Koizumi et al. BMC Cancer 2010, 10:423 http://www.biomedcentral.com/1471-2407/10/423 lesion) had a better prognosis than those with multiple skeletal metastases (multiple bone lesions) [14]. These results suggest that early diagnosis of skeletal metastasis and treatment with bisphosphonates could improve a patient’s quality of life by reducing the number of skele- tal complications. There have been many studies investi- gating skeletal metastasis in breast cancer patients but most of these were conducted before the emergence of therapies such as bisphosphonates. Pain is an important indicator of the presence of skeletal metastasis [15]. However, no clinical symptoms are evi- dent in the early phase of skeletal metastasis. There are many prognostic factors related to survival, cause specific death (CSD). The relationship between these factors and SRE is not fully understood. Bone pain is a symptom pro- duced by skeletal metastasis that could be related to SRE. The aim of the present retrospective study was to clarify the clinical meaning of bone pain at diagnosis of skeletal metastasis by investigating the relationship of pain to SRE and survival, and comparing this with other factors. Methods Patients Breast cancer patients undergoing surgery at the Cancer Institute Hospital, Tokyo, Japan, between January 1988 and December 1998 formed the patient pool, and were fol- lowed up until December 2006. As the aim of this study was to clarify skeletal metastasis after surgery, patients with skeletal metastasis at the time of surgery were excluded from the pool (5429 eligible patients). Six hun- dred and sixty-eight patients developed skeletal metastasis during the duration of the study. The follow-up protocol after surgery was as follows: patients visited hospital and received a physical check every three months for the first two years, every six months thereafter until five years had elapsed, and then annually after that. Patients who received adjuvant therapy were followed up more fre- quently. Bone scanning was used to confirm the presence of skeletal metastasis; it was performed at the time of sur- gery for staging purposes, annually thereafter for five years, and then seven and 10 years after the date of sur- gery. Bone scanning was also performed if physicians sus- pected the presence of skeletal metastasis or wanted to exclude it as a possibility. In the event of positive or equi- vocal bone scans, other imaging techniques including X-ray, computed tomography and magnetic resonance imaging were used to confirm the diagnosis. The above procedures were conducted as routine clinical practice at the Cancer Institute Hospital, Tokyo, Japan. Pain and the values of tumor marker at the diagnosis of skeletal metastasis The presence of bone pain at the time of diagnosis of skeletal metastasis was investigated using the card Page 2 of 9 record, predominantly in the form of an inquiry card that was given to patients. In the inquiry card, patients were asked about the presence or absence of pain, and sites of pain. The grade of pain (visual-analog scale) was obtained from a limited number of patients. Therefore, the focus was on the presence or absence of pain. The values for tumor markers (carcinoembryonic antigen, CEA, and cancer antigen 15-3, CA 15-3) when osseous metastasis was diagnosed were classified as below, equal to or above the reference value. Reference values were 5.0 ng/ml for CEA and 30 ng/ml for CA 15-3. Factors at initial therapy The following factors were used in a Cox proportional hazards mode: age at surgery (Age), menstruation state, breast tumor (T) with minor modification (T2 tumors were classed as small (2.1-3.0 cm) or large (3.1-5.0 cm)), clinical and pathological lymph node state (N and pN), histopathology, and estrogen receptor and progesterone receptor status. Tumors were classified as: in situ, non- invasive cancer; T0, no detectable tumor; T1, ≤ 2.0 cm; T2 small, 2.1-3.0 cm; T2 large, 3.1-5.0 cm; T3, ≥ 5.1 cm; T4, any size with direct extension to chest wall or skin according to the 2002 UICC-TNM classification [16]. Histological classification was performed according to the criteria of the Japanese Breast Cancer Society [17], which differs from the WHO classification. The Japanese system divides invasive ductal carcinoma not otherwise specified (NOS) according to the WHO classi- fication into three categories based on morphology: papillotubular, solid-tubular and scirrhous carcinoma [17,18]. Lymph node status can be classified by two methods: N, clinical or preoperative classification; and pN, pathological classification. Pathological classification was used in this study as it is more accurate than clini- cal classification. The ER status of a tumor was classed as positive when the concentration was greater than 13 fmol/mg cytosol protein. The PgR status of a tumor was defined as positive when the concentration was greater than 10 fmol/mg cytosol protein. Analysis and statistical methods Data were analyzed as follows. First, the percentages of patients with or without pain and with or without eleva- tion of CEA or CA15-3 at the diagnosis of skeletal metastasis were calculated, and the time from surgery to the appearance of skeletal metastasis with or without pain was calculated and tested using the Mann-Whitney U test. Secondly, Kaplan-Meier’s method with a log-rank test was used to compare SREs (pathological fracture, spinal cord paralysis, hypercalcemia, radiation therapy for osseous metastasis, orthopedic surgery for bone metastasis, and the use of morphine for pain) and survi- val (cause-specific death, CSD) in patients with and