KL-6 is a sialylated carbohydrate antigen discovered by Kohno et al. [5]. It is widely known as a biomarker of interstitial pneumonia [4]. Clinicians use sKL-6 for diagnosis of interstitial pneumonia as well as for evaluating the activity of the illness. KL-6 has also been used as a marker of tumors, and has been found to be elevated in patients with several malignant tumors. One study reported sKL-6 to be increased in 52% (17/33) of patients with lung adenocarcinoma, 18% (4/22) with lung squamous cell carcinoma, 8% (1/13) with hepatocellular carcinoma, 44% (4/9) with pancreatic cancer, and 40% (8/20) with breast cancer [5]. Ogawa et al. [6] similarly reported that sKL-6 was increased in 31% of patients with breast cancer. Kawata et al. [7] reported a case of KL-6-producing invasive thymoma, and Mogami et al. [8] reported two cases of ovarian carcinoma with elevated sKL-6. Fukuhara et al. [9] reported a case of colon cancer with elevated sKL-6, and Tsuchie et al. [10] reported a case of ovarian cancer with elevated sKL-6 and a case of colon cancer with elevated sKL-6. Finally, Yonenaga et al. [11] reported a case of gallbladder cancer with elevated sKL-6. However, to the best of our knowledge, there have been no previous reports of GC with elevated sKL-6. Indeed, although Kohno et al. [5] investigated sKL-6 levels in 19 patients with GC, no significant change was found.

In the present cases, despite the absence of interstitial pneumonia, sKL-6 was found to be elevated at GC diagnosis and was reduced following effective chemotherapy. There was no history of medications that could cause drug-induced pneumonia, like anti-cancer drugs at previous clinics. We suspected these cancer cells might produce KL-6. Therefore, it was considered that the production of KL-6 in tumor cells should be measured. However, unfortunately, we were unable to precisely detect KL-6 in tumor cells due to technical problems. KL-6 is defined as a kind of MUC1. We performed immunohistochemical staining for MUC1 in tumor tissues taken by endoscopic biopsy. Tumor cells showed a cytoplasmic positive reaction for MUC1 in both cases. There have been reported to be several patterns for the immunohistochemical localization of MUC1 and/or KL-6 [9, 11,12,13]. The relationship between elevated sKL-6 and staining patterns of KL-6/MUC1 has not yet been established and is still controversial. Fukuhara et al. [9] reported that sKL-6 was elevated in one colon cancer patient, with positive staining for KL-6 in the cytoplasm of cancer cells, but not in another colon cancer patient, with KL-6-positive staining found only in the apical membrane. Tanaka et al. [13] performed immunohistochemical analysis of KL-6 expression in 103 surgically resected non-small cell lung cancer (NSCLC) tissues. They reported that KL-6 expression was observed at apical membranes, circumferential membranes, and/or cytoplasm in all 103 NSCLC tissues, and that circumferential membrane and/or cytoplasmic KL-6 expression patterns were associated with a high level of sKL-6 [13]. The circumferential and/or cytoplasmic expression of KL-6 was reported to be related to malignancy when compared to expression on the apical surface in several cancers. Tang et al. [14] performed immunohistochemical analysis of ampullary cancer tissues using a KL-6 murine monoclonal antibody and found positive staining in 68.4% of all cases. They also reported that positive KL-6 expression was related to lymph node metastasis and that the prognosis of patients positive for KL-6 mucin expression was significantly poorer than those without KL-6 mucin expression [14]. According to the immunohistochemical analysis of 82 colorectal adenocarcinoma patients by Guo et al. [12], the five-year survival rate, the presence of lymph node metastasis, and the presence of liver metastasis in the patients showing positive staining in the circumferential membrane and/or cytoplasm was significantly worse when compared to that of those that showed positive staining in the apical membrane or no staining at all. Tanaka et al. [13] reported that circumferential membrane and/or cytoplasmic KL-6 expression patterns were associated with a poor prognosis in NSCLC patients who underwent curative surgery as well as a high level of sKL-6. MUC1 was predominantly present on the apical surface of normal glandular epithelial cells in many secretory organs [15, 16]. So, it is thought that circumferential membrane and/or cytoplasmic expression of KL-6 represents aberrant subcellular expression. It has been proposed that aberrant expression of MUC1 facilitates detachment of tumor cells from the primary tumor because MUC1 mediates anti-adhesion activity by interfering with cell-to-cell and/or cell-to-extracellular matrix interactions [17,18,19,20,21,22]. Guo et al. [12] and Tanaka et al. [13] suggested that aberrant subcellular expression of KL-6 might facilitate detachment of tumor cells from the primary growth in colorectal adenocarcinoma and in NSCLC, resulting in an increased ability of tumor cells to metastasize. Tanaka et al. [13] also demonstrated that aberrant expression patterns of KL-6 were associated with elevated sKL-6. In the present two cases of GC accompanied by multiple distant metastases, we demonstrated elevated sKL-6 and aberrant expression patterns of MUC1. Thus, tumors with elevated sKL-6 may tend to be accompanied by multiple metastases, like in the present two cases.

As KL-6 is mainly expressed on type 2 alveolar pneumocytes and respiratory bronchiolar epithelial cells, sKL-6 is useful as an indicator of disease activity in interstitial pneumonia [4]. It is well known that chemotherapy for metastatic cancer patients occasionally induces drug-induced interstitial pneumonia. We routinely examined sKL-6 every 3 months and performed pulmonary function tests and CT of the chest before and during chemotherapy in these patients. Although, in Case 1, sKL-6 was within the normal range during chemotherapy, it was significantly elevated after the 42 cycles of SOX therapy. We continued SOX therapy expecting CR efficacy of the tumor because no severe adverse events, including bone marrow suppression and peripheral neuropathy, were observed. We detected interstitial changes in both the lungs without any respiratory symptoms in Case 1. It is necessary that sKL-6 be periodically examined in metastatic GC patients before and during chemotherapy in order for the early detection of interstitial pneumonia.

In these cases, serum levels of KL-6 and CEA showed a similar clinical course transition. When CT scans showed a reduction in lesion sizes due to chemotherapy, serum levels of both CEA and KL-6 decreased similarly. This suggested that these cancer cells might be producing KL-6. However, in Case 1, sKL-6 increased after the 42 cycles of SOX therapy despite a decrease in serum CEA levels. It was thought that this increase in sKL-6 was not due to KL-6 production from the tumors but from the lungs.

Conversion surgery after chemotherapy has been focused as a promising tool for improving prognosis in GC patients with stage IV. Conversion surgery with R0 resection for stage IV GC could be a new therapeutic strategy to improve patient survival [23]. However, there is only one ongoing randomized controlled trial comparing survival after chemotherapy for stage IV GC with conversion surgery or continued chemotherapy [24]. In Case 1, the efficacy of chemotherapy was so good that the size of the lesions decreased well and there were no new lesions. However, she did not undergo conversion surgery due to her age. In Case 2, she was diagnosed with stage IV GC for the distant lymph node metastases. For locally advanced GC with extensive lymph node metastasis, chemotherapy followed by surgery including para-aortic lymph nodes dissection was effective for some patients [25]. However, she did not undergo conversion surgery because the lymph node metastases were widespread, extending around the common iliac arteries.

To the best of our knowledge, there have been no previous reports of metastatic GC patients with elevated sKL-6 being treated by chemotherapy. Therefore, our two patients are exceedingly rare cases.