Residual gastric cancer with a mixed small cell neuroendocrine and keratinizing squamous cell carcinoma: A case report

Abstract

BACKGROUND

Despite advancements in early detection and treatment, the prognosis and histological types for residual gastric cancer (GC) remains poor.

CASE SUMMARY

This case report presents a rare occurrence of residual GC featuring a combination of small cell neuroendocrine carcinoma (SCNEC) and squamous cell carcinoma (SCC) in a 60-year-old male patient. The patient, with a history of Billroth II gastrectomy for duodenal ulcer bleeding, presented with gastrointestinal bleeding. Preoperative computed tomography and positron emission tomography-computed tomography indicated adenocarcinoma with tumor and abdominal lymph node metastasis. The patient underwent laparoscopic total gastrectomy and lymph node dissection for residual GC. Histological examination of the resected tumor confirmed the presence of both SCNEC and SCC. Postoperatively, the patient underwent adjuvant chemotherapy four times. Two years later, the patient was found to occur esophageal cancer and was performed a small bowel stoma and radical esophagectomy.

CONCLUSION

In this case report, we detail a rare instance of residual GC with mixed SCNEC and SCC, emphasizing the complexity of diagnosis and treatment, and the need for ongoing research.

Key Words: Gastric stumper cancer; Small cell neuroendocrine carcinoma; Squamous cell carcinoma; Adjuvant chemotherapy; Case report

Core Tip: This case report presents a unique instance of residual gastric cancer with a combination of small cell neuroendocrine carcinoma and squamous cell carcinoma, highlighting the emergence of such rare histological types post-gastrectomy underscores the need for vigilant surveillance and further research into their management. The complexity of diagnosing and treating this mixed histology gastric cancer is further emphasized by the current trends in gastric cancer management. The pursuit of integrated, resource-sensitive approaches to surveillance and treatment is crucial for enhancing outcomes in this patient population.

INTRODUCTION

Gastric cancer (GC) ranks among the most prevalent malignant neoplasms worldwide. Previous statistical data indicated that GC accounted for 5.6% of new cancer cases and 7.7% of cancer-related deaths[1]. The disease continues to be a significant oncological challenge worldwide. A concerning trend is the increasing incidence of GC among younger adults that has been observed over the past decade[2]. In terms of GC treatment, early-stage GC is usually resected via endoscopy, whereas for most advanced GC cases, curative radical gastrectomy is performed[3,4]. The current indications for partial gastrectomy include benign and malignant tumors, refractory peptic ulcers, and weight loss surgery, among other indications[5]. Gastric stump cancer (GSC) is a recognized long-term complication that occurs after distal gastrectomy and accounts for 1%-8% of all GC cases[6]. The most common type of GSC is adenocarcinoma, followed by signet ring cell carcinoma. However, a spectrum of gastric stump malignancies has been documented, and the treatment and prognosis of residual GC depend on the specific pathological type, depth of invasion, presence of metastasis, and overall health of the patient. The emergence of neuroendocrine carcinoma (NEC) and squamous cell carcinoma (SCC) in the gastric stump context is exceedingly rare[7]. To the best of our knowledge, only several cases of NEC mixed with adenocarcinoma arising in the gastric stump have been previously reported in the English medical literature[8,9]. Here, we present a case of NEC mixed with SCC in the gastric stump that was diagnosed several decades after distal gastrectomy was performed for benign duodenal ulcer bleeding.

CASE PRESENTATION

Chief complaints

Melena for three days.

History of present illness

On November 19, 2021, a 60 years old male patient was admitted to the hospital due to melena that had lasted for three days.

History of past illness

The patient had a history of Billroth II gastrectomy for bleeding from a duodenal ulcer approximately 40 years prior and had not undergone follow-up gastroscopy post-surgery. Additionally, the patient had as a history of appendectomy and hepatitis B virus infection.

Personal and family history

The patient had a 40-year history of smoking and alcohol consumption.

Physical examination

Only surgical scars on the abdominal skin were found during the admission examination, with no other positive findings.

Laboratory examinations

Laboratory tests revealed a haemoglobin level of 100 g/L, with no abnormal findings for the other blood counts. Coagulation function, liver and kidney function, electrolytes, and lipid profiles were normal. A stool occult blood test was positive. The levels of tumor markers were as follows: 2.2 ng/mL alpha-fetoprotein, 1.24 ng/mL carcinoembryonic antigen, 7.53 U/mL cancer antigen 199, 1.530 ng/mL prostate-specific antigen, and 0.139 ng/mL free prostate-specific antigen; all of these test results were within the normal range. The hepatitis virus panel was positive for hepatitis B surface antigen, negative for hepatitis B e antigen, positive for hepatitis B e antibody, positive for hepatitis B core antibody, negative for hepatitis B pre-S1 antigen, and negative for other hepatitis viruses.

Imaging examinations

Electronic gastroduodenoscopy examination: Postgastrectomy: (Billroth II style) with residual gastritis and bile reflux; anastomosis inflammation with a raised mucosal lesion at the anastomosis (nature to be determined); and gastric xanthoma (Figure 1A and B).

Figure 1 Endoscopy, endoscopic ultrasound and pathologic findings in our hospital. A and B: Endoscopy shows a prominent lesion in the remnant stomach; C and D: Tumor manifestations observed through endoscopic ultrasound; E: Histological findings of hematoxylin and eosin (100 × on the left, 200 × on the right).

Endoscopic ultrasound: Endoscopic ultrasound revealed a raised mucosal lesion at the anastomosis site (suspected anastomotic cancer) and postgastrectomy (Billroth II style) with residual gastritis, bile reflux, and anastomotic inflammation (Figure 1C and D).

Histopathological examination (biopsy from the anastomosis): Examination revealed moderate chronic nonatrophic gastritis with acute activity, Helicobacter pylori (+), neutrophils (+), lymphocytes (++), atrophy (-), and intestinal metaplasia (-) (Figure 1E).

Abdominal computed tomography scan with contrast: Scan revealed changes after gastrectomy, with significant thickening and elevation of the residual gastric wall and enlarged lymph nodes in the hepatogastric space. This suggests a high possibility of postoperative recurrence and lymph node metastasis in the hepatogastric space (Figure 2A-D).

Figure 2 Pre-operation abdominal computed tomography images and positron emission tomography-computed tomography. A and B: Abdominal computed tomography (CT) revealed the gastric wall at the greater curvature of remnant stomach were obviously thickened; C and D: Enhanced CT revealed the gastric wall at the greater curvature of remnant stomach were obviously thickened; E: Positron emission tomography-CT showed metabolism nodular thickening of the residual gastric wall, enlarged lymph nodes beside the abdominal aorta (at the T12 level) and in the middle abdomen (at the L2 level).

Positron emission tomography-computed tomography: Results revealed changes after gastrectomy, with nodular thickening of the residual gastric wall and increased metabolism, suggesting residual GC. Enlarged lymph nodes beside the abdominal aorta (at the T12 level) and in the middle abdomen (at the L2 level) with increased metabolism suggested metastasis (Figure 2E).

FINAL DIAGNOSIS

In March 2022, the patient experienced a severe episode of gastrointestinal bleeding, which prompted an urgent referral to another hospital for surgical intervention. Upon arrival, a repeat gastroscopy was conducted at the secondary facility, and subsequent pathological examination revealed the presence of residual gastric, small cell carcinoma and SCC. To address the life-threatening haemorrhage, the patient underwent an emergent surgical procedure that included resection of the remaining stomach, the creation of an oesophagojejunal anastomosis to restore gastrointestinal continuity, and the release of abdominal adhesions to facilitate surgery. During the operation, the source of the massive gastrointestinal bleeding was identified and traced back to the anastomotic site, likely due to a rupture of vessels within the cancerous lesion. Histological typing suggested a mixed neuroendocrine tumor [70% small cell NEC (SCNEC) and 30% keratinizing SCC (KSCC)]; the depth of invasion reached the subserosa; there were vascular tumor emboli and nerve invasion; the resection margins were not involved; and one of the thirteen peri-gastric lymph nodes showed cancer metastasis (1/13), with the cancer components being SCNEC - KSCC (T4aN2M1, according to the Eighth Edition American Joint Committee on Cancer staging)[10]. Two of the two pericolic lymph nodes showed cancer metastasis (2/2), with the cancer component being SCNEC - KSCC (Figure 3A). Immunohistochemical staining revealed the following: SCNEC component, isocitrate dehydrogenase 1 (+), somatostatin receptor 2 (2 +), synaptophysin (+), cluster of differentiation 56 (+), chromogranin A (+) (Figure 3B); SCC component, P40+, CK5/6 (+) (Figure 3C); mismatch repair proteins, postmeiotic segregation increased 2 (+), mutS homolog 6 (+), mutL homolog 1 (+), mutS homolog 2 (+); P53 (+, mutant type), Ki-67 (approximately 80% + in the SCNEC component, approximately 60% + in the SCC component) (Figure 3D and E).

Figure 3 The histological examination and immunohistochemical profiling of the surgically resected tissue. A: Results of hematoxylin and eosin staining; B: The expression of marker proteins specific for small cell neuroendocrine carcinoma; C: Immunohistochemical results for P40 and cytokeratin 5/6 protein expression; D and E: The expression of mismatch repair protein-related indicators postmeiotic segregation increased 2, mutS homolog 6, mutL homolog 1, mutS homolog 2, as well as the expression of tumor protein P53 and Ki67. SSTR2: Somatostatin receptor type 2; SYN: Synaptophysin; TTF-1: Thyroid transcription factor-1; CgA: Chromogranin A; CD56: Cluster of differentiation 56. MLH1: MutL homolog 1; MSH6: MutS homolog 6; MSH2: MutS homolog 2; PMS2: Postmeiotic segregation increased 2.

TREATMENT

Following the surgical procedure, the patient received chemotherapy on four occasions: April 25, 2022, May 20, 2022, June 13, 2022, and July 8, 2022. The chemotherapeutic drugs that were used were 100 mg of etoposide and 30 mg of cisplatin. The patient was in good condition and underwent a follow-up examination in May 2024. An endoscopic examination at an external hospital revealed a protruding lesion in the oesophagus, of which a biopsy was collected. Pathology revealed oesophageal cancer (Figure 4).

Figure 4 Endoscopy and pathologic findings in another hospital. A: Endoscopy shows a prominent lesion in the remnant stomach; B: Histological findings of hematoxylin and eosin (100 ×); C: Histological findings of hematoxylin and eosin (200 ×).

OUTCOME AND FOLLOW-UP

The patient was subsequently transferred to another thoracic hospital for a small bowel stoma and radical oesophagectomy. The patient is currently in fair condition and is receiving enteral nutrition.

DISCUSSION

Rare and aggressive nature of GSC

This case report presents a unique case of a 60-year-old male who developed mixed SCNEC and KSCC in the gastric remnant after distal gastrectomy for duodenal ulcer bleeding. GSC is a rare and aggressive malignancy that can arise in the gastric remnant after gastrectomy for benign or malignant conditions. Surgical outcomes for patients with GSC vary significantly across studies, with reported 5-year survival rates ranging widely from 10%-70%[11]. The uniqueness of this case lies in the development of a mixed SCNEC and KSCC in the gastric remnant of a patient with a history of distal gastrectomy.

Development of GSC post-gastrectomy

Peptic ulcer disease, once predominantly a surgical issue, especially when there is no endoscopic technology, is now predominantly managed medically for most patients[5]. Surgical intervention for ulcer disease is now strictly limited to life-threatening complications, such as free perforation, refractory bleeding, and gastric outlet obstruction, that cannot be controlled with medical therapy[12]. The development of GSC is often attributed to the persistence of risk factors such as Helicobacter pylori infection, chronic inflammation, and genetic predisposition. In this case, the patient’s history of smoking and alcohol consumption may have contributed to the multifaceted carcinogenesis process. According to the World Health Organization’s classification criteria for digestive system tumors[13], a tumor is considered truly mixed when both constituent elements are prominent, with a minimum of 30% of each element discernible within the tumor. Therefore, the tumor could be classified as having a mixed histology of SCNEC and KSCC in this case.

Rareness of primary SCC and NEC of the stomach

Primary SCC of the stomach is an exceedingly rare malignant neoplasm, constituting approximately 0.04% to 0.07% of GC cases[14]. According to the literature, NEC may arise from a GC precursor at the anastomotic site in the gastric remnant. For genomic alterations, a previous study provided additional support that NECs often have genomic alterations in KRAS,NF1, CDKN2A, and TP53[15]; however, further studies are needed to confirm these findings. In the present case, we identified a mutation in the P53 gene within the patient’s tumor tissue. The mixed elements suggest a complex interplay of molecular pathways and cellular differentiation, potentially influenced by the patient’s prior gastrectomy and subsequent alterations in the gastric microenvironment[16]. The management of NEC typically requires total gastrectomy. For those presenting with distant metastases, the combined therapeutic approach of cisplatin and etoposide is often recommended, offering a particularly effective synergistic effect in such advanced disease stages[17]. Consequently, in this case, the patient underwent chemotherapy after surgical intervention. This subtype of GC is rare and notably aggressive, characterized by swift progression and, unfortunately, a generally poor prognosis[18]. In approximately 70% of cases, NEC of the gastric remnant is found in conjunction with an adenocarcinoma component, but the etiology of NEC remains to be fully elucidated[18]. The coexistence of SCNEC and KSCC in GSC is exceptionally rare. To our knowledge, we present an inaugural case report of an SCNEC mixed with a KSCC originating from a GSC.

Challenges in diagnosing and treating GSC

The diagnosis of GSC is challenging due to nonspecific symptoms and the limitations of endoscopic biopsies in capturing the full extent of the tumor. In this case, the initial endoscopic biopsy did not yield positive findings. However, the use of endoscopic ultrasound, computed tomography and positron emission tomography-computed tomography was instrumental in identifying the tumor and its metastatic potential[19]. The histological confirmation of SCNEC and KSCC was crucial for determining the therapeutic approach, as this histotype has distinct treatment implications and prognostic significance[19]. The treatment of GSC with mixed histology requires a multimodal approach, often involving surgery, chemotherapy, and radiation therapy[14]. In this case, the patient underwent total gastrectomy and lymph node dissection, followed by adjuvant chemotherapy. The choice of chemotherapy regimen was based on the aggressive nature of SCNEC, which typically requires a combination of cytotoxic agents. As shown by immunohistochemical staining, Ki67 expression was increased, and the tumor was positive for mutant P53, suggesting that the carcinoma was aggressive. Moreover, the mismatch repair proteins in this patient were normal, suggesting that this tumor was a microsatellite stable (MSS) tumor. Previous studies have shown that patients with MSS tumors have a poorer median overall survival time than do GC patients with microsatellite instability and that patients with MSS tumors have poorer sensitivity to chemotherapy[20,21].

Prognosis of GSCs with mixed SCNEC and KSCC

The prognosis for GSCs with mixed SCNEC and KSCC is generally poor because of the advanced stage at presentation and the aggressive biological behavior of these tumors. Despite aggressive treatment, the risk of recurrence and metastasis remains high, and long-term follow-up with regular imaging and endoscopic evaluations is essential for the early detection of recurrence and to guide further therapeutic interventions. In this case, the patient was found to have oesophageal cancer in 2024. The potential reasons for the development of oesophageal cancer in our patient included chronic inflammation, history of smoking, and genetic predisposition. For example, the patient’s long history of smoking and alcohol consumption, along with chronic inflammation from residual gastritis and bile reflux, may have contributed to the development of a second primary malignancy in the oesophagus. Additionally, genetic factors, potentially revealed by initial gastrectomy and subsequent changes in the gastric microenvironment, may have predisposed the patient to developing oesophageal cancer. While it is currently unclear whether oesophageal cancer represents a recurrence of the original GC or a new primary tumor, ongoing investigations aim to elucidate the cause, which remains a subject of further research and analysis. Therefore, future studies, including larger studies to better understand the risk factors, molecular mechanisms, and optimal management strategies for patients with GSC who develop second primary malignancies, are essential.

CONCLUSION

In conclusion, this case highlights the complexity of GSC with mixed histology and the importance of a comprehensive diagnostic and therapeutic approach. These findings highlight the need for further research into the molecular mechanisms underlying the development of GSC, particularly in the context of mixed histology.