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Multiple primary malignant neoplasm (MPMN) occur frequently than can be explained on the basis of random chance. They are divided into two groups; synchronous and metachronous. Metachronous cancer is detected after 6 months of the first diagnosis and synchronous cancer within 6 months of the first diagnosis. The incidence of developing synchronous gastrointestinal malignancies is noted to rise with increasing age as the long-term survival for each cancer is increasing, more sophisticated treatments available and better application of screening programs. Synchronous cancers are clinically relevant with regard to their diagnosis and treatment.¹ The frequency of multiple primaries is reported to be in the range of 2-17%.² Synchronous cancer has an incidence of 3.4% in gastric cancer (GC)patients. The most common type of synchronous cancer in GC patients is colorectal cancer (CRC).³ Most synchronous cancers consist of two lesions, rarely three or even four. In an exceptional case, Kibera et al. reported a case with 7 simultaneous colon cancers.⁴

A male patient aged 72 years presented with recurrent non bilious vomiting, jaundice, itching, and anorexia and weight loss of 10 kg for 2 months. He developed increased stool frequency, which was small in volume, non-bloody for 15 days. Physical examination of the patient revealed pallor, icterus, cachexia, and a distended gall bladder. His background and family history were not significant. He was a chronic smoker and had a history of alcohol abuse for 20 years. There was no history of any chronic illness in the past. Blood investigations revealed a hemoglobin concentration of 9.2g/dl, leucocyte count of 12000/ul and a blood group O.Liver profile demonstrated total bilirubin 6 mg/dL, direct bilirubin 4 mg/dL, aspartate aminotransferase 124 U/L, alanine aminotransferase 119 U/L, and alkaline phosphatase 412 international U/L.Stool occult blood test was positive.Esophagogastro-duodenoscopy showed a rigid stomach with uniformly thickened gastric folds from fundus to pylorus with few ulcerations creating a challenging duodenal intubation (Figure 1A and B). The first, second part of duodenum and ampulla was normal on esophagogastro-duodenoscopy. Multiple gastric biopsies were taken with conventional forceps that revealed a poorly differentiated adenocarcinoma with signet-ring cell appearance and negative for Helicobacter pylori (Figure 3A and B). Multislice Computed tomography (MSCT) revealed marked wall thickening of the stomach with peri gastric lymph nodes, an abrupt cut off at distal common bile duct (Figure 2A and C),wall thickening of transverse colon, splenic flexure and rectum (Figure 2B and D). ERCP (endoscopic retrograde cholangiopancreatography) scope traversed with difficulty across the pylorus. A brush cytology and a distal common bile duct biopsy was taken after a precut sphincterotomy that revealed a moderately differentiated adenocarcinoma (Figure 4B). Colonoscopy revealed an ulcerative, partially obstructing circumferential mass in the rectum and an ulceroproliferative mass at splenic flexure that could not be traversed, with a normal intervening mucosa (Figure 1C and D). Carcinoembryonic antigen (CEA) level was 6ng/ml (normal range 5ng/ml). Thecolonoscopic biopsies from rectum and splenic flexure showed a poorly differentiated adenocarcinoma with signet ring appearance (Figure 3C and 4A). The immunohistochemistry panel demonstrated the gastric neoplasm to be cytokeratin (CK)7 positive and negative for CK20 and CDX2 while the colonic neoplasm was positive for CK7/CK20/CDX2 (Figure 5A-E). The IHC proved the gastric and colonic lesions to be separate cancers and not metastatic lesions. He was diagnosed as a case of synchronous gastrointestinal neoplasm.

In patients with a gastric neoplasm there is also an increased risk of second tumor, mainly during the first year after the diagnosis of the index neoplasm, with an important decrease in survival⁵. The incidence of synchronous or metachronous cancer in gastric carcinoma is 3.4%⁶. Synchronous triple neoplasms of gastrointestinal tract involving the stomach, common bile duct and colon is extremely rare. The median age at diagnosis of gastric cancer is 67 years (range, 37-84 years), 69 years for patients with synchronous tumors versus 60 years for those withmetachronous tumors⁷. Patients with synchronous GC and CRC present in older age, with higher comorbidities, and advanced cancer stage than with metachronous CRC and GC. The incidence of synchronous cancers is significantly higher in men than in women, and it also generally increased with age⁸. The presented patient clinical profile coincided with the epidemiological characteristics described in the literature. Signet ring cell cancer (SRCC) is a rare entity representing less than 14% of GC and 1% of CRC⁹. It is a subtype of poorly cohesive carcinoma (WHO classification)¹⁰. Due to decreased expression of E-cadherin, the signet cells do not adhere to each other leading to migration and invasion of adjacent tissues. In patients with gastric cancer diagnosed with MMPN, most frequent locations of second neoplasms are, in order of frequency: colorectal (19%), uterus and ovarian (16%) and breast (13%)⁵. Kibera et al. showed that the incidence of synchronous cancer with multiple gastric cancers was statistically higher than that of synchronous cancer with single gastric cancer¹¹. In the 23 year study by Malgorzata GC patients with second primary were more commonly blood group O (50%) and blood group A (27%) and a significant association between older age and blood group O prevailed. Gastric cancer without second primary was associated with blood group O¹². Another study found that 27% of patients with Gastric cancer with second primary was blood group O and the rest were blood group A who were Helicobacter pylori positive¹³. Our patient was in the extremes of age with blood group O and Helicobacter pylori negative. There is need to include gastric cancer patients with blood group O as controls in the study of synchronous neoplasms.

The dominant symptoms in the patient addressed pointed towards gastric etiology and obstructive jaundice and the presence of colonic disease was incipient. In most of cases of patients with synchronous cancers, there was the dominance of obstructive colon symptoms, while the gastric disease symptoms were moderate or overlapping¹⁴. Recent studies indicate that after a diagnosis of GC, older patients in particular should be investigated for second malignancies. The detection of synchronous GC and CRC can be obtained by easily available diagnostic methods. Synchronous CRC was detected with a high prevalence of 4% by Saito et al. when colonoscopy was selected as the screening method of choice in gastric cancer patients. Saito et al detected synchronous colorectal adenoma (39%) and CRC (4%) in patients of GC who were older than 50 years through screening colonoscopy. Therefore, it is recommended that if possible, a colonoscopy screening is performed before treatment of patients older than 50 years with GC¹⁵. The use of colonoscopy in asymptomatic elderly men for CRC is beneficial to identify patients with synchronous colonic neoplasia¹⁶. CT colonography is valuable in those patients with stenosis that leads to incomplete colonoscopy. In our case scenario CT colonography guided us in detecting the transverse colon lesion due to an incomplete colonoscopy.

A favorable prognosis in early GC but a poor or similar prognosis for SRCC in advanced GC has been reported in literature^17,18. Patients with multiple metachronous primary neoplasms showed better survival rates in contrast to patients with synchronous neoplasms^19,20. Metachronous gastric and colon cancer is an independent predictor of survival and it had a better prognosis than synchronous cancer²¹.

CDX2 expression is an excellent marker of adenocarcinomas arising in the GI tract, particularly colon and high levels (> 75% positive cells) of CDX2 expression were found almost exclusively in adenocarcinomas of the colorectum²². The CK7-/CK20+ pattern was identified in 65% to 95% of the colorectal adenocarcinomas and gastric cancers are CK7+ in different series. Few cases of colorectal carcinomas demonstrate CK7+ pattern^22,23.The immunohistochemistry in our patient differentiated the colorectal cancer from metastatic gastric cancer and directed toward a synchronous malignancy. Patients with colorectal tumors with MSI (microsatellite instability)are usually young and have longer survival times than patients with tumors without MSI and correlated with the tumor location in the proximal colon²⁴. Kim et al. in their study concluded that the presence of microsatellite instability (MSI) in gastric cancer may be a predictor of synchronous gastric and colorectal neoplasms. MSI-H (microsatellite high) GC prevalence in Asians is commonly?<?10% of all GC cases²⁵. The patient in our case had no family history of cancer, was in the extremes of age, had a distal colonic malignancy and capitulated to the aggressive nature of the neoplasm. The case highlights theneed for early diagnosis of synchronous cancer and awareness of clinicians about this aggressive form of tumors and enlightens the role immunohistochemistry in synchronous neoplasms.