Gastric metastasis of small cell lung carcinoma: Three case reports and review of literature

Abstract

BACKGROUND

Small cell lung carcinoma (SCLC) is highly susceptible to metastasis in the early stages of the disease. However, the stomach is an uncommon site of metastasis in SCLC, and only a few cases of this type of metastasis have been reported. Therefore, SCLC gastric metastases have not been systematically characterized and are easily missed and misdiagnosed.

CASE SUMMARY

We report three cases of gastric metastasis from SCLC in this article. The first patient presented primarily with cough, hemoptysis, and epigastric fullness. The other two patients presented primarily with abdominal discomfort, epigastric distension, and pain. All patients underwent gastroscopy and imaging examinations. Meanwhile, the immunohistochemical results of the lesions in three patients were suggestive of small cell carcinoma. Finally, the three patients were diagnosed with gastric metastasis of SCLC through a comprehensive analysis. The three patients did not receive appropriate treatment and died within a short time.

CONCLUSION

Here, we focused on summarizing the characteristics of gastric metastasis of SCLC to enhance clinicians' understanding of this disease.

Key Words: Small cell lung cancer; Gastric neoplasms; Neoplasm metastasis; Diagnosis; Case report

Core Tip: Due to the rarity of small cell lung carcinoma (SCLC) gastric metastasis, few cases have been reported internationally, and clinicians are not sufficiently aware of the clinical features of this group of diseases. In this article, we report three cases of SCLC gastric metastasis to summarize the characteristics of this type of disease and improve the understanding of the diagnosis and treatment of SCLC gastric metastasis.

INTRODUCTION

The incidence of small cell lung carcinoma (SCLC) has gradually increased in recent years. Approximately 70% of patients have already developed distant metastases at diagnosis[1]. The liver, brain, bones, adrenal glands, and lymph nodes are common sites of metastasis for this disease[2]. In contrast, SCLC metastasis to the stomach is very rare, and the related clinical features have not been systematically described, which makes it easily missed and misdiagnosed. Therefore, an in-depth understanding of the clinical features of these diseases is essential for early diagnosis and timely treatment.

CASE PRESENTATION

Chief complaints

Case 1: A 56-year-old male presented with a complaint of persistent cough and hemoptysis for one year and epigastric fullness for six months.

Case 2: A 67-year-old male presented with a complaint of persistent epigastric discomfort for one month.

Case 3: A 77-year-old male presented with a complaint of persistent subxiphoid swelling and pain for two months.

History of present illness

Case 1: One year previously, the patient was admitted to our hospital due to cough and hemoptysis. The patient was diagnosed with SCLC via bronchoscopic pathologic biopsy. Then, six months prior to the present presentation, the patient developed abdominal distension.

Case 2: The patient had a 1-month history of persistent subxiphoid fullness and discomfort, which was aggravated by eating and accompanied by nausea. No other specific discomfort was described.

Case 3: The patient had a 2-month history of persistent subxiphoid swelling and pain. No other specific discomfort was described.

History of past illness

The three patients had no previous abnormalities.

Personal and family history

Case 1: The patient had a 25-year history of smoking, with an average of 40 cigarettes smoked per day.

Case 2: The patient had a 30-year history of smoking, with an average of 20 cigarettes smoked per day.

Case 3: The patient had a 50-year history of smoking, with an average of 35 cigarettes smoked per day.

Physical examination

Case 1: The physical examination was unremarkable.

Case 2: There was mild epigastric tenderness on abdominal examination.

Case 3: There was mild subxiphoid tenderness on abdominal examination.

Laboratory examinations

Case 1: Laboratory examinations revealed that the patient's level of neuron-specific enolase (NSE) was slightly greater (39.960 ng/mL) and that the levels of serum tumor markers were elevated [carcinoembryonic antigen (CEA) 16.44 µg/L (< 5), CA199 111.70 U/mL (< 35), and CA125 283.3 U/mL (< 35)]. Other laboratory data revealed no abnormalities.

Case 2: Laboratory examination revealed no abnormalities.

Case 3: The patient's CA199 and CEA levels were elevated to 310.5 U/mL and 655.55 U/mL, respectively.

Imaging examinations

Case 1: In April 2020, the patient underwent a chest scan, which revealed centralized lung cancer in the left hilum (Figure 1A). The patient subsequently underwent immunohistochemistry after biopsy via bronchial fibroscopy, which revealed positivity for cytokine (CK), CD56, thyroid transcription factor (TTF-1), and chromogranin A (CgA) and negativity for CK7 and P40. Consequently, the diagnosis was SCLC. After developing abdominal discomfort, the patient returned to the hospital for gastroscopy, which revealed two masses approximately 1 cm in diameter in the body and fundus of the stomach, accompanied by central depression and ulcer formation (Figure 2A and B). Endoscopic ultrasound (EUS) revealed a hypoechoic lesion at the lesion site (Figure 2C) and portal vein thrombosis, which was thought to be due to metastasis (Figure 2D). Immunohistochemistry of the biopsy samples obtained from the gastric fundus revealed that the samples were positive for CK, CD56, TTF-1, CgA, and synaptophysin (Syn). The ki-67 index was 70% (Figure 3).

Figure 1 Chest computed tomography image. A: A mass of approximately 5.0 cm × 4.0 cm in the left hilar region of the lung (case 1); B: A mass of approximately 7 cm × 3 cm in the left lower lobe of the lung (case 2).

Figure 2 Gastroscopy and endoscopic ultrasound findings. A and B: Gastroscopy suggested submucosal lesions with two central depressions and ulcer formation in the body and fundus of the stomach, respectively; C: Endoscopic ultrasound (EUS) suggested submucosal hypoechoic lesion of the gastric body; D: EUS suggested hypoechoic lesions of the portal vein (A-D; case 1); E: Gastroscopy suggested a submucosal lesion with ulcer formation was seen in the greater curvature of the stomach; F: EUS showed a submucosal hypoechoic lesion in the greater curvature of the stomach (E and F; case 2); G: A 4 mm × 5 mm mucosal lesion with a depressed tip (G; case 3).

Figure 3 Immunohistochemical examination of the lesion of case 1. A: Positive expression of CD56; B: Positive expression of thyroid transcription factor; C: Positive expression of chromogranin A; D: Positive expression of synaptophysin; E: Immunohistochemical staining displaying Ki-67 (70%); A-D: Magnification, × 200.

Case 2: Gastroscopy revealed a lesion at the greater curvature of the stomach measuring approximately 1.5 mm × 1.8 mm, with an ulcer forming on the surface, and biopsy of the primary lesion was performed (Figure 2E). EUS revealed hypoechoic lesions in the area, and multiple hypodense masses were found in the pancreas, which were considered to be due to tumor metastasis (Figure 2F). Unexpectedly, using a computed tomography (CT) scan of the chest, we found a mass approximately 7 cm × 3 cm in size in the left lower lobe of the lung, accompanied by enlarged lymph nodes in the left hilar and mediastinal septum, which had metastasized to the second rib on the right side (Figure 1B). The transbronchial fibroscopic biopsy pathology suggested SCLC. Biopsies of 4 L and 7 L lymph nodes suggested metastatic malignancy. Histological examination of biopsy samples obtained from the gastric fundus revealed positive results for CD56, CgA, and Syn, and the ki-67 index was 70% (Figure 4). Moreover, the immunohistochemistry results suggested TTF-1 positivity (Figure 4).

Figure 4 Immunohistochemical examination of the lesion of case 2. A: Positive expression of CD56; B: Positive expression of chromogranin A; C: Positive expression of synaptophysin; D: Immunohistochemical staining displaying Ki-67 (70%); E: Positive expression of thyroid transcription factor; A-D: Magnification, × 200.

Case 3: Gastroscopy revealed a 4 mm × 5 mm red mucosal lesion in the fundus of the stomach with elevated margins and a central visible depression (Figure 2G). However, a CT scan at an outside hospital suggested multiple lesions in both lungs, possibly indicating tuberculosis or tumors, whereas an abdominal CT suggested multiple metastases in the liver. Immunohistochemistry of the liver biopsy sample revealed positivity for TTF-1, CA199, CD117, and CK and negativity for vimentin, villin, AFP, S100, CK20, hepatocytes, VD34, CK19, and CK7, which was considered to indicate a metastatic tract of small cell carcinoma to the liver. Histological examination of biopsy samples obtained from the gastric fundus revealed positive expression of CD56, CgA, CK, and TTF-1 and negative expression of Syn and Napsin-A. In addition, the ki-67 index was as high as 80% (Figure 5).

Figure 5 Immunohistochemical examination of the lesion of case 3. A: Positive expression of CD56; B: Positive expression of chromogranin A; C: Positive expression of thyroid transcription factor; D: Immunohistochemical staining displaying Ki-67 (80%) (magnification, × 200).

FINAL DIAGNOSIS

On the basis of CT, endoscopy, ultrasound, immunohistochemistry and other relevant examinations, the three patients in this study were ultimately diagnosed with gastric metastasis of SCLC.

TREATMENT

All three patients refused to undergo the relevant treatment for personal reasons.

OUTCOME AND FOLLOW-UP

The three patients died between 3 and 6 months after diagnosis.

DISCUSSION

Lung cancer is the leading cause of cancer death, and approximately 50% of lung cancer patients may develop distant metastases at an early stage. The liver, adrenal glands, bone, brain, and lymph nodes are common sites of metastasis for lung cancer[3]. However, metastasis to the gastrointestinal tract is rare, and studies have shown that the rate of gastrointestinal metastasis detected at autopsy is approximately 4.7%-14%, with an incidence of approximately 1.77% in the clinic, and cases of metastasis to the stomach are much rarer[3-5]. Previous studies have shown that adenocarcinoma is the most common type of gastrointestinal metastasis in lung cancer, followed by squamous cell carcinoma and large cell carcinoma[6]. Reports of gastric metastases from SCLC are rare. According to Peng et al[7], the total number of patients with gastric metastasis from small cell lung cancer is currently approximately 20 cases. Consequently, there is a lack of awareness of SCLC gastric metastases among clinicians and pathologists due to the small number of cases. In this paper, we report three cases of gastric metastasis from SCLC and summarize the characteristics of this type of disease from the following aspects.

The clinical presentation of patients with gastric metastases from SCLC is nonspecific. Patients usually present with digestive symptoms. For example, the patients in this case report presented mainly with symptoms of abdominal pain and bloating. Additionally, respiratory symptoms may be present. Previous studies have reported that symptoms arising from metastases tend to appear later than those arising from the primary tumor[8]. In contrast, in our case, two patients first presented with gastrointestinal symptoms but no obvious respiratory symptoms. Hence, when gastrointestinal metastasis occurs in SCLC patients, some patients will first present with signs and symptoms of the digestive system while not having any obvious respiratory signs and symptoms. Therefore, when diagnosing small cell carcinoma of the stomach, clinicians should consider whether the tumor has metastasized from other sites, especially the lung. This will reduce the incidence of clinical underdiagnosis and misdiagnosis.

Indeed, SCLC gastric metastases are usually first detected via gastroscopy and are further confirmed after gastroscopic biopsy. Owing to the low incidence of gastric metastasis in SCLC, few studies have been conducted on its endoscopic characterization. Among them are reports that the most common site of metastatic gastric cancer is often located in the mucosa and submucosa, which is related mainly to blood or lymphatic spread of the primary tumor through the submucosa[9]. Previous studies have shown that gastric metastases of SCLC are located primarily in the gastric body or fundus, and the microscopic manifestations are mainly mucosal or submucosal elevated lesions, which can form ulcers in the center, often between 2-5 cm in size[10-13]. Similarly, in the cases reported here, the lesion site and endoscopic features were the same as those described above for metastatic gastric tumors, which were located mainly in the mucosal and submucosal layers of the fundus and body of the stomach, with ulcerations forming on the surface. In addition, gastric metastases from SCLC usually present as a single lesion. However, in our study, there was one patient with multiple lesions. Therefore, SCLC cannot be differentiated from other tumors only by the number of lesions. Indeed, small cell carcinoma of the stomach is a neuroendocrine tumor. Neuroendocrine tumors can originate in the stomach. Among them, well-differentiated gastric neuroendocrine tumors can be classified into three types. Type I is most common, and type III is less common, but the cause is unclear[14]. However, we found that the endoscopic features of the patients in the cases were similar to those of type III patients, with both showing isolated lesions in the form of masses, polyps, and craters greater than 2 cm in diameter[15,16]. The pathogenesis of type III gastric neuroendocrine tumors is unclear. We therefore speculate that the gastric metastases of SCLC are essentially type III gastric neuroendocrine tumors. However, more research is needed to confirm this conjecture. In addition, all three of our patients had hypoechoic lesions on EUS, but the above features were not significant in differentiating them from other tumors. Nevertheless, tissue biopsy and immunohistochemistry are the gold standard for the diagnosis of gastric metastases from SCLC[17].

The cytomorphology of SCLC metastatic to the stomach closely resembles that of the original tumor. The main endoscopic manifestations are less cytoplasm, indistinct cell borders, fine nuclear chromatin, and absent or inconspicuous nucleoli. The tumor cells are round, elliptical, or spindle shaped[18]. Currently, immunohistochemistry is important for determining the tumor origin[19]. Syn, CD56, NSE, and CgA can be used as markers for pulmonary SCLC[20]. In our case, the immunohistochemistry results of all three patients were suggestive of CD56, CgA and TTF-1 positivity. The immunohistochemistry results of patient 1 suggested Syn positivity. Neuroendocrine tissues and tumors such as SCLC specifically express CD56, a cell surface protein[21,22]. Its expression rate in SCLC tissues is approximately 89%-100%, and the literature suggests that it can be used as a marker for SCLC[23,24]. More important than CD56 is TTF-1. TTF-1 is a transcription factor found mainly in brain, thyroid, and lung tissues, especially in SCLC[25]. Some researchers have reported that the rate of TTF-1 expression in SCLC is as high as 96%, which is significantly greater than that in extrapulmonary tissues[26]. Therefore, positivity for TTF-1 combined with the difference in its expression rate can be used to determine whether it originates from lung tumors. Additionally, previous studies have noted that TTF-1 and CK7 positivity and CDX2 and CK20 negativity are mostly suggestive of gastrointestinal tumors of lung origin[27]. In addition, CD56 and Syn are often used in combination to diagnose SCLC, but CD56 is more sensitive to SCLC[28].Consequently, TTF-1 and CD56 play very important roles in the diagnosis of gastric metastasis in SCLC. Other markers, such as CgA, NSE, and Syn, can assist in diagnosis. Therefore, immunohistochemistry is indispensable for the diagnosis of gastric metastasis in SCLC patients.

The three patients in this study died without treatment several months after the diagnosis of SCLC with gastric metastases. These findings indicate that the disease prognosis is poor. The therapeutic effects of the different treatment regimens could not be evaluated because the patients in this case did not undergo relevant treatment. When gastric metastasis occurs in SCLC, it often occurs at an advanced stage of the disease, often combined with metastases to other organs, and the opportunity for surgery is lost; thus, platinum-etoposide combination chemotherapy remains the treatment of choice[29,30]. In the future, as the molecular biology of SCLC is better understood, it may have a significant impact on improving the prognosis of this disease.

CONCLUSION

Gastric metastasis from SCLC has a low probability of occurring, but it is easily misdiagnosed and missed. Its clinical symptoms are nonspecific, and gastrointestinal symptoms may appear first; therefore, clinicians should be more vigilant. The diagnosis relies mainly on endoscopy, pathological biopsy, immunohistochemistry, and imaging examinations. Of these, the immunohistochemical results are critical. Chemotherapy is currently the first-line treatment option for patients with SCLC with gastric metastasis, but the clinical condition of such patients is more complicated, and a comprehensive treatment plan needs to be formulated on the basis of various factors. Early diagnosis and early individualized treatment can improve the survival rate of patients; Therefore, clinicians should improve their understanding of the diagnosis and treatment of SCLC gastric metastases.

ACKNOWLEDGEMENTS

The authors would like to thank each of the investigators who contributed to this article. We also thank the patients' families for their cooperation.