Jie Dong, Lin Cong, Tai-Ping Zhang and Yu-Pei ZhaoBeijing, China

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Pancreatic metastasis of renal cell carcinoma

Jie Dong, Lin Cong, Tai-Ping Zhang and Yu-Pei Zhao
Beijing, China

Author Affiliations: Department of Surgery (Dong J), Department of General Surgery (Cong L, Zhang TP and Zhao YP), and National Laboratory of Medical Molecular Biology (Zhao YP), Chinese Academy of Medical Sciences, Medical College Hospital, Peking Union Medical College, Beijing 100730, China

? 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

Published online January 7, 2016.

BACKGROUND: Renal cell carcinoma (RCC) is a common cancer, but pancreatic metastasis of RCC is unusual. Because of the rarity and peculiarity, pancreatic lesions from RCC metastasis were described mostly in case reports which highlight the importance of a systematic analysis of this clinical condition.

DATA SOURCES: Data of 7 patients with pancreatic metastasis of RCC treated in the Peking Union Medical College Hospital were extracted and 193 similar patients reported in the past 10 years from the literature were analyzed. Epidemiological, pathological and follow-up information were investigated. Potential prognostic factors were compared with corresponding data reported 10 years ago.

RESULTS: Multivariate Cox regression showed that asymptomatic metastasis and surgical procedure were independent factors associated with better survival. Compared with the data reported 10 years ago, follow-up of RCC patients has been emphasized in recent years, and atypical surgery is frequently used since it has similar effect as typical surgery on tumor resection while it is able to preserve more pancreatic function.

CONCLUSION: Surgical treatment should be an option as long as the pancreatic metastasis of RCC is resectable.

(Hepatobiliary Pancreat Dis Int 2016;15:30-38)

KEY WORDS:pancreatic metastasis; renal cell carcinoma; surgery; prognostic factor; survival analysis

Introduction

According to the American Cancer Society report, renal cell carcinoma (RCC) is the sixth most common cancer in the United States, accounting for an estimated 13 860 deaths in 2014.[1]Among patients with RCC, 20%-30% have metastases at presentation and up to 40%-50% develop widespread metastatic disease after nephrectomy.

The pancreas is an uncommon location for metastasis from other primary cancers and pancreatic metastases account for less than 5% of all pancreatic malignancies.[2, 3]A variety of cancers have been shown to metastasize into the pancreas, such as colon cancer, non-small cell lung cancer, and melanoma. In particular, RCC shows, besides metastases to lymph nodes, lung, liver and bones, an increased disposition for metastasis to rare sites, such as the thyroid gland and the pancreas.[4, 5]

Finding reliable prognostic factors for patients with RCC metastatic to the pancreas would facilitate selection of different treatment strategies. A number of articles have proposed several prognostic models to predict the survival of these patients and showed different results. Some suggested that surgeons should preserve as much pancreatic tissue as possible to protect exocrine and endocrine function of the pancreas,[6]whereas others suggested atypical tumor resection might lead to higher morbidity and recurrence rates.[7]

Due to the rarity and peculiarity, pancreatic lesions for RCC metastasis were described mostly in case reports. In 2006, Sellner and colleagues[8]conducted a high volume systemic research which thoroughly reviewed the literature of RCC with pancreatic metastasis from 1952 to 2003. In this study, we reviewed cases reported at the Peking Union Medical College Hospital (PUMCH) in the past decade and compared the relevant factors between our data and Sellner’s, attempting to identify the differences which could help investigate the underlying changes during the past 10 years. This study is to perform a systematic review of previous reports on patients with RCC metastasized to the pancreas and those with this condition admitted to our center, to portrait the characteristics of this condition, and to investigate theprognostic factors in this population.

Methods

Study selection

Firstly, we performed a literature search in PubMed (2003 to 2014). The key words used were as follows: pancreatic metastasis, renal cell carcinoma, kidney cancer and surgery. The search was conducted using the term “related article”. All selected articles were studied and then screened to match pre-defined criteria. Articles containing duplication of case descriptions were excluded. Articles not containing individual patient data were excluded. And patients who were pathologically proved to have tumor other than clear cell carcinoma were excluded. As a result, 70 articles were included in the study.[6, 8-76]Secondly, patients treated for pancreatic metastasis of RCC at our center (PUMCH) were included to expand patient population. Data for each patient were collected retrospectively, and the patients were followed up with clinical visits and telephone.

Data extraction

A total of 200 patients (193 from the literature and 7 from our center) were included in this study. The following data were extracted from the literature or our patients: patient characteristics, primary RCC, pancreatic metastasis, pancreatic surgery or other therapies performed, overall survival and date of death. Surgery strategies were classified into two categories: typical resection (pancreatoduodenectomy, distal pancreatectomy, total pancreatectomy) and atypical resection (enucleation and others).

Statistical analysis

All these data were analyzed with SPSS statistical software (version 13.0; IBM Corporation, Armonk, NY). Continuous data were present as mean and standard deviation. Potential risk factors for survival were first analyzed with univariate Cox regression. Variables with P<0.10 by univariate analysis were further analyzed by multivariate Cox regression. The clinically significant parameters (P<0.05) were then considered independent predictors of survival. The Kaplan-Meier method was then applied to depict survival curves and to compare the survival of patients with different distributions of these significant parameters. A subgroup evaluation utilizing the Kaplan-Meier method and the log-rank test was conducted to compare the prognosis of patients with typical surgery and atypical surgery. Moreover, to delineate the changes in the management of this patient population, we compared the patient characteristics and treatment options using Student’s t test (continuous variables) and binomial distribution test (categorical variables). For all analyses, a P value <0.05 was considered statistically significant.

Results

Cases from PUMCH

Table 1. Characteristics of the patients with pancreatic metastasis of RCC in PUMCH

A total of 7 patients with RCC metastatic to the pancreas, 4 men and 3 women with a mean age of 59 years (range 45-68), were treated in our center (Table 1). All the pancreatic metastases were metachronous. The average interval time between the renal tumor resection and the finding of pancreatic lesions was 6.91 years (range 1.17-17.00). Six patients presented with right renal tumors, 5 were symptomatic when metastatic lesions were found: two had abdominal pain, two had jaundice, and one suffered from upper gastrointestinal bleeding. The lesions were solitary in 3 patients, located in the head of the pancreas in 5 patients, and had a mean size of 3.81 cm (range1-6). One of our patients had extrapancreatic metastasis of disease (liver). Surgical approaches for pancreatic lesions were taken in 5 patients, among whom 4 stayed alive with disease recurrence at 1, 14, 48 and 76 months after surgery, while one had no evidence of disease at 7 months after the resection. One patient did not receive any treatment due to personal reasons and another patient chose chemotherapy (hepatic artery infusion chemotherapy with mitomycin and epirubicin) because the lesions were deemed as unresectable. These two patients (without surgical interventions) died from the tumor at 2 and 11 months after diagnosis, respectively.

Epidemiology and pathology

The characteristics of the patients included are summarized in Table 2. The information on age and gender was available in 188 patients. There were 109 men and 79 women with a mean age of 63.5 years (range 43-86). Primary renal tumors from left kidney were in 65 patients (59.6%), right in 43 (39.5%) and bilateral in 1 (0.9%). The stages of primary renal carcinoma were documented in 20 patients: 5, 10, 4 and 1 patients diagnosed with G1, G2, G3 and G4 grade of RCC, respectively. In 11 patients (5.5%), pancreatic metastases were synchronous with RCC. The mean interval time from nephrectomy to pancreatic metastasis was 9.9 years (range 0.17-27).

Most patients were clinically asymptomatic, and the diagnoses of pancreatic metastasis were incidental during follow-up, mostly detected as hypervascular lesions localized in the pancreas by CT or ultrasound screening. In 51 patients (38.9%), clinical symptoms were present upon diagnosis: abdominal pain in 21 patients, jaundice in 16, upper gastrointestinal bleeding in 5, weight loss in 9, melena in 3, anemia in 1, fever in 1, dizziness in 1, neck mass in 1, and fatigue in 1. In 68 patients, symptoms were not specified.

Pancreatic metastases were located in the head of the pancreas in 61 patients (35.9%), body in 20 (11.8%) and tail in 39 (22.9%); 50 patients (29.4%) had lesions metastasized to multiple pancreatic locations. The lesions were solitary in 110 patients (60.4%), with a mean size of 3.91cm (range 1-12).

Information of treatment strategies was available in 186 patients. Of them, 151 patients (81.2%) underwent surgical resection, 112 of them were subjected to resections with typical procedures including pancreatoduodenectomy (31), total pancreatectomy (37), and distal pancreatectomy (44) and 39 patients underwent resections with atypical procedures including enucleation (14) and other types of procedures (25). In 35 patients (18.8%), surgery was not performed due to locally advanced diseases or personal reasons. Fourteen of the 35 patients received adjuvant therapies.

Table 2. Characteristics of the patients with pancreatic metastasis of RCC

Pathological information of the lesions in the pancreas was documented in only a few papers. Among theevaluable patients, 49 (87.5%) had clear margins whereas 7 (12.5%) had involvement at cut edges; and 39 (90.7%) had negative lymph nodes whereas 4 (9.3%) had lymph node metastases.

Follow-up data were available for 173 patients. 136 patients (78.6%) who were alive at the end of observation had a mean follow-up of 31.8 months (range 1-137). Among these patients, disease recurrences, including pancreatic and extrapancreatic recurrences, were found in 46 patients (26.6%). Thirty-seven patients (21.4%) died at a mean of 21.9 months (range 0.6-96).

Table 3. Univariate analysis of potential prognostic factors for RCC metastatic to the pancreas

Prognostic factors of pancreatic metastasis RCC

Univariate Cox regression analysis identified four significant predictors of patient survival (Table 3). Symptomatic metastases (HR=2.19; 95% CI: 1.01-4.79), margin involvement (HR=8.05; 95% CI: 1.99-32.55) and lymph node involvement (HR=7.04; 95% CI: 1.16-42.7) were associated with poor survival. Surgical intervention (HR=0.29; 95% CI: 0.15-0.59) was a predicator for better prognosis. Subsequently, Kaplan-Meier survival curves were used to identify the differences in survival of patients based on the presence of the significant risk factors (Fig.). Moreover, a Kaplan-Meier analysis and the log-rank test showed no changes (P=0.94) in survival of patients undergoing typical surgery compared with those having atypical surgery (Fig.).

A multivariate Cox regression was then performed to determine the independent prognostic factors for patients with RCC metastatic to the pancreas. The variables were incorporated in a multivariate Cox regression (P<0.10). Since resected margin and lymph node affection were not specified in the majority of patients, the two factors were not included in the multivariate analysis. The results showed that symptomatic metastasis (HR=2.42; 95% CI: 1.01-5.40) and surgical intervention (HR=0.15; 95% CI: 0.03-0.67) were clinical significant and independent predictors for survival (Table 4).

Comparison with the data 10 years ago

Fig. Kaplan-Meier survival curves. A: symptomatic metastasis vs asymptomatic metastasis; B: surgical procedure vs non-surgical intervention; C: clear margin on histological observation vs margin involvement; D: negative lymph node on histological observation vs lymph node metastasis; E: typical surgery vs atypical surgery.

In 2006, Sellner et al[8]conducted a systemic reviewabout the literature of RCC with pancreatic metastasis published from 1952 to 2003. In 236 patients reviewed, age, gender, interval time, metastasis number, metastasis location, metastasis size, surgery procedure and survival time were analyzed. The authors concluded that radical removal of metastases should be done in eligible patients.

Table 4. Multivariate analysis of potential prognostic factors for pancreatic metastasis of RCC

Table 5. Comparison of relevant variables with those 10 years ago

In our study, we also analyzed the parameters such as age, gender, interval time, metastasis number, metastasis size and surgical procedure. Further, to delineate the changes in patient characteristics and treatment options in the past decade, we compared the relevant factors between our population and Sellner’s to detect differences which could help to investigate the underlying changes during the past 10 years (Table 5). The comparison revealed that the rates of metachronous metastasis and atypical surgical procedures were higher in the last decade than a decade ago (P<0.05).

Discussion

RCC is a common cancer type. When the tumor is limited and remains in stage 1, it is characterized by a high 5-year survival rate (up to 95%).[77]However, once it develops widespread metastases, the 5-year survival rate of the patients will drop to less than 10%.[78]

Pancreatic metastasis accounts for 2%-5% of pancreatic malignancies. However, it seems to be related to a relatively good prognosis and leads to a different therapy strategy.[79]Therefore, it is very important to preoperatively diagnose pancreatic metastasis. Solitary pancreatic metastases are difficult to differentiate and may be misdiagnosed as primary pancreatic cancer. However, imaging methods, such as CT and MRI, may help to discriminate between them. Peripherally enhanced tumors are more likely to be metastatic than primary pancreatic cancers, which tend to be non- or poorly-enhanced masses.[80]At the same time, the diagnostic workup for tumors in the pancreas needs a meticulous elaboration of the medical history of patients, especially for those with a longer disease-free period. In our study, the percentage of metachronous metastasis was 94.5% vs 87.9% as indicated in Sellner’s article (P<0.01), suggesting that more patients with RCC are developing metachronous pancreatic metastasis than those seen a decade ago. This may due to medical progress and long-life of RCC patients as well as patients with pancreatic metastasis of RCC being followed up more closely than before.

A consensus on the efficacy of surgery in RCC patients has been reached with thorough and systemic review.[3, 8]However, it is still controversial whether to perform typical or atypical procedures: some prefer atypical procedures and suggest that surgeons should dig out only the metastatic lesions to protect exocrine and endocrine function of the pancreas,[6]whereas others support typical procedures and suggest that atypical procedures may lead to higher morbidity and recurrence.[7]Our results revealed that surgical interventions could prolong patients’ survival. But there was no survival benefit from typical procedures compared with atypical ones. We also found that during the past decade, fewer patients (60% vs 72%, P=0.03) received typical operations, indicating that more surgeons prefer atypical procedures because of its effectiveness in preserving pancreas function. In the current therapeutic environment, pancreatic metastases of RCC represent a relatively indolent tumor phenotype, which further supports the strategy of atypical operation.[81, 82]

The emergence of targeted therapy has provided more treatment options for this subset of patients. Recently, Grassi et al[83]retrospectively studied patients with metastatic RCC treated with targeted therapy. In their cohort, there were 24 patients with pancreatic metastases and 8% received surgical treatment. However, many of the patients had multiple metastatic sites other than the pancreas and the authors did not focus on the comparison between the surgery group and non-surgery group. Still, the authors concluded that the presence of pancreatic metastasis seems to be associated with a longer survival other than the presence of metastasis at the sites which supported a less aggressive treatment strategy (eg. atypical surgery) for this subset of patients. Currently, we recommend surgical treatment for symptomatic patients and those with solitary lesions and no metastaticsites other than the pancreas. Surgical procedures could differentiate solitary metastasis from neuroendocrine neoplasms and symptomatic patients could benefit from surgeries to improve quality of life. However, the recommendation needs further evidence to support. Our study suggested a relationship between symptoms at the time of metastasis and prognosis. Univariate and multivariate analyses revealed that compared with metastatic patients without symptoms, symptomatic metastasis indicated a poor prognosis (both P<0.05). Similar findings have been reported previously.[8]Like most tumors, clinical symptoms of pancreatic metastasis may be evidenced by tumor enlargement, necrosis, depletion and invasion. The results showed that close follow-up for patients with RCC is essential to find possible metastasis in the early phase.

Our study has three limitations. First, it is a retrospective study that inevitably influenced by selection bias, the baseline characteristics and indications for surgery were not the same in our patients. Therefore, although there was a significant relationship between surgery and prognosis, a causal relationship could not be established in our patients. Patients who did not undergo surgery might have locally unresectable tumors, poor performance status, and severe extrapancreatic diseases, which may interfere with the decision-making of surgeons. And these might also contribute to a poorer survival rate. Second, most of the included studies were case reports. Patient information described in these articles was not intact and many data were missing. In our study, only 4 articles mentioned adjuvant therapy of 19 patients. Hence it was difficult to assess the efficacy of adjuvant therapy in these patients. Moreover, patient preference, surgeon referral patterns, and evaluation of resectability could have introduced additional bias into the study. Although a prospective, randomized controlled study would draw an accurate conclusion, pancreatic metastasis of RCC is rarely detected in a single center.

In 1999, Memorial Sloan-Kettering Cancer Center (MSKCC) identified five prognostic factors for metastatic RCC (performance status, lactate dehydrogenase level, hemoglobin level, corrected serum calcium level, and disease-free survival from nephrectomy) to predict the outcome of patients with metastatic RCC.[84]In 2005, this model known as the MSKCC prognostic model was validated and modified, adding prior radiotherapy and metastatic sites instead of performance status as prognostic factors.[85]In 353 patients with metastasis RCC, their prognosis could be precisely predicted by the model. The patients were classified into 3 different risk groups: good, mediate and poor prognosis groups by the model. Then the effect of surgical procedure was examined in each group. This method can eliminate the selection bias of baseline characteristics of patients and can be conducted in a single center. Unfortunately, only few articles provided the above findings. Other than the MSKCC model, metastatic sites of RCC is another risk factor for patients’ prognosis: while metastasis to the lymph nodes, liver and brain suggests worse survival, metastasis to the pancreas is associated with better prognosis.[81, 82]Unfortunately, we were unable to analyze the prognostic role of extrapancreatic metastatic sites due to lack of precise documentation in most cases of our study.

In conclusion, when pancreatic metastases of RCC are resectable, surgical treatment might be an option as long as no comorbidities are contraindicated for resection. The optimal resection strategy involves adequate resection margins and maximal tissue preservation of the pancreas. Therefore, atypical surgery, related to better survival in our cohort, should be taken into consideration. A rigid follow-up scheme for these patients, including a regular follow-up with ultrasound and CT is necessary so that any possible metastases could be found before symptoms occur.

Contributors: DJ and CL proposed the study. ZTP and ZYP took care of the patients from PUMCH. DJ and CL performed the research and wrote the first draft. DJ searched the databases and analyzed the data. ZTP and ZYP reviewed the draft and gave comments. All authors contributed to the design and interpretation of the study and to further drafts. ZYP is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received June 9, 2015

Accepted after revision October 21, 2015

Original Article / Liver

doi:10.1016/S1499-3872(16)60052-8

Corresponding Author:Yu-Pei Zhao, MD, PhD, Department of General Surgery, Peking Union Medical College Hospital and National Laboratory of Medical Molecular Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China (Tel: +86-10-65296007; Fax: +86-10-65124875; Email: zhaoyp8028@163.com)