoma include Helicobacter pylori infection, bile reflux, smoking, high intake of dried and salted foods, and inherited/genetic factors. Presentation is varied and ranges from dyspepsia, diarrhea, upper gastrointestinal tract hemorrhage, and vomiting to systemic symptoms due to metastatic disease. PCC may be composed primary/entirely of signet ring cells, or it may have few to no signet ring cells, such as the current case. Poorly cohesive gastric carcinoma can be difficult to identify endoscopically due to the absence of mass lesions or ulcerations.

Gastric adenocarcinoma represents a major cause of cancer-related morbidity and mortality worldwide. It is the fifth most common carcinoma and the third leading cause of cancer death. Most are sporadic, but inherited cancer syndromes underlie some cases of gastric carcinoma. These inherited cancer syndromes include Li–Fraumeni syndrome, Lynch syndrome, Peutz–Jeghers syndrome, hereditary breast and ovarian cancer, MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, juvenile polyposis syndrome, and PTEN hamartoma tumor/Cowden syndrome. PCC may occur sporadically or due to a heterozygous germline mutation of the CDH1 gene, which encodes E-cadherin or cadherin-1. This mutation confers a diagnosis of Hereditary Diffuse Gastric Cancer and also increases risk for lobular carcinoma of the breast. Prophylactic gastrectomy is often offered to patients with this mutation.

Linitis plastica is the descriptive term for a stomach that is diffusely thickened, rigid and leather-like due to infiltration by the tumor cells of PCC. Histologically, PCC is comprised of discohesive tumor cells. These cells can be signet-ring cells, epithelioid cells, or a combination of the two, and may resemble histiocytes or lymphocytes. The tumor appears to originate from the mid-mucosal region, and transmural infiltration is common. Other findings include desmoplasia, muscularis propria hyperplasia, and varying amounts of inflammatory reaction. PCC has a similar immunohistochemical profile to other variants of gastric adenocarcinoma (CK7+, CK20-); however, in the setting of CDH1 gene mutation, E-cadherin staining will be lost.

Gastric adenocarcinoma requires biomarker testing for HER2 (ERBB2) to guide treatment. HER2 overexpression/amplification is present in up to 38% of gastric adenocarcinomas. It is generally believed that there is a higher frequency of HER2 overexpression in the intestinal, rather than the poorly cohesive, subtype. The Trastuzumab for Gastric Cancer (ToGA) trial showed prolonged survival in patients treated with anti-HER2 antibodies compared with chemotherapy alone when HER2 was amplified/overexpressed. As a result of these findings, biomarker testing is now indicated for patients with locally advanced disease, metastases, or recurrence.

Biomarker testing for HER2 may be performed on biopsy or resection specimens. The National Comprehensive Cancer Network (NCCN) recommends that immunohistochemistry (IHC) be performed initially, with in situ hybridization (ISH) testing reserved for equivocal IHC results. A 4-tier scoring system is used for IHC, which includes intensity of staining and percentage of tumor with positive staining. The IHC staining pattern for HER2 is membranous with a basolateral or lateral staining pattern. The staining is heterogeneous, which is different from the pattern in breast carcinoma.

To be considered adequate for HER2 immunohistochemistry, a biopsy sample must contain a minimum of 5 tumor cells on the H&E or pap stain. In resections or other specimens with ample tumor cells, at least 10% of the tumor cells must demonstrate membranous staining to be considered positive. A score of 0 or 1+ is interpreted as negative, 2+ as equivocal and 3+ as positive.

The ISH assay is indicated for cases equivocal (2+) by IHC to identify the presence or absence of HER2 gene amplification. The most commonly used assays include a chromosome enumeration probe (CEP17), which allows a ratio of HER2 signals to copies of chromosome 17 to be determined. A ratio of 2.0 or higher is considered positive for amplification. In rare (up to 4.1% of) cases, 3 or more copies of chromosome 17 are present resulting in Her2/CEP17 ratio of less than 2. This is ostensibly due to segmental duplication within chromosome 17 overlapping the centromere and spanning the location of the HER2 gene. When this occurs, 6 or more Her2 signals on average should be scored ISH positive. Currently, the Food and Drug Administration approves trastuzumab for use in patients with positive immunohistochemistry (3+) or HER2 amplification by ISH.

Lobular carcinoma of the breast accounts for 5% to 15% of all breast cancers and is the most common type of breast cancer presenting with distant metastases. It is characterized by discohesive round cells that commonly grow in a single-file pattern and do not elicit a stromal response. Like PCC, they are positive for CK7 and negative for TTF1, but unlike PCC, they react to GATA3 and ER. Both lobular carcinoma of the breast and PCC can occur in the setting of inherited CDH1 mutation.

Diffuse large B-cell lymphoma of the stomach often presents as a thickened gastric wall or ulcerated mass. It may arise de novo, in the setting of immune suppression or secondary to transformation of a low-grade lymphoma. Microscopically, it consists of sheets of large cells that efface the mucosal architecture. These cells may have centroblastic, immunoblastic, or anaplastic features and are immunoreactive for B-cell markers such as CD20, PAX5, and CD79a, but are negative for CK7 and other cytokeratins.

Malignant gastrointestinal neuroectodermal tumor (GNET), also known as clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT), is a rare mesenchymal neoplasm that arises within the wall of the small bowel, stomach or large bowel. Histologically, it is composed of ovoid or epithelioid cells with pale or clear cytoplasm; these cells can form papillary or alveolar-like structures or be arranged in sheets. It is characteristically positive for S100, SOX10, and synaptophysin. The major differential diagnosis includes clear cell sarcoma of soft parts (CCS-SP). CCS-SP and GNET/CCSLGT are both immunoreactive for S100 and SOX10 and harbor EWSR1::ATF1 fusions. However, GNET/CCSLGT is negative for HMB45 and other melanocytic markers and also lacks the ultrastructural evidence of melanocytic differentiation found in CCS-SP.

Xanthoma are typically seen as single or multiple white nodules or plaques on endoscopy. They are comprised of aggregates of foamy lipid-laden histiocytes and often arise in the setting of atrophic gastritis with areas of intestinal metaplasia. The cells are positive for CD68 and negative for CK7 and other epithelial markers, which helps to differentiate these cells from gastric signet ring cell carcinoma or other metastatic carcinomas.

1. A 52-year-old woman with a history of poorly cohesive gastric adenocarcinoma developed recurrent disease. Testing for HER2 (ERBB2) was requested on a resection specimen. Which of the following is true? 
   
   
   1. A patient whose tumor has a HER2:CEP17 ratio of 2.0 is eligible for trastuzumab therapy.
   2. Accurate scoring of a resection specimen for HER2 immunohistochemistry (IHC) in gastric cancer requires a minimum of 25% tumor cells staining for interpretation.
   3. Gastric adenocarcinoma does not harbor HER2 amplification and is exempted from HER2 testing.
   4. HER2 IHC scoring of 2+ means further testing is not needed.
   5. HER2 testing is only indicated for metastatic disease and should not be performed on this specimen.
2. Which of the following immunohistochemical profile is characteristic of malignant gastrointestinal neuroectodermal tumor?
   
   
   1. DOG1-, HMB45-, pan-keratin-, S100-, synaptophysin-, vimentin+
   2. DOG1-, HMB45-, pan-keratin-, S100+, synaptophysin+, vimentin+
   3. DOG1-, HMB45-, pan-keratin+, S100+, synaptophysin+, vimentin+
   4. DOG1-, HMB45+, pan-keratin-, S100+, synaptophysin-, vimentin+
   5. DOG1+, HMB45-, pan-keratin+, S100-, synaptophysin-, vimentin+
3. A 29-year-old woman developed bilateral lobular carcinoma of the breast (LCB) and has a strong family history of diffuse-type gastric adenocarcinoma (DGA). Which of the following genetic abnormalities or cancer syndrome is she most likely to carry?
   
   
   1. EWSR1::ATF1 fusions
   2. Inherited germline CDH1 mutation
   3. Inherited germline TP53 mutation
   4. Neither LCB nor DGA occurs in a genetic or syndromic setting
   5. Peutz–Jeghers syndrome

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3. Burke JS. Lymphoproliferative disorders of the gastrointestinal tract: a review and pragmatic guide to diagnosis. Arch Pathol Lab Med. 2011;135(10):1283-1297.
4. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52(7):797-805.
5. Oviedo J, Swan N, Farraye FA. Gastric xanthomas. Am J Gastroenterol. 2001;96(11):3216-3218.
6. Stockman DL, Miettinen M, Suster S, et al. Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract. Am J Surg Pathol. 2012;36(6):857-868.
7. van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52(6):361-374.
8. Wang J, Thway K. Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity. Arch Pathol Lab Med. 2015;139(3):407-412.

Stephanie Reid, MD
Gastrointestinal Pathology Fellow
University of Toronto
Toronto, ON

Oyedele Adeyi, MB, BS, FCAP
Surgical Pathology Committee Member
University Health Network/ University of Toronto
Toronto, ON

1. A patient whose tumor has a HER2:CEP17 ratio of 2.0 is eligible for trastuzumab therapy. (a)
2. DOG1-, HMB45-, pan-keratin-, S100+, synaptophysin+, vimentin+ (b)
3. Inherited germline CDH1 mutation (b)