AIM: To investigate the clinicopathological characteristics of late-stage lung cancer patients with gastrointestinal (GI)-tract metastases, focusing on therapeutic options and outcomes.

METHODS: Our institution (the National Taiwan University Hospital) diagnosed 8159 patients with lung cancer between 1987 and 2008, of which 21 developed symptomatic GI metastases. This study reviewed all of the patients’ information, including survival data, pathological reports, and surgical notes.

RESULTS: The most common histological type of lung cancer was adenocarcinoma, and 0.26% of patients with lung cancer developed GI metastases. The median duration from lung cancer diagnosis to GI metastases was three months (range, 0-108 mo), and the average time from diagnosis of GI metastasis to death was 2.8 mo. Most patients with symptomatic gastric and/or duodenal metastases exhibited GI bleeding and were diagnosed by panendoscopy. In contrast, small bowel metastases typically presented as an acute abdomen and were not diagnosed until laparotomy. All patients with small bowel or colonic metastases underwent surgical intervention, and their perioperative mortality was 22%. Our data revealed a therapeutic effect in patients with solitary GI metastasis and a favorable palliative effect on survival when metastases were diagnosed preoperatively. In patients with multiple GI metastases, the presentation varied according to the locations of the metastases.

CONCLUSION: Surgical treatment is worthwhile in a select group of patients with bowel perforation or obstruction. Physicians should be more alert to symptoms or signs indicating GI metastases.

Lung cancer is a major cause of cancer-related death worldwide. In Taiwan, it is the second leading cause of cancer death, with nearly 8700 new cases and 7500 deaths per year[1]. Approximately one-half of lung cancer patients develop metastases[2,3], the most common sites of which are the lymph nodes, liver, adrenal glands, bone, and brain[2]. Symptomatic gastrointestinal (GI) tract metastases are not uncommon[4,5], although GI metastases from lung cancer are rare. The reported incidence of GI metastasis from lung cancer varies from 0.5%-10%, and mainly depends on the evaluation method used (endoscopy, surgical specimens, or autopsy)[2,5-7]. The typical presentations of GI metastases are abdominal pain, bleeding, obstruction, and perforation, of which perforation is the most serious complication, necessitating surgical intervention to prevent a life-threatening event. GI tract involvement with lung cancer is generally considered to be associated with a late or advanced stage of the disease. Therefore, the question of how to manage patients with symptomatic GI metastases from lung cancer is important; however, management of the disease remains a controversial topic[2,3,6].

The present study describes the clinicopathological features of a large series of primary lung cancers manifesting GI metastases and discusses therapeutic options, with a particular focus on the role of surgeons in this uncommon oncological setting.

This research reviewed the surgical pathology reports of patients diagnosed with GI metastases from 1987 to 2008 at the National Taiwan University Hospital. Only those cases in which the primary source of the metastases was documented as lung cancer were included in our analysis. The diagnostic criteria were (1) radiological demonstration of a primary lung tumor and exclusion of tumors elsewhere, and (2) the morphology and immunohistochemical profiles were consistent with a primary pulmonary tumor. Of 8159 patients diagnosed with lung cancer, 21 were found to have GI metastases. Metastatic disease originating from a lung primary tumor was confirmed from biopsy specimens or from surgical resection of the GI tract in patients.

Patient information, including age, sex, pathology, initial lung cancer stage, interval between lung tumor diagnosis and discovery of GI involvement, clinical presentation, other metastatic site locations at the time of GI metastases, and patient survival, was recorded and reviewed retrospectively. Clinical and other follow-up data were obtained in all cases from patient records and referring physicians. Analysis of the survival data was performed by the Kaplan-Meier method. Differences between subgroups were compared for statistical significance using the log-rank test. P values were two-sided and the significance level was set at 0.05.

Lung cancer is the leading cause of death from cancer worldwide, and about one-half of lung cancer patients have metastatic disease at the initial diagnosis[2,3]. The most common sites of metastatic disease are the lymph nodes (48%), liver (45%), adrenal glands (41%), bone (31%), and brain (25%)[2]. Before the 1980s, GI tract involvement was considered an unusual metastasis site from lung cancer[9,10], and the pathogenesis of bowel metastases was considered to be due to tumor-cell spreading via the hematogenous or lymphatic routes. A review of autopsy data by Antler et al[7] reported the incidence of GI metastasis to be 14%; however, 14% may be higher than the true incidence of GI metastasis, because a large number of esophageal metastases in their study were the result of direct invasion. The incidence of symptomatic small bowel metastasis has been reported to be 0.4%-0.5%[4,5]. In our series, there were 21 cases of symptomatic gastrointestinal metastases among the 8159 lung cancer patients (0.26%). The disparity between subclinical and clinical GI metastases is still high.

Gastric and/or duodenal metastases from lung cancer are very rare, and there are only a few cases of varying malignant cell types reported in the literature[11-13]. These cases exhibited symptoms of abdominal pain, chronic bleeding, anemia, or hematemesis, and the pathological results of panendoscopic biopsy provided accurate diagnoses. In contrast to the small bowel, the most common metastatic site of lung cancer in the GI tract[4,5,14,15], there have been few reports of lung cancer metastases to the colon, appendix, or anus[16-19]. Small intestine involvement often leads to an acute abdomen as a result of perforation or obstruction[4,5,15], whereas colon metastases usually result in vague symptoms. In our cases of small bowel or colon metastases, all patients required surgery to relieve the obstruction or control peritonitis. In general, the use of CT, abdominal sonography, or endoscopy plays an important role in identifying lesions.

Even with endoscopy, lung cancer involving the GI tract has no specific features, appearing as a diffuse involvement of the mucosa and multiple nodules with or without mucosa ulceration[20,21]. An experienced pathologist might be able to conclude a metastatic tumor based on morphological study of tumor tissue from surgical resection. However, in most cases histological examination with staining using cell type-specific markers is the only way to identify metastatic tumors of the GI tract. Several different CK and other protein markers are widely used to distinguish carcinomas of different origins. Rossi et al[21] concluded that lung carcinomas usually demonstrate a CK7+/CK20- immunoprofile, whereas intestinal carcinomas have a different CK7-/CK20+ pattern. Thus, CK7 is a good marker for distinguishing those cell types. In general, primary lung tumors can be identified by CK7; however, studies have demonstrated that primary adenocarcinomas of the rectum or small intestine may also express CK7 in a significant number of cases, and may even lose CK20 expression[22,23]. Therefore, to exclude a possibility like this, employing a more specific marker of lung tumor origin, such as TTF-1[24], together with CK7 and CK20 could more effectively differentiate metastatic GI tumors from lung cancer.

Every type of lung cancer can result in GI metastasis. McNeill et al[2] and Berger et al[5] reported that squamous cell carcinoma causes small bowel metastases more frequently than other lung tumor cell types. In the series of Antler et al[7], small cell carcinoma and large cell carcinoma were more likely to result in GI metastases. However, in our series, adenocarcinoma was the most frequent type resulting in GI metastases. In accordance with our results, Garwood et al[4] reported that adenocarcinoma (23.7%) and squamous cell carcinoma (22.7%) were the most common histological types causing small bowel perforations.

Our results showed that the median time from lung cancer diagnosis to GI metastasis was three months and the longest period of time was 108 mo (patient #7). Observations of previous data show that, in patients with lung metastases from colon cancer, a longer interval between colon cancer diagnosis and lung metastasis was associated with a significantly longer survival[25]. However, our findings did not show a similar survival difference when patients with an interval greater than 1 year were compared with those with an interval less than 1 year (P = 0.79). Our results also revealed no significant difference in overall survival in patients with initial stage I-III lung cancer upon GI metastasis diagnosis in comparison with those with stage IV disease. Taken together, these findings indicate that patients with GI metastases from lung cancer have a poor prognosis.

The perioperative mortality rate reported in the literature ranges from 60% to 100%[2,15]. The series of Berger et al[5] indicated no perioperative mortality in patients with small bowel metastases who underwent resection. However, in our experience, the perioperative mortality rate was 100% in the two patients with gastric and/or duodenal metastases and 22% (2/9) in patients with small bowel or colon metastases. We observed longer survival in patients with gastric and/or duodenal metastases that were managed by supportive treatment without surgery (P = 0.005). However, the relatively small sample size in this retrospective subgroup analysis and the nature of the different underlying conditions (these nine patients had other metastases at the same time) may limit the conclusion that surgical treatment is not suitable for patients with gastric or duodenal metastases from lung cancer. On the other hand, in two of our patients, radiological work-up did not show other metastases. These patients then underwent surgical resection and one is still alive. Although surgery for localized extrathoracic metastasis from lung cancer still has a palliative intent[21], some authors have reported prolonged survival in cases of surgically-resected isolated bone[26], brain[27], or small bowel[14] metastasis from lung cancer. Our results (Figure 1) are the first to show a longer survival or more favorable outcome in patients diagnosed with GI metastasis before surgery. Consequently, surgical treatment still plays an important role in lung cancer patients with GI metastases that cause bowel obstruction, perforation, or massive hemorrhage.

In summary, patients with GI metastases from lung cancer are in the latter stages of the disease. However, physicians and surgeons should be aware that surgical intervention is typically required for patients exhibiting bowel perforation or an acute abdomen. Therefore, early detection of GI metastasis in lung cancer patients and timely surgical management may provide symptom palliation in patients with a life-threatening GI event and long-term survival in those with only a solitary GI metastasis.