Reported Outcome Factors for Pulmonary Resection in Metastatic Colorectal Cancer

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1 ESTS METASTASECTOMY SUPPLEMENT Reported Outcome Factors for Pulmonary Resection in Metastatic Colorectal Cancer Joachim Pfannschmidt, MD, Hans Hoffmann, MD, and Hendrick Dienemann, MD Abstract: Pulmonary resection of metastatic colorectal cancer is widely practiced in surgical oncology. However, only a highly selected subset of patients is eligible for resection, and the average recurrence rate is still high. We reviewed the recent literature on pulmonary metastasectomy for colorectal cancer and tried to address the issue of patient selection based on prognostic parameters associated with long-term survival. No randomized phase III trials are available, and data for this review were retrieved only from retrospective studies. We excluded papers reporting on patients earlier than In summary, there is a substantial body of evidence demonstrating that resection of pulmonary metastases can be performed safely and with a low mortality rate. For a subset of highly selected patients, the overall results of a 5-year actuarial survival rate after complete resection ranged between 40 and 68%. These outcomes exceed those normally associated with metastatic colorectal cancer. It is this perception that has encouraged surgeons and caused the practice to grow. Key Words: Pulmonary metastases, Colorectal cancer, Surgery. (J Thorac Oncol. 2010;5: S172 S178) Colorectal cancer is the third most common cancer and the third leading cause of cancer-related mortality estimated for 2009 in the United States. 1 Patients outcome is most closely related to the extent of disease at presentation. At the time of presentation, synchronous metastases are present in up to 30%. 2 The commonest sites of involvement are the regional lymph nodes, liver, lungs, and peritoneum. Most deaths from cancer are still due to metastases. 3 This knowledge has heightened awareness in detecting metastatic disease during the management of all patients with colorectal malignancy. The best estimate of isolated lung metastases without liver metastases in colorectal cancer has been estimated to lie between 1.7% probable and 7.2% possible. 4 In both estimates, the exclusion of liver metastases From the Department of Thoracic Surgery, University of Heidelberg, Thoraxklinik, Heidelberg, Germany. Disclosure: The authors declare no conflicts of interest. Address for correspondence: J. Pfannschmidt, MD, PhD, Department of Surgery, Thoraxklinik Heidelberg, Amalienstr 5, D Heidelberg, Germany. joachim.pfannschmidt@thoraxklinik-heidelberg.de Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ (thus making the lung metastases isolated ) was based on computed tomography (CT) scanning. Although the incidence of isolated lung metastases is twice as common in patients with rectal cancer, it is still significant in patients with colon cancer. 4 Surgical resection is the primary treatment modality for pulmonary metastases in colorectal cancers in patients who met the criteria for potentially curative operation. United Kingdom National Institute for Clinical Excellence guidance makes a similar recommendation. 5 The National Comprehensive Cancer Network 6 : Clinical Practice Guidelines in Oncology; preconditions for potentially curative operation are as follows: (1) the metastases seem to be technically resectable, (2) the general and functional risks are tolerable, (3) the primary tumor is controlled, and (4) no extrathoracic lesions are detected (with the exception of hepatic lesions in which it is possible to completely remove both hepatic and pulmonary metastases). Patient selection for pulmonary metastasectomy should be based on good pulmonary function. 7 The presence of associated comorbid conditions increases the risk of death and surgical complications. Several studies have evaluated the usefulness of preoperative exercise testing for predicting post operative morbidity and mortality, leading to the British Thoracic Society 8 and American College of Chest Physicians guidelines 9 for selection of patients for lung cancer surgery, which are also applicable to patients with pulmonary metastases. In recent years, several series have sought to define prognostic parameters for patient selection, but the effectiveness of such surgery remains unclear. The primary aims of this review are to determine the role of pulmonary metastasectomy, to determine the prognostic parameters in patients with colorectal cancer, and to evaluate the evidence of published contemporary studies on pulmonary metastasectomy. A systematic review of the literature of pulmonary metastasectomy in colorectal metastases was published in However, in the last years, there have been significant advancements in the treatment of colorectal cancer including new systemic therapies; further literature analysis was therefore indicated. Criteria for Selecting Studies To ensure that the reviewed surgical series reflected the outcome for patients treated with modern surgical, anesthetic, and diagnostic care techniques, we have restricted our qualitative analysis to surgical series reporting on patients included in the studies no earlier than There should be a S172 Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010

2 Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010Reported Outcome Factors for Pulmonary Resection FIGURE 1. Flow chart of articles found and progressive selection of data. reporting of at least 40 patients in each study. Studies were required to follow-up on patients for at least 30 days after operations for inclusion of data for postoperative morbidity and mortality, and for at least 20 months for inclusion of survival data. All eligible English articles in thoracic surgery recruiting adult patients were included. Search Strategy Studies were identified by searching Pub Med supplemented by a manual search of reference lists of retrieved studies. The following terms and keywords were used: metastases, lung metastases, pulmonary metastases, resection, surgery, pulmonary metastasectomy, and colorectal (PubMed user query: lung metastases, colorectal OR pulmonary metastases, colorectal AND Surgery AND (( 1990/01/01 [EDat]: 2009/10/01 [EDat]) AND (Humans[Mesh]) AND (English[lang])). The following information was extracted from each study: first author, year of publication, study type, study population, population characteristics, number of patients, and key outcomes (Fig. 1). No randomized trials comparing surgical resection versus no surgery have ever been conducted; therefore, we have attempted to identify all relevant prospective and retrospective studies reporting the outcome of surgical resection with curative intent of colorectal pulmonary metastases. Patients undergoing repeat pulmonary resection and hepatic and pulmonary metastases resection were included with at least 30 patients in each of this study being investigated. RESULTS Eleven studies including 1307 patients investigated pulmonary metastasectomy in colorectal cancer, and four studies with 232 patients specifically addressed the outcome after resection of hepatic and pulmonary metastases (Table 1). The study period was between 7 and 13 years, in one study on hepatic and pulmonary metastases resection 19 years. Intestinal localization was reported in the range 33.3 and 74% with colon localization. Most studies reported on patients with complete surgical resection, but four studies left the question of margins unclear. Patients were highly selected in eleven center, one multicenter, and two by two center studies. Survival All studies reported overall 5-year survival as between 40 and 68% for patients after complete surgical resection (Tables 1 and 2). Three studies did not distinguish between R0 and R1/2 resections and reported on a 5-year survival rate between 32.7 and 56%. 11,24,25 Three studies reported on 5-year disease-free survival after complete resection with 19.5, 18 25, 19 and 34.4%. 20 In studies addressing the problem of hepatic and pulmonary metastases resection, overall survival was between 31 and 60.8%, with an estimated disease-free survival by 3 years of 8%. 22 It is generally stated that radicality is a most important and constant prognostic factor for long-term survival in patients with pulmonary S173

3 Pfannschmidt et al. Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010 TABLE 1. Author Institution Recruitment Period Selection of Patients Patients With Solitary Lesions (%) Characteristics of Patients Follow-Up (mo) Postoperative Mortality 5-yr Survival, R0 (%) Survival (mo) Chemotherapy Ike 11 Yokohama, Saito 12 Osaka, multicenter Shiono 13 Chiba, Lee 14 Seoul, Melloni 15 Milan, Welter 16 Essen, Dahabre 17 Athens, two center Lin 18 Taipei, Onaitis 19 Durham, two centers Chen 20 Kyoto, Watanabe 21 Chiba, Author Institution Takahashi 22 Chiba, Lee 23 Seoul, Shah 24 Toronto, Miller 25 New York, NR 59.5 n 42, age range: yr, median: 60.7 yr, men: 27, women: 15, colon/rectum: 14/ R0 only 63.0 n 165, age range: yr, median: 61.6 yr, men: 97, women: 68, colon/rectum: 70/ R0 only 75.9 n 87, age range: yr, median: 61 yr, men: 57, women: 30, colon/ rectum: 47/37, NR: R0 only 52.5 n 59, age range: yr, mean: age 55 yr, men: 39, women: 20, colon/rectum: 24/ R0: 74 patients, 54.3 n 81, age range: yr, median: R1: 7 patients 61 yr, men: 49, women: 32, colon/ rectum: 41/ NR 47.9 n 169, age range: yr, mean: 62.6 yr, men: 96, women: 73, colon/rectum: 73/ R0: 52 patients, 59.7 n 57, age range: yr, median: R1/2: 5 patients 60 yr, men: 34, women: 23, colon/ rectum: NR R n 63, age range: yr, median: 58.7 yr, men: 39, women: 24, colon/rectum: 33/ R n 378, age range: yr, median: 61 yr, men: 225, women: 153, colon/rectum: 158/197 NR: R n 84, age range: yr, mean: 65 yr, men: 54, women: 30 colon/ rectum: 38/ R0: 113 patients, R1: 9 patients 68.0 n 122, age range: yr, mean: 62 yr, men: NR, women: NR, colon/rectum: 73/40 Patients With Recruitment Selection of Period Patients Solitary Lesions (%) Characteristics of Patients NR 60.0 n 30, age range: yr, mean: 59 yr, men: 19, women: 11, colon/ rectum: 17/13, simultaneous detection of lung and liver: R n 32, age range: yr, median: 61.5 yr, men: 27, women: 5 colon/ rectum: 18/14 simultaneous detection of lung and liver: NR NR 62 n 39, age range: yr, median: 54 yr, men: 26, women: 13, colon/ rectum: 24/15, simultaneous detection of lung and liver: (1990) Liver R0: 114 R1: Lung: R0: 113 R1: n 131 (103), age range: yr, median: 60 yr, men: 73, women: 58, colon/rectum: 97/34, simultaneous detection of lung and liver: NR NR % 39.6 NR Adjuvant: 63 patients 32 0% 61.4 NR Neoadjuvant: 11 patients, adjuvant: 2 patients % 50.3 NR 47 patients d: 0% patients NR 330 d: 0% All: NR NR 30 d: 0% All: NR 37.3 (12 122) mo NR OS: 43.9, NR Adjuvant: 63 patients DFS: 19.5 NR 1% OS: 56, NR Neoadjuvant: 87 patients DFS: 25 Adjuvant: 169 patients 28 (2 135) mo 0% OS: 60.5 NR NR DFS: % All: 67.8 NR Neoadjuvant: 2 patients, Adjuvant: 2 patients 5-yr Survival, Follow-Up (mo) Postoperative Mortality (%), Second Site of Metastasis d: 0% All: OS, 58; All: DFS, 8 (3-YS) Survival (mo) Chemotherapy OS: 39 No patient adjuvant: 0 Neo-adjuvant: NR OS: 60.8 NR Neoadjuvant: 21 patients, adjuvant: 12 patients 73 0 All: OS: 42.2 Adjuvant: 20 patients mo 3.2 yr NR DSS: yr Adjuvant regional: 18 patients neoadjuvant: NR, Adjuvant: NR metastasectomy. Radicality was evaluated by four studies within this review and Melloni et al. 15 found prognosis is significantly worse in patients with an incomplete resection. Postoperative mortality is reported with mostly a rate of 0% and in one study 2.4%. 11 The low rate of operative deaths attests not to much to the safety of the operation wherever and in whoever it is performed but to outcomes in this highly selected subset of patients mostly operated upon in highly specialized treatment centers. Of parameters that can be evaluated preoperatively, the stage and site (colon versus rectal cancer) of the primary tumor, disease-free interval between the resection of the primary colorectal cancer and detection of pulmonary metastases, the location of pulmonary metastases (unilaterally or S174

4 Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010Reported Outcome Factors for Pulmonary Resection TABLE 2. Prognostic Factor, Multivariate Analysis Yes No Nonreporting Stage of the primary tumor Melloni et al., Takahashi et al. Lee et al. (2008), Lin et al., Miller et al., Onaitis et al., Shah et al., Watanabe et al. Distribution Chen et al. Lee et al. (2008), Lee et al. (2006), Lin et al., Melloni et al., Miller et al., Saito et al., Takahashi et al., Watanabe et al. Liver resection Lin et al., Melloni et al., Onaitis et al., Saito et al., Shiono et al., Welter et al. Repeat pulmonary resection DFI CEA Lin et al., Onaitis et al., Miller et al. Lee et al. (2006), Saito et al., Watanabe et al. Chen et al., Lee et al. (2006), Melloni et al., Saito et al., Watanabe et al., Welter et al. Chen et al., Ike et al., Lee et al. (2006), Melloni et al., Saito et al., Shiono et al., Takahashi et al., Watanabe et al., Welter et al. Chen et al., Ike et al., Lee et al. (2008), Lin et al., Melloni et al., Miller et al., Onaitis et al., Shiono et al., Takahashi et al. Gender Onaitis et al. Chen et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Lin et al., Melloni et al., Miller et al., Saito et al., Shiono et al., Welter et al. Age (continuous variable) Histology primary tumor Parameter, Postoperative Onaitis et al., Miller et al. Chen et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Lin et al., Melloni et al., Saito et al., Shiono et al., Welter et al. Chen et al., Dahabre et al., Ike et al., Lee et al. (2006), Saito et al., Shiono et al., Welter et al. Dahabre et al., Ike et al., Onaitis et al., Shah et al., Shiono et al., Welter et al. Chen et al., Dahabre et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Miller et al., Shah et al., Takahashi et al., Watanabe et al. Dahabre et al., Ike et al., Lee et al. (2008), Lin et al., Miller et al., Onaitis et al., Shah et al., Shiono et al., Takahashi et al. Dahabre et al., Lee et al. (2008), Shah et al. Dahabre et al., Shah et al., Welter et al. Dahabre et al., Shah et al., Takahashi et al., Watanabe et al. Dahabre et al., Shah et al., Takahashi et al., Watanabe et al. Ike et al. Chen et al., Lin et al., Miller et al. Dahabre et al., Lee et al. (2006), Lee et al. (2008), Melloni et al., Onaitis et al., Saito et al., Shah et al., Shiono et al., Takahashi et al., Watanabe et al., Welter et al. Prognostic Factor, Multivariate Analysis Yes No Nonreporting Lung resection Lin et al. Chen et al., Ike et al., Lee et al. (2006), Saito et al., Shiono et al. Melloni et al., Watanabe et al., Welter et al., Dahabre et al., Lee et al. (2008), Miller et al., Onaitis et al., Shah et al., Takahashi et al. R0 vs R1/2 Melloni et al. Ike et al., Miller et al., Shah et al. Chen et al., Lee et al. (2006), Saito et al., Shiono et al., Welter et al., Dahabre et al., Lee et al. (2008), Lin et al., Onaitis et al., Takahashi et al., Watanabe et al. Number of lesions (lung) Thoracic Lymph Node Involvement Maximum tumor size (lung) Onaitis et al., Welter et al. Saito et al., Welter et al. Chen et al., Ike et al., Lee et al., Lee et al., Lin et al., Melloni et al., Miller et al., Saito et al., Shah et al., Shiono et al., Takahashi et al., Watanabe et al. Chen et al., Ike et al., Lin et al., Shiono et al., Takahashi et al., Watanabe et al. Chen et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Lin et al., Melloni et al., Onaitis et al., Shiono et al., Takahashi et al., Watanabe et al., Welter et al. Dahabre et al. Dahabre et al., Lee et al. (2006), Lee et al. (2008), Melloni et al., Miller et al., Onaitis et al., Shah et al., Welter et al. Dahabre et al., Miller et al., Saito et al., Shah et al. Chemotherapy Lee et al. (2006), Saito et al. Chen et al., Dahabre et al., Ike et al., Lee et al. (2008), Lin et al., Melloni et al., Miller et al., Onaitis et al., Shah et al., Shiono et al., Takahashi et al., Watanabe et al., Welter et al. Vascular invasion, ASFC Shiono et al. Chen et al., Dahabre et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Lin et al., Melloni et al., Miller et al., Onaitis et al., Saito et al., Shah et al., Takahashi et al., Watanabe et al., Welter et al. Lymphatic invasion Watanabe et al. Chen et al., Dahabre et al., Ike et al., Lee et al. (2006), Lee et al. (2008), Lin et al., Melloni et al., Miller et al., Onaitis et al., Saito et al., Shah et al., Shiono et al., Takahashi et al., Welter et al. CEA, carcinoembryonic antigen; NR, non reported; DFI, disease-free interval; ASFC, aerogenous spread with floating cancer cell clusters. S175

5 Pfannschmidt et al. Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010 FIGURE 2. Liver resection previous to PM. Series size: small-sized dot, 100 patients; mediumsized dot, patients; large-sized dot, 200 patients. bilaterally), the level of prethoracotomy serum-carcinoembryonic antigen, and age and gender were reported prognostic factors in studies. The majority of studies either found no prognostic significance of the named parameters or there was no reporting of the parameters as prognostic markers. In the reporting of Onaitis et al., 19 age younger than 65 years and female gender predicted recurrence. Ike et al. 11 investigated the histology of the primary colorectal cancer and found that patients who have had well-differentiated adenocarcinoma of the primary tumor are likely to be longterm survivors; conversely, Lin et al. 18 could not support this finding in their study. Stage of the primary tumor was defined as an independent prognostic factor for survival in the study by Melloni et al., 15 nevertheless this could not be confirmed in studies by Lin et al. 18 and Onaitis et al. 19 The disease-free interval between the resection of the primary tumor and pulmonary metastasectomy was confirmed to be a prognostic parameter by multivariate analysis in the studies by Lin et al. 12 and Onaitis et al. 19 Longer survival was associated with a metachronous detection and a disease-free interval of more than 1 year. 18,19 Although no analysis has been published on the prognostic value of tumor doubling time (TDT) within the different studies being reviewed within this compendium, there are two recent studies 26,27 presenting an analysis of growth rate in patients with pulmonary metastases by CT scan. Tomimaru et al. 27 found, that the TDT was a significant prognostic factor in patients with a solitary pulmonary metastasis from colorectal cancer. In multiple metastases, there was an unpredictable growing pattern for every independent lesion. 26 Most likely, TDT reflects such biologic factors as tumor growth properties and vascular supply. The best method to quantify the variation of TDT in the preoperative workup is by two consecutive CT scans. 28 Patients were selected for pulmonary metastasectomy with a limited number of pulmonary metastases, solitary metastases were found in 26 to 88% of the patients within the different studies. Onaitis et al. 19 and Welter et al. 29 found post-thoracotomy survival less favorable in patients with multiple pulmonary metastases. Maximum tumor size was not a significant prognostic parameter for colorectal cancer metastases. The presence or absence of thoracic lymph node metastases is discussed as a prognostic factor for estimating the prognosis in pulmonary metastasectomy for most extrapulmonary malignancies. When either systematic lymph node dissection or sampling of mediastinal and hilar lymph nodes was performed, the rate of nodal metastases ranged between 12 and 32% Routine systematic mediastinal and hilar lymph node dissection simultaneously with pulmonary metastasectomy has not been uniformely performed and was reported vaguely or not at all in the majority of the studies within this review. Thoracic lymph node involvement was a significant ominous prognostic parameter in the studies by Saito et al. 12 and Welter et al., 29 but it was of no statistical significance in the studies by Chen et al., 20 Ike et al., 11 Shiono et al., 13 Lin et al., 18 and Watanabe et al. 21 The role of chemotherapy in the treatment of patients with metastatic colorectal cancer is evolving. Although in most studies chemotherapy has been a standard therapy for metastatic colorectal cancer, the impact of neoadjuvant and adjuvant chemotherapy in the context with pulmonary metastasectomy on long-term survival had not been sufficiently addressed. In a subgroup multivariate analysis Lee et al. 14 and Saito et al. 12 could not find a significant impact of perioperative chemotherapy, and in the majority of studies, small numbers of patients with similar regimens prohibited meaningful statistical analysis. New monoclonal antibodies have been shown to improve progression free survival and overall survival when added to oxaliplatin-based regimens. However, the survival figures quoted after chemotherapy alone include a far less selective group of patients than those undergoing metastasectomy. Combined Liver and Lung Resection The liver is the most frequent site of distant metastases in patients with colorectal cancer (Fig. 2). There is a substantial body of evidence from retrospective case series that resection of colorectal hepatic metastases alone can lead to a 5-year survival rate of 30 to 40%, and around two-thirds of these are recurrence free. 33 Resection of isolated hepatic and pulmonary metastases has been shown to be safe with low-perioperative mortality. In the recent published literature of this highly selected subgroup of patients, 5-year survival rates between 31 and 60% were reported. No difference in overall survival for patients with synchronous versus metachronous presentation of liver and lung metastases were revealed by Shah et al., 24 Takahashi et al., 22 and Lee et al. 23 However, Miller et al. 25 found the disease-free interval greater than 1 year between the development of the 1st and 2nd sites metastases favorable for long term survival. In this S176

6 Journal of Thoracic Oncology Volume 5, Number 6, Supplement 2, June 2010Reported Outcome Factors for Pulmonary Resection FIGURE 3. Recurrent procedures PM. Series size: small-sized dot, 100 patients; mediumsized dot, patients; large-sized dot, 200 patients. study, age under 55 years and solitary liver metastasis were further associated with improved survival. Takahashi et al. 22 additionally defined primary colon cancer, stage IV at the time of primary cancer resection, and the size of the hepatic tumor at initial hepatectomy 3 cm as ominous prognostic factors for survival. Repetitive Resection Although the role of reresection has not been specifically addressed within the publications analyzed, improvements in surgical techniques, perioperative management, and safety of pulmonary resections have paved the way for more frequently performed repeat resections (Fig. 3). Welter et al. 34 and Kim et al. 35 reported on no perioperative mortality after repeat resections in 39 patients and 69 patients; the overall 5-year survival rate was 53.8 and 29%, respectively. Since only subsets of patients are eligible for reresection, prognostic indicators of survival are important for determining patient eligibility. Welter et al. 34 defined the number of pulmonary metastases as a independent prognostic parameter for survival after repeat resections. There is a need for a large-scale prospective control trial to determine the true survival advantage of repeat pulmonary resection. Interestingly this has historically gone up and down without much change overall, but very unreliable estimates of real practice probably. Comment There are several studies being conducted to describe criteria for patient selection with pulmonary metastases of colorectal cancer based on clinical data. The problem of having no prospective randomized trials for pulmonary metastasectomy makes it difficult to summarize and evaluate the available evidence for the effectiveness of this operation. Based on a body of retrospective case series, it has been demonstrated that resection of colorectal pulmonary metastases can be performed safely with a low mortality rate. After pulmonary metastasectomy, the overall 5-year actuarial disease-free survival rate ranged between 19.5 and 34.4%. Overall, current results are better than historical controls but far from being satisfactory. Traditional risk factors and selection criteria are being discussed, but decision making presuppose a personalized strategy with predictive models. Such predictive models have a number of uses. In particular, they can help select patients who may more specifically benefit from prethoracotomy chemotherapy, surgery, or aggressive adjuvant therapy. And this can also be used to plan early operations on patients with favorable prognostic scores and to delay surgery in those with unfavorable scores. This delay, or trial of time, can allow a better assessment of additional disease and provide time for neoadjuvant therapy or a plan to give more aggressive adjuvant therapy. Moreover, this delay may enable patients at increased risk of recurrent disease to be included in prospective randomized trials or to offer a more intensive postoperative surveillance strategy. Kanemitsu et al. 36 published a predictive model based on 313 patients between 1989 and They used five prognostic factors identified by multivariate analysis (primary histology, hilar or mediastinal lymph node involvement, number of metastases, preoperative carcinoembryonic antigen-level, and extrathoracic disease) as criteria for a clinical risk score. This score was highly predictive of long-term outcome, and this model has the advantage of being simple and easily applicable in the clinical setting. 37 The evaluation of biologic criteria as prognostic parameters may further improve the grade of accuracy for prediction of long-term survival and enhance the understanding of the metastatic process. Prognostic subgroups of lung metastases in patients with colorectal cancer and renal cancer have been characterized by gene expression analysis using Affymetrix GeneChip microarray technology. 38,39 However, because their prohibitive costs, reliance on frozen tissue, and the advanced technical expertise required to use the technology it is debatable whether they will ever be clinically applicable. In these situations, the immunohistochemical (IHC) staining profile can be a useful surrogate of gene expression analysis. Many studies were focused on the correlation between histopathologic and IHC measurements and survival. 13,15,40 43 Shiono et al. 13 analyzed histopathologic features of pulmonary metastases in 87 patients; they revealed the morphologic feature of aerogenous spread with floating cancer cell clusters and vascular invasion at metastatic sites of prognostic significance for survival. In another study, Watanabe et al. 21 found postmetastasectomy long-term survival associated with no lymphatic invasion by the pulmonary tumor. Melloni et al. 15 found in a study with 74 patients no correlation between microsatellite instability determined by IHC evaluation of primary tumors and metastases with survival. Given the limited number of pulmonary metastases being investigated by modern molecularbiological methods in diagnosing, there S177

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