Very-early-stage gastric amphicrine carcinoma with mixed histology: A case report and review of literature

Abstract

BACKGROUND

Amphicrine carcinoma is an extremely rare entity. In this article, we report the first known case of very-early-stage amphicrine carcinoma characterized by a mixed growth pattern with multiple pathological components.

CASE SUMMARY

A 59-year-old male patient underwent gastroscopy for abdominal discomfort, which revealed a 1.5 cm elevated lesion on the lower part of the anterior aspect of the gastric body close to the gastric angle. Initial biopsy indicated signet-ring cell carcinoma (SRCC) confined to the mucosa. Following endoscopic submucosal dissection, pathological examination revealed signet-ring cells arranged in both nested clusters and diffuse infiltration demonstrating immunohistochemical positivity for periodic acid-Schiff staining for mucin, chromogranin A, and synaptophysin. The coexistence of these endocrine and exocrine markers supported the diagnosis of amphicrine carcinoma. A mixed growth pattern comprising poorly differentiated adenocarcinoma, neuroendocrine tumor, and SRCC was identified. Whether the amphicrine carcinoma arose directly from multipotent stem cells or differentiation from signet-ring cells remains unclear.

CONCLUSION

Routine neuroendocrine immunohistochemical marker staining for SRCC may improve the diagnosis of amphicrine carcinoma and provide guidance for subsequent treatment.

Key Words: Gastric cancer; Amphicrine carcinoma; Mixed growth pattern; Early stage; Endoscopic submucosal dissection; Case report

Core Tip: Based on white-light endoscopy findings and biopsy pathology results, this case was initially diagnosed as pure signet-ring cell carcinoma. Subsequent narrow-band imaging magnifying endoscopy supported this diagnosis. However, post-endoscopic submucosal dissection pathology revealed a very-early-stage amphicrine carcinoma with a mixed growth pattern comprising poorly differentiated adenocarcinoma, neuroendocrine tumor, and signet-ring cell carcinoma. We subsequently re-evaluated the endoscopic manifestations of this lesion and, in conjunction with the pathological findings, proposed the endoscopic features of amphicrine carcinoma presenting with signet-ring cell morphology.

INTRODUCTION

Amphicrine carcinoma refers to cells capable of both neuroendocrine and exocrine secretion. Advancements in morphological knowledge and immunohistochemical applications have led to the recognition of neoplasms with hybrid-phenotypic features in pathology. This hybrid-phenotypic nature has been ultrastructurally confirmed by the presence of both mucous and neuroendocrine granules within the cytoplasm. Amphicrine carcinoma is distinct from both adenocarcinoma and neuroendocrine neoplasms in terms of morphology, immunohistochemical features, and transcriptomic investigations[1,2]. Due to its rarity, specific incidence data for gastric amphicrine carcinoma is unavailable, with only a few cases reported - all presenting at advanced stages[3-5]. One study of pancreatic tumors reported that approximately 5.4% of neoplasms showed amphicrine differentiation[6]. Here we report the first case of very-early-stage amphicrine carcinoma, including endoscopic features. We believe that when formulating treatment plans, the occurrence of this unique neoplasm should be taken into consideration[7,8].

CASE PRESENTATION

Chief complaints

A 59-year-old male patient was admitted to our hospital because of abdominal discomfort for 1 week.

History of present illness

The patient’s primary symptom was dull pain in the upper abdomen.

History of past illness

The patient had no relevant past illness.

Personal and family history

The patient had a 30-year drinking history, with approximately 1.5 L of beer two or three times per week.

Physical examination

Physical examination revealed slight tenderness in the upper abdomen without rebound tenderness. No hepatosplenomegaly, lymphadenopathy, or other abnormalities were detected.

Laboratory examinations

Complete blood count, coagulation profiles, liver function tests, and renal function tests showed no abnormalities. Tumor markers, including carbohydrate antigen 19-9, carbohydrate antigen 72-4, alpha-fetoprotein, and carcinoembryonic antigen, were normal. Serum levels of gastrin-17 and pepsinogen II were normal, while pepsinogen I was elevated at 247.20 μg/L (reference range: 70-165 μg/L).

Imaging examinations

Outpatient gastroscopy revealed a flat elevated lesion (0-IIa), approximately 1.5 cm × 1.5 cm in diameter, located on the lower part of the anterior aspect of the gastric body close to the gastric angle. The lesion appeared as a submucosal tumor-like elevation with a faded surface color. The gastric folds were interrupted at the oral side of the lesion. The overlying mucosa was smooth, without evidence of ulceration (UL0) or erosion (Figure 1A). Pathology and immunohistology revealed that the biopsy specimen was cytokeratin pan (CK-P) positive, Ki-67 (approximately 1% +), focal carcinoembryonic antigen positive, S-100 negative, and periodic acid Schiff-alcian blue (AB-PAS) positive, suggesting undifferentiated carcinoma confined to the mucosa, with a possible diagnosis of signet-ring cell carcinoma (SRCC). Narrow-band imaging magnifying endoscopy revealed the fading color change, with an indistinct demarcation line and regular microvascular pattern. An ulcer-like change, likely resulting from a previous biopsy, was observed on the anterior wall side of the lesion, accompanied by distortion of adjacent glandular structures (Figure 1B-G). Enhanced abdominal and chest computed tomography (CT) scans were performed for pre-treatment staging. The scans showed no evidence of enlarged regional lymph nodes or distant metastasis. The primary gastric lesion was not clearly visible on CT images. Endoscopic submucosal dissection (ESD) was planned one week after endoscopy. Four-quadrant biopsies were taken every 1 cm from the lesion margins before the procedure. All pathology results revealed mild active inflammation.

Figure 1 Endoscopic examination of the lesion. A: White light; B: Biopsy site [narrow-band imaging magnifying endoscopy (NBI-ME)]; C: Anal side of the lesion (NBI-ME); D: Greater curvature side of the lesion (NBI-ME); E: Oral side of the lesion (NBI-ME); F: Near the ulcer at the oral side of the lesion (NBI-ME); G: Anterior wall side of the lesion (NBI-ME).

Pathological findings

Postoperative pathological examination (Figures 2, 3 and 4) revealed a lesion measuring 1.5 cm × 1.2 cm. Strip #8 demonstrated loss of surface glandular epithelium, with mucosal and submucosal layers diffusely infiltrated by cord-like atypical cells with enlarged pleomorphic nuclei and moderate-to-abundant cytoplasm, while adjacent glands remained normal. In strips #7 and #8, tumor cells were arranged in nests and gland-like patterns, appearing as round and uniform nuclei, distributed in linear or micronodular patterns along both sides of the muscularis mucosa, reaching to the lateral margin. In strip #8, some atypical cells with signet-ring cell morphology were arranged in nested clusters within the mucosa and submucosa, alongside goblet cell-like cells forming tubular structures. In strips #5 to #7, abundant signet-ring-like atypical cells were observed, with mucin-rich cytoplasm pushing nuclei to the periphery.

Figure 2 Postoperative pathology. A: Pathological tissue strip #4 [hematoxylin and eosin (HE) 15 ×, scale bar = 1000 μm]; B: Green box: Nodular distribution of neuroendocrine tumor cells (HE 100 ×, scale bar = 100 μm); C: Yellow box: Signet-ring-like cell clusters with nested distribution (HE 100 ×, scale bar = 100 μm); D: Cord-like poorly differentiated adenocarcinoma infiltrating into submucosa (HE 15 ×, scale bar = 100 μm).

Figure 3 Immunohistochemistry (pathological tissue strip #4). All photograph magnifications are × 100. A: Periodic acid Schiff-alcian blue (amphicrine carcinoma area), scale bar = 100 μm; B: Cytokeratin pan (amphicrine carcinoma area), scale bar = 100 μm; C: Synaptophysin (amphicrine carcinoma area), scale bar = 100 μm; D: Chromogranin A (amphicrine carcinoma area), scale bar = 100 μm; E: Cytokeratin pan (poorly differentiated adenocarcinoma area), scale bar = 100 μm.

Figure 4 Pathological tissue strip #7. The magnifications of all photographs are × 200. A: Signet-ring cell carcinoma cells, scale bar = 100 μm; B: Periodic acid Schiff-alcian blue (+), scale bar = 100 μm; C: Cytokeratin pan, scale bar = 100 μm; D: Signet-ring cell carcinoma cells were positive for synaptophysin, scale bar = 100 μm; E: Chromogranin A (+), scale bar = 100 μm; F: Ki-67 low expression, scale bar = 100 μm.

Immunohistochemistry results: Poorly differentiated carcinoma: P53 (20% +), Ki-67 (10% +), synaptophysin (Syn) (-), mucin 5AC (partial +), vascular endothelial markers CD34 (+) and lymphatic endothelial marker D2-40 (+), and no tumor emboli were found.

Invasion depth: 600 μm into the submucosa, and no carcinoma was found at the vertical margin (300 μm clear).

Neuroendocrine tumor: P53 (20% +), Ki-67 (≤ 2% +), Syn (+), mucin 5AC (-), CD34 (+) and D2-40 (+), and no tumor emboli were found.

Signet-ring cell nested clusters: AB-PAS (+), CK-P (+), Syn (+), partially expressing chromogranin A (CgA) (+).

Signet-ring cells with focal areas of diffuse infiltration: AB-PAS (+), CK-P (+), Syn (+), CgA (+).

FINAL DIAGNOSIS

Gastric adenocarcinoma (poorly differentiated adenocarcinoma and signet-ring cells); well-differentiated neuroendocrine tumor (G1 grade); amphicrine carcinoma. Reconstructed pathology (Figure 5) indicated that strips #5 to #7 demonstrated diffusely infiltrating SRCC, with focal areas exhibiting an endocrine-exocrine co-expression feature, specifically amphicrine carcinoma. Poorly differentiated adenocarcinoma infiltrating into the submucosa was found in site #8, possibly explaining the submucosal tumor-like appearance. Amphicrine carcinoma was present at both oral and anal sides of poorly differentiated adenocarcinoma of approximately 2 mm. Neuroendocrine tumor cells distributed linearly along the muscularis mucosae were observed in pathological tissue strips #7 and #8, reaching the lateral margin.

Figure 5 Endoscopic submucosal dissection specimen fixation and reconstruction. A: Endoscopic submucosal dissection specimen fixation; B: Yellow dashed line: Neuroendocrine tumor; yellow solid line: Amphicrine carcinoma; red solid line: Poorly differentiated adenocarcinoma; orange solid line: Signet-ring cell carcinoma.

TREATMENT

Following ESD, additional surgical procedures were required. However, the patient declined further surgical intervention based on personal preference after informed consent. To date, the patient has not received any additional treatment. Given the non-curative nature of the ESD and the patient’s decision to decline surgery, a strict surveillance protocol was recommended. This strategy included intensive endoscopic monitoring of the post-ESD scar with biopsies every 3-6 months for the first two years, along with regular contrast-enhanced CT of the chest and abdomen to screen for any locoregional recurrence or distant metastasis.

OUTCOME AND FOLLOW-UP

Post-ESD follow-up endoscopic examinations at 2 months and 6 months showed healing with S1-stage ulcer scarring (Figure 6). Also, the biopsy specimen revealed chronic inflammation only.

Figure 6 Follow-up white light images. A: Long range view at 2-month follow-up; B: Close-up view at 2-month; C: Long range view at 6-month; D: Close-up view at 6-month.

DISCUSSION

The coexistence of exocrine and endocrine secretory products within single cells was first reported by Feyrter[9] in 1938. Based on the 2022 World Health Organization Classification of Neuroendocrine Tumors[10], the diagnostic criteria for amphicrine carcinoma are: Neuroendocrine markers (Syn, CgA, and insulinoma associated protein 1) and non-neuroendocrine markers positive in the same epithelial neoplastic cells. The terminology for tumors exhibiting this dual secretion phenomenon remains controversial. Nevertheless, tumors sharing this characteristic include goblet cell adenocarcinoma[11-15]. According to the 2019 World Health Organization Classification of Tumors of the Digestive System[16], only appendiceal-origin tumors with dual secretion are termed goblet cell adenocarcinoma. Amphicrine carcinoma is of monoclonal origin, and evidence suggests its molecular profile is more aligned with adenocarcinoma than with neuroendocrine neoplasms; this is supported by pan-cancer transcriptome analyses, which show a closer genetic link to adenocarcinoma[17]. Hanamatsu et al[18] reported that amphicrine carcinoma cells immunohistochemically expressed CD44v9 - a functional cancer stem cell marker. This result supports the hypothesis that amphicrine carcinoma originates from multipotent stem cells. Signet-ring cells intrinsically exhibit a high positivity rate for neuroendocrine markers. Bartley et al[19] demonstrated that 40% of signet-ring cells showed positive expression of neuroendocrine markers. Fujiyoshi and Eimoto[20] found that 37.3% of signet-ring cells showed diffuse or focal positivity for CgA staining, and in 6% of cases, > 50% tumor cell positivity. Huang et al[17] demonstrated that four of 10 patients with amphicrine carcinoma exhibited coexisting components of adenocarcinoma or neuroendocrine carcinoma, indicating that mixed growth patterns are not uncommon in these tumors. Special characteristics from recently reported cases of gastric amphicrine carcinoma are shown in Table 1[3,17,18,21,22].

Table 1 Clinicopathological features of recently reported cases of gastric amphicrine carcinoma.

Ref.	Age/sex	Tumor location	Size/stage	Histological components & growth pattern	IHC findings	Treatment	Outcome/follow-up
Current case	59/male	Gastric body	1.5 cm/T1b (SM)	Poorly differentiated adenocarcinoma, NET, SRCC	Syn (+), CgA (+)	ESD only	Alive, no recurrence at 6 months
Huang et al[17], 2019	61-69/male (10 cases)	Stomach (8), intestine (2)	2-5.5 cm/T1-T4	Tubular, fusion, or single-file growth of goblet/SRCC-like cells. Mixed with adenoma or NEC in 4 cases	Syn (+), CgA (+)	Surgery +/- chemo/radio	3/10 DOD. High-grade worse prognosis
Hanamatsu et al[18], 2019	60/female	Gastric corpus	5.0 cm/T4aN2	Poorly cohesive carcinoma with SRCC	Syn (+), CgA (+), CD56 (+)	Total gastrectomy	Not specified
Qian and Feng[21], 2022	69/male	Gastric body/antrum	8.5 cm/T4aN3b (stage IIIC)	Tubular, solid nests, cribriform, single-file patterns	Syn (+), CgA (-)	Surgery + chemotherapy (adenocarcinoma regimen)	Alive, no recurrence at 6 months
Sciarra et al[22], 2023	63/male	Gastric cardia	1.2 cm/T1b (SM)	Nests, trabeculae, acinar structures. Pancreatic acinar differentiation	Syn (+), CgA (+), trypsin (+), BCL10 (+)	Wedge resection	Alive, no recurrence at 18 months
Ebedes et al[3], 2024	55/female	Gastric body (lesser curvature)	2.6 cm/T2 (MP)	Nested and glandular patterns with intracytoplasmic mucin	Syn (+), CgA (+)	Total gastrectomy	Not specified

IHC: Immunohistochemistry; SM: Invasion into submucosa; NET: Neuroendocrine tumor; SRCC: Signet-ring cell carcinoma; Syn: Synaptophysin; CgA: Chromogranin A; ESD: Endoscopic submucosal dissection; NEC: Neuroendocrine carcinoma; DOD: Died of disease; MP: Invasion into muscularis propria.

Amphicrine carcinoma is a rare entity with no specific clinical manifestations, and is definitively diagnosed only through pathology. In our case, the patient underwent gastroscopy due to dull pain in the upper abdomen. Based on the white-light endoscopic findings and application of the four-angle theory of gastric cancer, the lesion was primarily diagnosed as pure SRCC confined within the mucosal layer[23]. Since this was a very-early-stage lesion, narrow-band imaging magnifying endoscopy revealed no irregular microvascular or destruction of surface glandular structures of undifferentiated carcinoma. According to the Guidelines for Endoscopic Submucosal Dissection and Endoscopic Mucosal Resection for Early Gastric Cancer (second edition)[24], undifferentiated-type adenocarcinoma without ulceration (UL0), confinement of the lesion to the mucosa, and diameter ≤ 2 cm constitutes an absolute indication for ESD. In addition, the latest international guidelines, including those from the European Society of Gastrointestinal Endoscopy and the Japanese Gastric Cancer Association, also provide comprehensive recommendations for endoscopic treatment of early gastric cancer, further supporting the clinical rationale for ESD in this case[25,26]. The patient underwent ESD. The lesion was classified as eCura C-2 based on the eCura system[27-29]. Zhang et al[30] demonstrated a 15% risk of lymph node metastasis for lesions measuring 1-2 cm, ulcer-negative, with submucosal invasion in undifferentiated carcinoma.

Given that the endoscopic features of very-early-stage amphicrine carcinoma have not been previously reported, a detailed analysis of the lesion’s appearance in the context of its underlying pathological components was warranted. Pathological findings revealed that the cellular morphology of the amphicrine carcinoma mainly presents as signet-ring cells, with molecular pathological characteristics approximating those of adenocarcinoma. Therefore, the endoscopic presentation of this lesion more closely resembled that of undifferentiated carcinoma. The lesion also contained components of SRCC, and poorly differentiated carcinoma that infiltrated both mucosal and submucosal layers, with epithelial erosion-like changes. Neuroendocrine tumor components were linearly distributed along both sides of the muscularis mucosae. Both poorly differentiated adenocarcinoma and neuroendocrine tumor components lacked characteristic endoscopic features in this lesion. Therefore, we reasonably conclude that amphicrine carcinoma with signet-ring cell morphology demonstrates endoscopic findings identical to those of pure SRCC, manifesting as mucosal faded color change.

This study has some limitations. This is the first report detailing the endoscopic features of the very-early-stage gastric amphicrine carcinoma in a single case. Therefore, these findings may not be generalizable to all such cases. Further accumulation and analysis of more cases are essential to validate our observations and establish a more definitive endoscopic profile for this rare entity.

CONCLUSION

Gastric amphicrine carcinoma is a rare entity with distinct biological and histological features[31]. This study analyzed its potential endoscopic manifestations and summarized both the endoscopic appearance and the mixed growth patterns of amphicrine carcinoma. Routine neuroendocrine immunohistochemical marker staining for signet-ring cells may improve the diagnosis of amphicrine carcinoma and provide guidance for treatment.