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Introduction

Gastric cancer is one of the most common malignancies in Asia, and the second most common cause of cancer-associated mortality in Japan, accounting for 49,830 mortalities and 13.9% of all Japanese cancer mortalities in 2011 (1). Gastric cancer typically disseminates via hematogenous routes, lymphatic metastasis, local invasion of adjacent tissues, or transcoelomic or peritoneal spread (2). Common sites of metastasis include the regional lymph nodes, liver, peritoneum, lungs and bones (3). Metastases to the colon are more rare, and typically originate from kidney, skin, breast, prostate or ovarian carcinomas (4). From gastric cancer, colonic metastasis is extremely rare; this typically presents as linitis plastica or an annular stricture resembling advanced primary colon cancer (5). There have been reports of cases of colonic metastases assuming a polypoid or non-polypoid form that mimics early colon cancer; however, all of these previous cases were multiple metastases (5–7).

The present study reports a case of a patient with early gastric cancer who developed a heterochronous, single, non-polypoid colonic metastasis in the sigmoid colon and unilateral Krukenberg tumor, composed of poorly differentiated adenocarcinoma and signet ring cell carcinoma.

Case report

In September 2010, a 58-year-old female presented to the University of Fukui Hospital (Fukui, Japan) with anemia and was scheduled for an upper-GI endoscopy. A gastroscopy revealed a typical type 0-IIc+IIa-like tumor on the lesser curvature of the gastric body (8). Endoscopic biopsy specimens revealed a well-differentiated tubular adenocarcinoma. The patient underwent a distal gastrectomy with D2 lymphadenectomy and Billroth I reconstruction in October 2010 (Fig. 1A). The histopathological examination of the gastric tumor revealed a well-differentiated adenocarcinoma, with submucosal invasion and no lymph node metastasis (Fig. 1B). However, poorly differentiated adenocarcinoma and signet ring cell carcinoma were detected in the deepest part of the lesion in the submucosal layer (Fig. 1B). The tumor was staged as T1bN0M0 according to the Japanese classification of gastric cancer (8).

Figure 1. (A) Macroscopic view of the lesion. A well demarcated 3×2-cm shallow depressed (0-IIc) lesion (Japanese classification of gastric cancer) (7) in the lower body of the stomach. (B) On histological examination, the resected gastric tumor was composed of well-differentiated adenocarcinoma, with submucosal invasion. (C) In the deepest lesion of the submucosal layer, poorly differentiated adenocarcinoma and signet ring cell carcinoma were confirmed

Following surgery, the patient was examined on outpatient basis. In February 2013, the patient's serum carcinoembryonic antigen (CEA) level had increased from the normal range (<5.0 ng/ml) to 42.1 ng/ml. An abdominal computed tomography (CT) scan and fludeoxyglucose-positron emission tomography (FDG-PET)/CT revealed recurrent paraaortic lateral lymph node metastasis (Fig. 2A and B). The patient received 7 cycles of chemotherapy with S-1 (80 mg/m2/day; days 1–21) and cisplatin (60 mg/m2/day; day 8). Following chemotherapy, radiotherapy was administered to the paraaortic lymph nodes of levels Th11-L3, to a total dose 54 Gy (2 Gy/fraction).

Figure 2. (A) CT scan revealed swollen lateral paraaortic lymph nodes (white arrow). (B) FDG-PET/CT showed hypermetabolism in the lateral paraaortic lymph nodes (white arrow); the maximum standardized uptake value of the tumor was 6.8. CT, computed tomography; FDG-PET, fludeoxyglucose-positron emission tomography.

Subsequent to chemotherapy and radiation therapy, abdominal CT and FDG-PET scans were performed for evaluation of the therapy. The abdominal CT scan revealed an enlarged left ovary, and FDG-PET/CT indicated abnormal uptake unilaterally in the left ovary and sigmoid colon (Fig. 3A and B). In addition, a barium enema examination revealed an elevated lesion with central depression in the sigmoid colon, located at the site exhibiting abnormal accumulation on FDG-PET/CT (Fig. 3C). However, no abnormal uptake was observed in the paraaortic lymph nodes. On the basis of these findings, a diagnosis of unilateral Krukenberg tumor from gastric cancer and early colon cancer was determined. The patient underwent an oophorectomy and sigmoidectomy with D3 lymph node dissection (Fig. 4A–C).

Figure 3. Fludeoxyglucose-positron emission tomography/computed tomography revealed a focal hypermetabolic lesion in the (A) left ovary and (B) sigmoid colon (white arrows). (C) Barium enema examination revealed an elevated lesion with central depression located in the sigmoid colon.

Figure 4. (A) Macroscopic appearance of resected both ovaries; the right ovary was normal in size, whilst the left ovary measured 10×7 cm. (B) Cross section of the ovary shows a predominantly yellow, solid tumor mass, almost replacing the ovary. (C) Gross appearance of the sigmoid tumor; the tumor mass exhibited central ulceration (inset: cut surface of the tumor).

Intraoperative findings indicated no peritoneal dissemination from gastric cancer, and intraoperative peritoneal washing cytology of the rectouterine pouch was negative for malignancy. On pathological examination, the left ovarian tumor was revealed to be a poorly-differentiated adenocarcinoma and signet ring cell carcinoma (Fig. 5A); the right ovary was unremarkable (Fig. 5B). The sigmoid colon tumor was also revealed to be a poorly-differentiated adenocarcinoma with scattered signet ring cell carcinoma (Fig. 5C), which had spread into the submucosal layer and partly permeated the serosal layer. Metastasis was detected in the sigmoid mesocolon lymph nodes, including the inferior mesenteric artery lymph nodes. Immunohistological staining revealed that the primary gastric cancer cells, ovarian tumor cells and sigmoid colon tumor cells were positive for cytokeratin (CK) 7 and negative for CK20 (Fig. 5D–I). Thus, the diagnosis was determined to be a unilateral Krukenberg tumor and sigmoid colonic metastasis from gastric cancer.

Figure 5. Histopathological analyses of gastric, colonic and ovarian tissues. (A, D and G) Gastric samples; (B, E and H) left ovary samples; (C, F and I) colon samples. (B and C) The left ovarian tumor and sigmoid tumor revealed a poorly-differentiated adenocarcinoma and signet ring cell carcinoma. (D-F) Immunostaining for CK7 was positive. (G-I) Immunostaining for CK20 was negative. CK, cytokeratin; H.E., hematoxylin and eosin.

Following the second surgery, the patient was administered with further chemotherapy consisting of S-1 (80 mg/m2/day; days 1–14) and docetaxel (40 mg/m2/day; day 1). The patient's clinical course is close observation; the patient has exhibited stable disease during this chemotherapy regimen, and is still disease-free with ongoing S-1 and docetaxel combined chemotherapy as of August 2015.

Discussion

Gastric cancer is one of the most fatal types of cancer, particularly in East Asian countries, including Japan. In clinical practice, the major routes of recurrence of gastric cancer following radical resection include hematogenous spread, peritoneal seeding, lymph node metastasis and local recurrence. Distant metastasis most frequently arises via the hematogenous route.

Colonic metastases are uncommon, typically originating from stomach, breast, skin (melanomas), renal, prostatic or ovarian carcinomas (4). In cases where colonic metastases arise from gastric adenocarcinoma, the hematogenous route is the most common mode of metastasis; metastatic deposits invade the submucosal lymphatic system, extending to form a linitis plastica appearance or an annular stricture (9). However, in the present case, lymphatic spread was considered to be the route of colonic metastasis from gastric cancer cells, which were determined to consist of poorly differentiated adenocarcinoma and signet ring cells in the deepest submucosal layer of the primary gastric cancer. The following features indicated a lymphatic route of metastasis: i) Metastatic paraaortic lateral lymph nodes were detected prior to the second surgery; ii) pathologically metastatic lymph nodes were detected in the sigmoid mesocolon, considered to originate from paraaortic lymph node metastasis via lymphatic vessels; iii) no intraoperative indications of peritoneal metastasis were observed, and free cancer cells were not detected by cytological examination of the peritoneal washings; and iv) a Krukenberg tumor was diagnosed; although Krukenberg tumors may also be induced by complex mechanisms, lymph node metastasis is considered to be the most potent risk factor for their recurrence (10–12).

Secondary gastric carcinomatous deposits (metastatic tumors) in the colorectum invariably appear as single or multiple strictures; this stricture appearance is similar to that of primary colorectal cancer or inflammatory bowel disease. In rare cases, flat or depressed lesions or polyps arising from colonic metastasis of poorly differentiated gastric cancer and signet ring cell carcinoma have been reported; however, all previously reported cases presented as multiple synchronous lesions, which further serves to accent the novelty of the current presentation of single colonic depressed metastasis (4,13–15).

It is thought that the confirmed diagnosis of metastatic colon cancer has the most useful pathological finding. Immunohistochemical analyses may be performed to differentiate between gastric and colonic primary tumors, with CK7 and CK20 commonly used as tumor markers (16). CK7 expression has been observed in the majority of types of carcinoma, in carcinoid tumors originating from lungs and gastrointestinal tract (17), and in Merkel cell tumors of the skin (18). CK20+ staining is observed in the vast majority of cases of colorectal carcinoma (17) and Merkel cell tumors (19), in addition to a high proportion of cases of gastric carcinoma, cholangiocarcinoma, pancreatic carcinoma and transitional cell carcinoma (16). In a previous study, all colorectal cancer samples metastatic to the ovary were CK7−/CK20+, while the majority of gastric carcinomas metastatic to the ovary exhibied a CK7+/CK20− staining pattern (20). In the present case, the following features were observed: i) Sigmoid colon tumor cells with similar appearance to the pathology of the previous gastric cancer; ii) no tumor cells in the colonic mucosa, and proliferating tumor cells in the colonic submucosal layer; and iii) positive CK7 expression and negative CK20 expression on immunohistochemical analysis of the primary gastric cancer cells, metastatic ovarian tumor cells and sigmoid colon tumor cells. Due to the aforementioned findings, a diagnosis of unilateral Krukenberg tumor and sigmoid colonic metastasis from gastric cancer was confirmed.

In conclusion, the present study reports the case of a patient with a unilateral Krukenberg tumor and sigmoid colonic metastasis derived from early gastric cancer. Although this is an extremely rare presentation, doctors must be aware of the possible occurrence of colonic metastasis from gastric cancer, particularly poorly-differentiated adenocarcinoma and signet ring cell carcinoma. It is necessary to postoperatively examine patients diagnosed with gastric cancer considering all possibilities, including colonic metastasis.

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