Metastasis to the stomach: a systematic review

Background: This study reviews the literature on gastric metastases (GM) in terms of diagnosis, treatment, and outcomes. The goal of this study was to provide clinicians with a reliable and beneficial source to understand gastric metastases arising from various primary tumors and to present the growing literature in an easily accessible form. Methods: Articles published in English language from implementation of MEDLINE and Cochrane databases until May 2022 were considered for the systematic review. Articles other than English language, letters to the editor, posters, and clinical images were excluded. Hematogenous and lymphogenic metastases were included whereas direct tumoral invasion and seeding were excluded. Articles and abstracts were analyzed and last selection was done after cross-referencing and by use of defined eligibility criteria. Results: In total 1,521 publications were identified and 170 articles were finally included totaling 186 patients with GM. The median age of patients was 62 years. Gynecologic cancer was the most common cancer type causing GM (67 patients), followed by lung cancer (33 patients), renal cancer (20 patients), and melanoma (19 patients). One of the main treatment methods performed for metastasis was resection surgery (n=62), sometimes combined with chemotherapy (ChT) or immunotherapy. ChT was the other most used treatment method (n=78). Also, immunotherapy was amongst the most preferred treatment options after surgery and ChT (n=10). Conclusions: As 172 case reports were screened in the systematic review from different journals, heterogeneity was inevitable. Some articles missed important information such as complete follow-up or clinical information. Moreover, since all of the included articles were case reports quality assessment could not be performed. Among 172 case reports reviewed, resection surgery was performed the most and was sometimes combined with ChT and immunotherapy. Further research about what type of treatment has the best outcomes for patients with gastric metastases is needed.


Introduction
Metastases to the stomach are rare conditions with poor prognosis that may present with both gastrointestinal and systemic symptoms, such as loss of appetite, abdominal pain, fatigue, nausea, and vomiting, with a reported incidence of 0.2-0.7%based on clinical and autopsy findings. 1Gastrectomy is thought to be the only potentially curative treatment for metastatic gastric cancer but the primary site of the tumor is also considered along with the type and grade of the tumor when planning treatment in gastric metastases.Therefore, chemotherapy is also an option for patients with higher grades and multi-focal cancers.This study reviews the literature on gastric metastases in terms of diagnosis, treatment, and outcomes.The intended goal of this study was to provide clinicians with a reliable and beneficial source to understand gastric metastases arising from various primary tumors and to present the growing literature in an easily accessible form by reviewing the case reports of different primary tumors separately with consideration of diagnosis, treatment, and clinical presentation which may vary from patient to patient depending on primary site of the tumor.

Methods
This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 172A computerized literature search through MEDLINE/PubMed and Cochrane databases was conducted until May 2022.
The following combination of keywords was used for the search: ({({gastric (MeSH Terms)} AND {neoplasm metastasis (MeSH Terms)}) OR (gastric metastasis)} OR {gastric metastases}) OR (metastasis to the stomach).The search was limited by filtering for "free full text" and "case reports."After the decision of inclusion and exclusion criteria by the team, two of the reviewers independently screened and retrieved each report.
Hematogenous and lymphogenic metastases were included whereas direct tumoral invasion and seeding were excluded from the study.Articles other than the English language, letters to the editor, posters, and clinical images were excluded.After the studies were screened and separated based on the inclusion and exclusion criteria, reviewers were divided to groups based on primary tumor location.Each group contained two reviewers to collect the data from studies of its specific location for example metastasis from gynecologic cancers or lung cancers.
The following data were extracted from the databases: first author, number of cases, age, sex, site of the primary tumor, histology and treatment of primary tumor, treatment of metastasis, clinical presentation of gastric metastases (GM), synchronous or metachronous GM, the time between primary and secondary GM, diagnostic procedures, other metastasis, and overall survival.
Since the study only contains screening of case reports, assessment of bias risk was not performed and thus it is mentioned as a limitation of study in discussion section.

Results
The PRISMA flow chart below illustrates details about data collection (Figure 1).In total, 1,521 publications were identified and 170 articles were finally included totaling 186 patients with GM (101 female and 85 male).The median age of patients was 62 years (IQR: 55-70.5).Gynecologic cancer (including breast cancer) was the most common cancer type causing GM (66 patients), followed by lung cancer (33 patients), renal cancer (20 patients), and melanoma (19 patients) (Figure 2).Results are presented below according to the origin of the primary tumor.The main treatment method performed for metastasis was resection surgery (n=62, total, subtotal or partial gastrectomy, proximal gastrectomy, radical total gastrectomy with Roux-en-Y, wedge gastrectomy, and laparoscopic resection of gastric metastasis), sometimes combined with chemotherapy (ChT) or immunotherapy.Chemotherapy was the other most used treatment method (n=78).Also, immunotherapy was among the most preferred treatment options after surgery and chemotherapy (n=10).

Gynecologic cancer
The median age of the 66 patients was 57 years.In total, 46 cases had metastases other than GM.Bone was the most common site of metastasis.Five cases had no other metastases.The total number of cases in the breast group was 54, and one of them was a male patient.The median age of the breast group is 56, the youngest patient was 36 years old and the oldest patient was 84 years old.Invasive lobular carcinoma (ILC) had the largest number of patients in comparison to ovarian and uterine groups.A total of 31 patients presented with ILC.The ovarian group had nine patients; the median age was 61 years.The oldest patient was 73 years old; the youngest patient was 47 years old.The uterine group had two patients with ages 49 and 80 years.In most cases, systemic therapy was more effective than surgery.Surgical treatment had a role in palliative treatment.As a systemic treatment, chemotherapy was the most utilized treatment.Overall survival  was given in only 25 cases and ranged from a few days to nine years.Six of the total patients are still alive.Table 1   summarizes the findings of included studies regarding gynecologic cancers.

Gastrointestinal cancer
Median age of the 16 patients (11 male, five female) was 69 years, ranging from 22 years to 85 years.Overall survival of the seven patients whose data were given ranged from two months to 16 months.Although, there were six cases who were still alive and the survival of three cases was not reported.Among histological types of gastrointestinal cancers, adenocarcinoma (Adeno Ca) was the most common cancer type (seven patients), followed by hepatocellular cancer (HCC) (four patients) and squamous cell carcinoma (two patients).Endoscopy is the most frequently used method in the diagnosis of metastases.Methods such as computer tomography (CT), positron emission tomography and computed tomography (PET-CT), and endoscopic ultrasound were also used for diagnosis.One patient underwent laparotomy and biopsy.According to this research nine of these patients had surgery.Transcatheter left gastric artery embolization was performed in one patient.On the other hand, seven patients received chemotherapy and one patient had palliative radiotherapy.Nevertheless, one patient is unknown.Findings regarding gastrointestinal cancers are summarized in Table 2. [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]

Lung cancer
The median age of the 33 patients (25 male, eight female) was 62, ranging from 39 years to 78 years.Twenty-seven of the total cases had other metastases in addition to gastric ones.The survival time of the 22 patients whose data were given ranged from two weeks to 30 months.Yet, there were two cases that were still alive four and five years after metastases were found, respectively.Among histological types of primary lung cancers that lead to gastric metastases, adenocarcinoma was the most typical diagnosis (13 patients), followed by small cell lung cancer (SCLC) and squamous cell carcinoma (SCC).Regarding the treatment of GM, different combinations of chemotherapy were the most common choice (15 patients).On the other hand, seven of the total cases received surgical treatment (one esophagogastrostomy, two total, and four partial gastrectomies).However, since one patient's metastasis was diagnosed after an autopsy, he could not receive any gastric treatment.Moreover, one patient refused any metastasis treatment, while six other cases' treatments are unknown.Data pertaining to GM originating from primary lung cancers are summarized in Table 3.

Malign melanoma
The median age of the 19 patients (seven female, 12 male) was 67, ranging from 28 years to 89 years.In 16 patients, other organ metastases were also discovered in addition to malign melanoma.Overall survival was not mentioned in 10 cases.Two of these cases deceased two and four days after hospital admission respectively, and one patient died after a year.Moreover, one of these patients was alive at five years, and another was alive at six months.Overall survival of three cases is three, 27, and four months, respectively.One of these patients refused treatment, and one of them did not receive treatment.However, immunotherapy was applied to six patients, surgery to five patients, radiotherapy to two patients, and only supportive treatment to three patients.In addition, the treatment of GM was not mentioned in three cases.[105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121]

Urogenital cancers
The median age of 20 patients (11 male and nine female) with kidney cancer was 68.5 years old.A total of 11 patients had metastases other than GM.Overall survival was mentioned only in four cases and ranged from two months to one year.One of the 20 patients did not receive any therapy for GM, whereas 13 patients underwent surgical treatment (four endoscopic mucosal resections, nine gastrectomies), four patients had chemotherapy and one patient was treated with radiotherapy.Regarding prostate cancer, the median age of the affected individuals was 67 years old.Concerning the GM treatment four patients received chemotherapy, one patient underwent mucosal resection, and one patient refused treatment.Overall survival was mentioned for three patients ranging from four months to 19 months.All four patients with testis cancer had other metastases and two of them received chemotherapy.One study included bladder cancer without other metastases and the patient was referred to palliative care.Data pertaining to gastric metastases originating from primary urogenital cancers are summarized in Table 5. 71,

Others
The median age of the four patients with Merkel cell carcinoma was 73 years old.Two patients had other metastases in addition to GM.Three patients underwent surgery, chemotherapy, and radiotherapy, whereas one patient was treated with chemotherapy and radiotherapy.One patient with squamous cell carcinoma had other metastases in addition to GM and received chemotherapy and radiotherapy for the primary tumor.
Regarding bone cancers (n=3) one of the patients was 14 years old and stood out as the youngest patient in this group.Concerning the GM therapy, one of the patients with a known treatment underwent surgery and chemotherapy the other              received only surgery.In all patients, GM was discovered metachronous.Three studies were included for soft tissue cancer.All three patients had metastases in addition to GM and underwent different types of GM treatment (including radiotherapy, chemotherapy, excision with snare, and cautery).For the thyroid cancer group, the median age was 71 years old.Overall survival (OS) was only mentioned for one patient (2.5 months).Regarding diffuse large B-cell lymphoma (DLBCL) (n=2), patients received chemotherapy for primary cancer and for GM.GM was discovered synchronously.Kovecsi et al., described the only case of GM from adrenocortical carcinoma of the adrenal gland. 152The patient underwent adrenalectomy for primary and total gastrectomy with splenectomy and end-to-side Roux-en-Y esophagojejunal anastomosis for GM.One patient with choriocarcinoma from retroperitoneum underwent chemotherapy for primary cancer and GM.Table 6 summarizes the findings of included studies regarding gastrointestinal cancers.  Discus Gastric metastases are uncommon and give information about the progressed stage of malignant disease, with a reported incidence of 0.2-0.7%based on clinical and autopsy findings. 1Furthermore, metastasis to the stomach frequently indicates short survival.These metastases are observed rarely due to clinical problems regarding their diagnosis and treatment. 2Progressively, with improvements in prognosis for cancer patients, metastatic tumors in the stomach are being detected more frequently. 1There are several symptoms of gastric metastases, such as abdominal pain, diarrhea, nausea, vomiting, weight loss, and dyspepsia.The most preferred treatment method for gastric metastasis is surgical resection of the tumor.Also, chemotherapy is the most applied alternative option.
This systematic review has a few potential limitations that need to be mentioned.As 172 case reports were screened in the systematic review from different journals the heterogeneity was inevitable.Some articles missed important information such as complete follow-up or clinical information.Moreover, since all of the included articles were case reports, quality or bias assessment could not be performed.

Gynecologic cancer
Gastric metastasis mainly occurs due to breast cancer.Both ovarian and uterine metastases are distinctly less frequent. 38nvasive lobular carcinoma is the type with the highest affinity to the digestive system with an incidence of 4.5% compared to 0.2% in ductal carcinoma. 26Breast cancer metastases to the gastrointestinal tract are rare, with a median time interval from the diagnosis of the primary tumor to metastasis up to seven years. 21The longest disease-free interval is 22 years after the initial diagnosis 17 of 24. 10 Some metastatic tumors may have a similar presentation as primary gastric cancer. 38The detailed immunohistochemical analysis will allow the most accurate diagnosis to differentiate between primary gastric cancer and gastric metastasis from breast cancer. 26Most gastric metastatic breast cancers are estrogen receptor (ER)-positive, progesterone receptor (PR)-positive/negative, and human epidermal growth factor receptor (HER2)-negative.However, in primary gastric adenocarcinoma, ER and PR can be positively expressed in 20-28% of patients. 19In a few cases, metastatic breast cancer is negative for ER and PR, so a diagnosis cannot be made based on these two investigations alone. 59ER and PR can be used as markers; however, they are not always suitable diagnostic markers to confirm if a tumor has originated. 11Treatment of gastrointestinal metastases from breast cancer is discussed frequently in the literature.Systemic therapy is the first option. 36The effective rate of systemic treatment is about 46%. 60urgical treatment may have a role in palliative treatment. 34Surgical treatment is considered in cases with obstruction or bleeding. 36Metastasis to the gastrointestinal tract can be the first presentation of breast cancer, therefore it is imperative to consider the possibility of breast cancer metastasis to the gastrointestinal metastasis. 26,46strointestinal cancer Among cancers that metastasize to the stomach, gastrointestinal system cancers are encountered in a minority.Gastric metastases gave unspecific findings, such as anemia, bleeding, and pain.Pancreas, liver, and colon account for the majority of primary cancers.Nine of the cases had other metastases in addition to gastric ones.Since pancreatic cancers are usually caught at an advanced stage, the chances of surgical treatment and their response to treatment are low.We see that three of five patients died within a year. 2,6,8Among these cases, the prognosis of pancreatic head cancers was worse than body and tail cancers.

Lung cancer
In fact, lung cancer is the most mortal type of all cancers.However, the stomach is not a common site for primary lung cancers' metastases, especially compared with brain, liver, adrenal glands, and bones. 74Yet, the expected lifespan after diagnosis of metastasis is found to be relatively low.The median survival time was four months (average 6.8 months) among 16 cases who died.On the other hand, data showed that endoscopy is the gold standard in diagnosis.In addition, pathology and immunohistochemistry are considered important factors to differentiate gastric metastases from primary cancers. 81Regarding the treatment of gastric metastases of the pulmonary origin, although non-invasive chemotherapy treatments were the most common choice, patients who received surgery, particularly partial gastrectomy, but also esophagogastrostomy and laparotomy, tended to have relatively much longer survival time. 77,90,95However, this conclusion is not definitive, since in some cases surgeries may be avoided when the patient's condition is extremely severe and the number of cases with given surgical treatments is scarce.So the potential benefit of surgeries to the expected lifespan of the patients needs further investigation.

Malign melanoma
Although melanoma accounts for only 5% of cutaneous malignancies, it makes up nearly 75% of skin cancer-related deaths. 103,107Malignant melanoma ranks as the most common metastatic tumor of the gastrointestinal (GI) tract. 103,110,120It takes an average of 52 months for a primary cutaneous melanoma to spread to the gastrointestinal tract. 107,110Only 1-4% of patients with malignant melanoma deceased before gastrointestinal metastases are diagnosed.On the other hand, GI tract metastasis was observed in more than 60% of melanoma patients by autopsy. 103,110,111,114,121he most commonly involved sites include the small and large bowels and rectum; however, gastric metastasis is a rare case 110,111,117,119,121 due to the non-specificity of its symptoms, such as epigastric discomfort, nausea, vomiting, weight loss, hematemesis, and melena. 103,107,110,111,114,117,121The average survival is four to six months. 103,107,121Endoscopy is an effective method for detecting melanoma metastases due to pigmentation, which can then be confirmed by histology and immunohistochemistry. 114,121 Treatment options include surgical resection, immunotherapy, chemotherapy, and targeted therapy.If a patient is symptomatic, surgical excision can be a palliative technique that can also prolong survival. 103,121ogenital cancer Regarding urogenital metastases GM is uncommon and the incidence is reported to vary between 0.2% and 0.7%. 123he most common clinical presentations are gastrointestinal bleeding (melena and hematemesis), anemia, and malaise.Whereas two patients had no symptoms associated with the gastrointestinal system. 131,140Esophagogastroduodenoscopy is often necessary for diagnosis and localized treatment. 131The presence of gastric metastases is considered an important indicator of advanced disease. 149Treatment options varied depending on the stage of the metastasis including endoscopic resection, partial or total gastrectomy, chemotherapy, and palliative care.Even though overall survival seems to be longer in patients who underwent surgery, the main reason for this may be that these patients have early-stage diseases suitable for surgery.Therefore, treatment options should be decided upon the stage of the disease and the general well-being of the patient.

Others
The most common symptoms, in terms of frequency, are melena, abdominal pain, vomiting, weight loss, anemia, fatigue, and loss of appetite.Gastrointestinal endoscopy plays an important role in the diagnosis of GM if suspected. 162Tumor seeding after endoscopic gastrostomy tube replacement was observed in two cases. 161,169Even though surgery is the frequent treatment for solid organ cancer metastasis, chemotherapy is the chosen treatment for DLBCL, skin cancer, and sarcoma.Overall survival was only mentioned for four cases; therefore, it is difficult to comment on which treatment method is more beneficial.Metastasis to the stomach is not reported frequently.Thus, determining the prognosis and planning the treatment based on scientific evidence seems to be problematic for clinicians.
In conclusion, among 172 case reports reviewed, resection surgery was performed the most for treatment and was sometimes combined with chemotherapy and immunotherapy.However, the literature regarding the management of patients with secondary gastric cancer is limited.Therefore, further multi-centric research to reach a consensus about what type of treatment has the best outcomes for patients with gastric metastases is needed.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?Yes

Are the conclusions drawn adequately supported by the results presented in the review? Yes
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Yes

Murat Sarı
Marmara University, Istanbul, Turkey The stomach is a rare organ in terms of metastasis sites.It would be valuable to write a review evaluating this issue.The review is clearly the result of extensive research.Figures and tables are adequate and informative.Therefore, acceptance of this article will provide impact and citations to the journal.

Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes
Are sufficient details of the methods and analysis provided to allow replication by others?Yes Is the statistical analysis and its interpretation appropriate?Yes

Are the conclusions drawn adequately supported by the results presented in the review? Yes
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Yes Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Medical oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart.

Figure 2 .
Figure 2. Pie chart demonstrating percentages of primary tumor sites of patients with metastasis to stomach.

Table 1 .
Illustrating the data regarding metastasis from gynecologic cancers.

Table 2 .
Illustrating data regarding metastasis from gastrointestinal cancers.

Table 3 .
Illustrating data regarding metastasis from lung cancers.

Table 4 .
Illustrating data regarding metastasis from malignant melanoma.

Table 5 .
Illustrating data regarding metastasis from urogenital cancers.

Table 6 .
Illustrating data regarding metastasis from other cancers.