Diagnostic issues

E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)

Primary versus metastasis

The pathologic diagnosis of gastric adenocarcinoma, particularly a poorly differentiated and nonintestinal subtype, can be challenging with a biopsy specimen. While stomach is not a common site for metastasis, a number of epithelioid neoplasms can metastasize to the gastric mucosa and the differential diagnosis between a primary gastric carcinoma and a metastasis may be difficult in small biopsies [82, 83]. Patients may be asymptomatic, present with a bleeding ulcer mimicking a primary gastric carcinoma (39% of the cases), or with a submucosal tumor (51% of the cases).

The most commonly observed error in the diagnosis of diffuse signet ring cell carcinoma occurs with metastatic lobular breast carcinoma, which has a propensity to metastasize and colonize the gastrointestinal tract as well as other hollow organs such as the uterus and the urinary bladder. Primary gastric diffuse signet ring cell carcinoma and lobular breast carcinoma share similar morphologic features and sometimes, the two neoplasms can be indistinguishable on the morphologic basis alone (Fig. 4.8a, b). Immunohistochemical studies can be helpful, since classic lobular breast carcinoma is usually immunoreactive to estrogen receptor (ER) (Fig. 4.8c), cytokeratin-7 (CK7), and mammaglobin; and a gastric primary carcinoma is immunoreactive for both CK7 and CK20, and should be negative for ER and mammaglobin.

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Fig. 4.8. Differential diagnosis of diffuse carcinoma in gastric biopsies. Primary diffuse gastric carcinoma (a) and metastatic breast lobular carcinoma to the stomach (b) share morphologic features (Arrow) and the distinction between them may sometimes be impossible. An immunostain for estrogen receptor is usually positive in classic lobular carcinoma (c)

Most importantly, a clinical history, even in the remote past, of breast carcinoma should prompt the appropriate work up to exclude a metastasis before the diagnosis of primary gastric diffuse signet ring cell carcinoma. Female patients with hereditary CDH1 mutation are at risk of developing both diffuse type gastric adenocarcinoma and lobular breast carcinoma, although the reported incidence of the latter is lower [45].

Gastrointestinal stromal tumor (GIST) can occur at any site of the GI tract; the stomach is one of the most common locations. When a GIST has epithelioid morphology, it can be difficult to distinguish from a poorly differentiated primary gastric carcinoma. Although subtle morphologic details may suggest the diagnosis of a GIST, such as intercellular myxoid stroma (Fig. 4.9a), a lack of cytokeratins immunoreactivity and positive reactivity to c-kit (CD117) confirms a diagnosis of GIST (Fig. 4.9b).

Other poorly differentiated malignant epithelial or epithelioid tumors, including seminoma (Fig. 4.9c), melanoma (Fig. 4.9d), and renal cell carcinoma, can metastasize to the stomach. Therefore, a poorly differentiated neoplasm in a gastric biopsy requires a thorough clinical and pathologic evacuation to exclude the possibility of a metastasis before the establishment of a primary gastric cancer. Among metastatic glandular/tubular carcinomas, pulmonary and pancreatic origins are more common than other primaries.

Biopsy diagnosis of early gastric cancer

Adenocarcinoma confined to the gastric mucosa (pathologic stage pT1a) or submucosa (pT1b) is defined as early gastric cancer (EGC) [7], and represents an early stage in tumor development. In Western series, EGC represents 15–20% of the newly diagnosed gastric cancers, whereas in Japan it accounts for more than 50% of the cases [2–5]. A higher prevalence of gastric cancer, more liberal use of upper endoscopy and chromoendoscopy, and differences in diagnostic criteria may explain the differences between Western and Japanese studies.

Most EGCs are typically located on the lesser curvature, around the angularis, and majority of them are well differentiated tubular or papillary variants [7]. These features create a challenging differential diagnosis between high-grade glandular dysplasia/carcinoma in situ (pTis) (Fig. 4.10a), and minimally invasive carcinoma (pT1a). The latter may present as either (1) individual cribriform glands with an associated expansile growth pattern (Fig. 4.10b) or (2) with nominal tumor invasion in the lamina propria (Fig. 4.10c); in both histologic prototypes, the tumor has progressed beyond the level of glandular dysplasia and met the diagnostic criteria of superficial gastric adenocarcinoma. When carcinoma invades through the muscularis mucosa, the tumor is staged as pT1b (Fig. 4.10d). Diffuse-type EGCs tend to exhibit greater width and depths of invasion and thus are less challenging to diagnose.

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Fig. 4.9. Differential diagnosis of poorly differentiated epithelioid neoplasms in gastric biopsies. a Epithelioid gastrointestinal stromal tumor (GIST) involves gastric mucosa; the tumor cells exhibit intercellular myxoid stromal (insert) which is a subtle feature of GIST. b) An immunostain of c-KIT (CD117) can confirm the diagnosis of GIST. c) Metastatic seminoma involving gastric mucosa and an immunostain of octamer-binding transcription factor 4 (OCT4) (insert) is usually positive in tumor cells. d) Metastatic melanoma involving gastric mucosa

In some situations, well differentiated tubular or papillary adenocarcinomas may be present as detached fragments in a superficial biopsy. In the absence of stroma in a biopsy, the distinction between glandular dysplasia (pTis), genuine superficial carcinoma (pT1a), or invasive carcinoma in an exophytic mass is difficult to establish on the basis of microscopic features (Fig. 4.11). Nevertheless, correlations of endoscopic impressions and histologic findings can facilitate the accurate diagnosis.

Intraoperative margin assessment

Resection margins are among the strongest predictors of cancer-related mortality for gastric adenocarcinoma. An intraoperative consultation with a pathologist, including a frozen section of the specimen to microscopically assess the margin status, offers an opportunity to modify surgical management with the goal of achieving an R0 resection. The frozen section interpretation of the proximal margin deserves special attention since this is where most errors occur. In one study, the estimated overall diagnostic accuracy of frozen section at the proximal margin was 93%, with a sensitivity of 67%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 91% [84]. Importantly, diffuse signet ring cell cancer constitute > 83% of the false-negative readings.

When assessing the margin status, the specimen is opened to examine the location of the tumor and its relationship to the resection margins. The decision as to where to take the frozen section is at the discretion of the pathologist based upon his/her judgment upon examination of the gross specimen. In the presence of a discrete lesion and gross margin clearance of more than 2 cm, a representative section at the site of the closest margin is adequate. When the tumor diffusely involves the entire stomach, particular in cases of diffuse signet ring cell subtype, it is necessary to submit the entire proximal and margin if this is surgically indicated. When the carcinoma is present in the mucosal surface, the interpretation of a positive margin is straightforward. Oversight usually occurs when the cancer is present deep in the gastric wall as scattered malignant cells, particularly in cases of diffuse signet ring cell subtype. Therefore, explicit knowledge of the specific subtype of gastric carcinoma facilitates the evaluation of margin status at the time of intraoperative assessment (Fig. 4.12).

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Fig. 4.10. Biopsy diagnosis of early gastric cancer. a High-grade glandular dysplasia with crowded glands in the superficial lamina propria is staged as in situ carcinoma (pTis). b) An example of early gastric adenocarcinoma which exhibits expansile and complex glandular architecture, thus the lesion has progressed beyond high-grade dysplasia. Although stromal invasion cannot be assessed in this superficial biopsy, the tumor should be staged as pT1a. c) Adenocarcinoma with extensive lamina propria invasion, but the tumor is confined to the mucosa without muscularis mucosae (marked by *) invasion and is staged as pT1a. d) Adenocarcinoma has invaded thought the muscularis mucosae (marked by *) and into the superficial submucosa, and the tumor is staged as pT1b

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Fig. 4.11. Biopsy diagnosis of detached gastric carcinoma. a Papillary variant of gastric adenocarcinoma exhibits well differentiated morphologic and cytologic features with minimal intratumoral stroma. b) A biopsy of papillary carcinoma may be indistinguishable from high-grade glandular dysplasia

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