Composite signet-ring cell/neuroendocrine carcinoma of the stomach with a metastatic neuroendocrine carcinoma component: a better prognosis entity

Adenocarcinoma and neuroendocrine carcinomas (NEC) are each well known to occur in the background of atrophic gastritis, but the concurrence of both adenocarcinoma and NEC (malignant carcinoid) together in the gastrointestinal tract (GI) is extremely rare [1, 2]. Over the past several years, classification of these tumors has been a subject of debate. As described by Lewin and Appelman [3], mixed neuroendocrine and conventional carcinomas of the stomach should be classified in one of five distinct groups. These include: carcinomas with interspersed neuroendocrine cells, composite glandular-endocrine carcinomas, collision tumors, amphicrine tumors, and combinations of the above [1, 3]. More recently, Fujiyoshi et al [4] reclassified the mixed endocrine and nonendocrine epithelial tumors by subdivision into six categories: 1) neuroendocrine cells interspersed within carcinomas; 2) carcinoids (neuroendocrine tumors/NET) with interspersed nonendocrine cells; 3) composite glandular-neuroendocrine cell carcinomas containing both areas of carcinoid and conventional carcinoma; 4) collision tumors in which neuroendocrine tumors and conventional carcinomas are closely juxtaposed but not admixed; 5) amphicrine tumors predominantly composed of cells exhibiting concurrent neuroendocrine and nonendocrine differentiation; and 6) combinations of the previous types. A variety of terms have been utilized in the designation of tumors along this continuum based on the predominant form of differentiation [5]. The occurrence of a composite tumor in the setting of atrophic gastritis has seldom been reported in the literature [6]. In adenocarcinomas of the gastrointestinal tract, the presence of both neuroendocrine and nonendocrine cells is a well-recognized finding [7]. However, mixed exocrine-neuroendocrine cell carcinomas are exceptionally rare. To our knowledge, only 15 cases of gastric mixed exocrine-neuroendocrine cell carcinomas have been reported in the literature (Table 1). Composite, or mixed glandular-neuroendocrine cell carcinomas, are defined as an intricate admixture of both elements which are present in equal proportions, unlike amphicrine tumors which demonstrate dual differentiation (exocrine and neuroendocrine) within the same cell. Moreover, collision type neoplasms occur as exocrine and neuroendocrine tumors that arise adjacent to one another and do not originate from the same cell type [8]. We review this literature, and present a case of a composite glandular-neuroendocrine carcinoma of the stomach emphasizing the light microscopy, immunohistochemical and electron microscopic characteristics of the tumor as well as the clinicopathological correlations.

A 64-year-old Caucasian woman with a history of a resected gastric carcinoid 38 years ago presented to the Department of Gastroenterology at the University of Maryland with symptoms of early satiety and a progressive, 6-months weight loss of 20 pounds. The patient had no other complaints. Her past medical history was significant for trigeminal neuralgia which had been surgically treated. She did not take any medications and denied a family history of cancer. On exam the patient was a thin, well-appearing woman without remarkable abnormal physical findings. Laboratory values revealed a mild anemia with a hemoglobin of 10 mg/dL. Her electrolytes, liver function tests, and coagulation panel were within the normal ranges.

The patient underwent upper endoscopy and endoscopic ultrasound (EUS), which revealed the following findings: an area of nodular mucosa in the distal esophagus at the gastroesophageal junction, an erythematous patch in the stomach, a 2-cm gastric polyp, which was then resected, and an extragastric mass, consistent with a group of matted lymph nodes, located between the left lobe of the liver and the anterior wall of the stomach. The pathology results of the biopsied sites showed that the gastric polyp and nodular mucosa represented tubular adenomas, the latter containing focal intramucosal adenocarcinoma. The fine needle aspiration (FNA) of the gastric mass was consistent with metastatic NEC (malignant carcinoid), and the erythematous patch in the stomach at 40-cm showed invasive poorly differentiated/signet-ring cell carcinoma.

The patient underwent a staging computed tomography (CT) scan of the abdomen and pelvis that demonstrated two large enhancing masses between the left lateral lobe of the liver and the anterior wall of the stomach corresponding to the extragastric mass seen on endoscopic ultrasound. There was no evidence of distant metastases on CT scan.

The patient was then referred to the Department of Surgical Oncology, for evaluation for surgical resection. Intraoperatively, there was no evidence of distant metastases. A D2 total gastrectomy with omentectomy and regional lymph node dissection with a Roux-en-Y J-pouch esophagojejunostomy was performed. There were no palpable masses in the stomach. However, there were two palpable masses in the gastrohepatic ligament, consistent with metastatic lymph nodes. The spleen and distal pancreas were preserved.

Postoperative recovery was uneventful with the exception of one urinary tract infection. The patient was discharged to a rehabilitation facility on the fifteenth postoperative day.

In the present study it was determined by light microscopy that the neoplastic cell population contained equal amounts of both tumor components, displaying on the one hand a typical signet-ring cell adenocarcinoma pattern admixed with clusters of small cells consistent with neuroendocrine differentiation on the other. The signet-ring cell carcinoma component showed positivity for pancytokeratin and CAM 5.2, as well as mucopolysaccharides but was negative for endocrine markers in the majority of neoplastic cells. The NEC portion of the neoplasm was positive for synaptophysin, chromogranin, NSE, pancytokeratin, and CAM 5.2. Only scattered rare single signet-ring cell carcinoma cells demonstrated amphicrine features (i.e. expression of both neuroendocrine immunohistochemical markers as well as positive mucicarmine and PAS staining), this being inconsistent with the diagnosis of a true amphicrine tumor. Furthermore, on ultrastructural examination, concurrence of mucous and endocrine granules within the same cell was not observed, whereas the presence of pure exocrine features e.g. intracellular lumina, was observed in the majority of the signet-ring cells with only a minority of them reaching the signet-ring cell morphology through lipid accumulation within an otherwise typical neuroendocrine cell. We thus concluded that the neoplasm contained two distinct cell types and therefore represents a composite signet-ring cell-neuroendocrine carcinoma.

The histiogenesis of these composite tumors remains unclear. It has recently been proposed that signet-ring cell carcinomas originate from the gradual dedifferentiation from enterochromaffin-like (ECL) cells through signet-ring cells with endocrine immunoreactivity [9]. In addition, two other hypotheses have been proposed, the first suggesting coincidental neoplastic changes in two different cell types and the second proposing a single common precursor cell that undergoes a bidirectional neoplastic change [10]. In the current case, the latter hypothesis appears to be better suited in accounting for the intimate admixture of the different cell types and patterns in this tumor. An interesting finding, supporting the above mentioned hypothesis, was the appearance of amphicrine cells in the signet-ring cell carcinoma component as well as in the adjacent nonneoplastic gastric mucosa.

Four types of "pure" neuroendocrine tumors (NET) can be distinguished in the stomach. Type 1 is the most common, occurring in 70–80% of all cases. In most cases, type 1 NETs of the stomach are small (0.1–1 cm in diameter), multifocal tumors, affecting women more than men, and always occurring in the background of chronic atrophic gastritis. Type 3 (sporadic and solitary) is the second most common, whereas types 2 (occurring in association with multiple endocrine neoplasia type 1) and 4 (undifferentiated solid neuroendocrine carcinoma) are considered rare [11]. The clinical setting and morphologic features of the NEC component in our case resemble the previously described clinicopathologic findings in type I gastric NETs [11]. Due to the fact that the NET component in the current case was significantly larger than 2 cm and had metastasized to a group of matted lymph nodes located adjacent to the lesser curvature of the stomach, we can hypothesize that this tumor would behave similar to a well-differentiated neuroendocrine carcinoma based on the WHO classification [11]. This was a very unusual finding, given that the NEC (malignant carcinoid) component was metastatic without any participation of the signet-ring cell component, even if the latter is typically the more malignant tumor. Previous studies have shown that regional lymph-node metastases occurred in very rare cases of type 1 NET in which the tumors were larger than 2 cm and infiltrated the muscularis propria [11]. One of the latest studies on gastrointestinal NETs demonstrated that small, low-grade NETs with low proliferation index may behave in a highly aggressive fashion, i.e. with multiple lymph node and hematogeneous metastases [12].

The general biologic behavior of gastric mixed exocrine-neuroendocrine neoplasms is unknown. A recent study suggests that composite tumors have a better prognosis than common gastric adenocarcinomas [2]. Certainly the course in our case represents a much less aggressive pattern than a classical signet-ring cell carcinoma. As recently emphasized in cases of advanced signet-ring cell carcinoma with better prognosis than expected [2], the diagnosis of composite glandular/neuroendocrine tumor needs to be considered.