Abstract
Several prognostic factors such as the extent of bone metastases (EOD) in advanced prostate cancer (PCa) have been reported. Metastasis of the lung is rarely a significant clinical factor in the management of prostate cancer. The present study evaluates the clinical significance of lung metastases. We retrospectively reviewed the PCa database to identify patients with pulmonary metastases at initial diagnosis. The medical records of the patients were examined with respect to age, histologic grade, EOD score, marker response to endocrine therapy and clinical outcome. We then compared several potential clinical factors between patients with and without pulmonary metastases. Next, we retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with particular focus upon metastatic profiles. A comparative study of stage D 2 patients with (n ¼ 20) and without (n ¼ 77) pulmonary metastases found no significant differences in EOD score, performance status, marker response and survival. Only tumor grade was better in the group with, than without pulmonary metastases (P ¼ 0.0120, chi-square analysis). In the series of autopsies, we found pulmonary metastases in 38 cases (63%), following metastases of the bone (57 cases, 95%) and lymph nodes (52 cases, 87%). A retrospective analysis of survival showed that patients with bone or lymph node metastases had a positive relative risk. In contrast, lung metastasis could be a positive prognostic indicator, although the findings were not statistically significant. These data suggest that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.
Introduction
Prostate cancer (PCa) is one of the most common cancers in Western countries and the incidence of this malignancy is currently increasing in Japan. 1 Despite the widespread use of prostate specific antigen (PSA) screening for early detection, PCa remains the second leading cause of cancer-related death among US males. 2 The outcome of PCa is mainly determined by metastases. The cornerstone of therapy in patients with metastatic PCa is androgen ablation, commonly referred to as endocrine therapy, since the Huggins and Hodges' report in 1941. 3 Approximately 70 -80% of PCa patients initially respond to endocrine therapy, but more than half of them gradually become resistant. Once disease progression occurs while on endocrine therapy, the mean survival is approximately 6 -12 months. 4 A number of clinical, endocrinological and pathological prognostic factors for PCa have been reported. 5 -12 Knowledge of prognostic factors for PCa may contribute to selecting the most appropriate therapy for individual patients. Several investigators have suggested prognostic indicators for metastatic PCa: the extent of bone metastases (extent of disease, EOD), pretreatment levels of serum testosterone, alkaline phosphatase, neuroendocrine markers, serum bone formation and absorption markers, as well as hemoglobin. 5 -15 The lungs are second or third only to bone and/or lymph nodes as metastatic sites postmortem, but pulmonary metastasis is not usually a significant factor in the management of PCa. 16 -18 As with other metastatic sites of PCa, pulmonary metastasis is treated by endocrine therapy. Several anecdotal reports have documented its effectiveness. Varkarakis et al reported that endocrine therapy failed to improve pulmonary metastases in 13 of 14 patients with metastatic PCa. 19 On the other hand, Fabozzi et al showed that endocrine therapy improved the radiographic appearance of pulmonary metastatic lesions in 13 (76.5%) of 17 patients who received no therapy before the development of pulmonary metastases. 20 Thus, the clinical impact of pulmonary metastases in the management of PCa remains obscure.
To estimate the clinical significance of pulmonary metastases from PCa, we initially characterized 20 stage D 2 PCa patients who presented with pulmonary metastases at initial diagnosis with respect to age, histologic grade, EOD score and clinical outcome in comparison with 77 stage D 2 PCa patients with no pulmonary metastases. Several potential clinical factors were compared between patients with and without pulmonary metastases. We then retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with specific focus on metastatic profiles.
Materials and methods
Comparative study of PCa patients with and without pulmonary metastases at initial diagnosis Between 1994 and 2000, a total of 152 consecutive stage D 2 patients were hormonally treated at Chiba University Hospital. Twenty of the 152 (13%) patients had pulmonary metastases at initial diagnosis and the remaining 132 had none. In this study, we performed a comparison between 20 stage D 2 PCa patients with pulmonary metastases and randomly selected 77 patients without pulmonary metastases. The diagnosis of all patients was confirmed histologically by needle biopsy.
Primary tumors obtained from an initial needle biopsy were histologically graded using the WHO classification as well as the Gleason histologic grading system. Performance status (PS) was classified according to Karnofsky. 21 The presence of pulmonary metastases was based on chest X-rays and/or computed tomography (CT) scans. Also, the assessment of metastases to bone was based on bone X-ray and/or radioisotopic bone imaging. Bones were scanned using 99m Tc-methylene-diphosphonate. The EOD metastases in each patient was classified according to Soloway et al at initial diagnosis. 22 Marker reaction to endocrine therapy was classified based on a PSA decline at 3 months from the commencement of therapy and patients were thereafter categorized into the following four groups: complete response (CR), normalization of the marker; partial response (PR), the marker declined more than 50%; no change (NC), a decrease of the marker level 50% or less, or an increase less than 25%, and progressive disease (PD), an increase of the marker level of 25% or more according to the biochemical response.
Autopsy study
A total of 60 Japanese patients who died of hormonerefractory metastatic PCa were autopsied in our institute between 1974 and 1999. The average ages of the patients at initial diagnosis and autopsy were 67.6 AE 8.58 y (range, 41 -89) and 71.7 AE 8.70 y (range, 46 -90), respectively. Survival was retrospectively analyzed (that is time to progression and time to death) with respect to metastasis of the four major sites (bone, lymph node, lung and liver).
We tried to estimate influence of metastatic lesions on progression-free and cause-specific survival, retrospectively. The relationships between each metastatic site (bone, lymph node, lung and liver) and time to progression/cancer-death were examined (Table 3 ). Only the relationship between time to death due to cancer and the lymph node metastasis was statistically significant (P ¼ 0.035). The presence of bone and lymph node metastases tended to shorten time to progression and time to cancer-death. In contrast, the prognosis of those with lung metastasis was better than those without such metastasis. Multivariate analysis demonstrated that bone and lymph node metastases indicated positive relative risk in term of prognosis, and that lung metastasis could be a positive prognostic indicator, although statistically insignificant (Table 4) .
Statistical analysis
Nominal parameters with continuous variables (eg age, time to progression) were estimated by chi-square analysis. Multivariate analysis was performed by multiple regression. The cause-specific and progression-free survival rates were calculated by the Kaplan-Meier method and compared using the Wilcoxon log-rank test. A Pvalue below 0.05 was considered significant.
Results

Clinical characterization of stage D 2 PCa patients with and without pulmonary metastases at initial diagnosis
This clinical analysis constitutes a review of 20 stage D 2 PCa patients with pulmonary metastases (average age: 71.2 AE 8.8-y-old) and 77 stage D 2 PCa without pulmonary metastases (average age: 74.2 AE 9.4-y-old; Table 1 ).
Based on chest radiography, pulmonary metastases were categorized into three types; that is nodular, lymphangitic and mixed. Of the 20 patients, pulmonary metastasis in 10 (50.0%) was nodular, lymphangitic in eight (40.0%) and mixed in two (10.0%). The type of pulmonary metastasis did not correlate with other pathological and clinical parameters (for example, tumor grade, EOD score, marker response to endocrine therapy).
Tumor grade was distributed as follows: 16 (80.0%) had moderately and four (20.0%) had poorly differentiated adenocarcinomas in the group with pulmonary metastases (Table 1 ). In the group without pulmonary metastases, tumor grade was classified in 75 of the 77 patients, with 33 (44.0%) having moderately differentiated and 42 (56%) having poorly adenocarcinomas (Table 1) . This difference was statistically significant (P ¼ 0.0120, chi-square analysis).
Performance status (PS) at initial diagnosis was classified in a total of the 89 of 97 patients (91.8%), with no significant difference between the two groups ( Table 1 ). In addition, the EOD score at initial diagnosis was determined in 77 of the 97 patients, with 41 (53.2%) having an EOD value of 0 or 1, and 36 (46.8%) with EOD values of 2 -4 ( Table 1 ). The distribution of EOD scores was similar between the two groups.
The marker reaction was classified in a total of 87 stage D 2 patients: 35 (40.2%) showed CR, 43 (49.4%) PR, four (4.6%) NC and five (5.7%) PD (Table 1) . No differences were significant between the patient groups with and without pulmonary metastases ( Table 1) .
The response of pulmonary metastases to endocrine therapy was determined by follow-up chest radiography in seven of the 20 patients. The radiographic appearance of chest lesions improved in all of them. Of the seven patients, four were CR in marker response to endocrine therapy and three were PR. No follow-up radiographs were available for the remaining 13 patients. Figure 1 Kaplan-Meier cause-specific survival curves for patients with and without pulmonary metastases. Figure 2 Kaplan-Meier progression-free survival curves for patients with and without pulmonary metastases. Figures 1 and 2 shows the results of cause-specific and progression-free survival analysis in stage D 2 patients, respectively. Despite the difference in tumor grade, survival did not significantly differ between the two groups. Table 2 shows the distribution of metastatic sites in 60 autopsies. The most frequent metastatic site was bone (57 cases, 95%), followed by lymph node metastases (52 cases, 87%), pulmonary metastases (38 cases, 63%) and liver metastases (34 cases, 57%). No correlation was identified among metastasis of PCa to the bone, lymph nodes, lungs and liver.
Pulmonary metastases of prostate cancer H Nakamachi et al

Discussion
The reported incidence of clinically apparent pulmonary metastases is 5 -27% at initial diagnosis, 19, 20 whereas autopsy rates show an incidence of between 23 and 74%. 16 -18 In our study, pulmonary metastases had already developed in 20 of 152 (13%) patients at initial diagnosis and in 38 of 60 (63%) at cancer-death, respectively. These rates were consistent with those of previous reports.
Saitoh et al suggested two lymph node metastatic profiles of PCa. 18 combined metastasis involving the pelvic and para-aortic lymph nodes and metastasis to the para-aortic lymph nodes, but not to the pelvic lymph nodes. Patients with the former profile had less frequent lung metastasis. Bubendorf et al 16 postulates two metastatic pathways of PCa: a backward venous spread to the spine occurring early, and a dissemination through the lung passages later in the course of the disease. They also found an inverse relationship between lung and spine metastases in autopsies. However, the present study did not identify any inter-relationship among bone, lymph node, lung and liver metastases of PCa in an autopsy series. The presence of lymph node metastasis was related to worse cause-specific survival according to our retrospective analysis, emphasizing the importance of preoperative or intra-operative lymph node staging.
Two basic radiological profiles generally predominate with pulmonary metastases of PCa: lymphangitic and nodular, with the former being more frequent. In the present study, the profile in half of the patients was nodular. This may be explained by the fact that this study was mainly based on the presence of pulmonary involvement determined by the radiographic appearance of chest lesions. Our study found no clinical differences in other parameters between patients with lymphangitic and those with nodular profiles.
A comparative analysis of stage D 2 PCa patients with and without pulmonary metastases at initial diagnosis found a statistical difference of only tumor grade among several clinical factors. Despite differences in tumor grade, neither cause-specific nor progression-free survival significantly differed between the two groups, while tumor grade is generally accepted as a potential The autopsy study found no inter-relationships among PCa metastases to the bone, lymph node, lung and liver. Since bone metastasis was evident in almost all autopsies, only the relationship between time to cancer-death and the presence of metastasis to lymph node was statistically significant. The prognosis of patients with lung metastasis was longer than that of those without metastasis to the lungs. This and the multivariate analysis data suggested that lung metastasis could be a good indicator for prognosis, although it was statistically not significant. These findings coincided with the results of our comparative study of PCa patients with and without pulmonary metastases at initial diagnosis, whose frequency of poorly differentiated adenocarcinomas was lower than that in the group without pulmonary metastasis. The reason for a rather better outcome of PCa patients with pulmonary metastasis remains unclear. Since it is generally accepted that PCa cells can be stimulated by growth factors derived from bone, 23 PCa cells in the lungs may have different characteristics. We therefore concluded that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.

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