Pancreatic metastases are rare, with a reported incidence varying from 1.6% to 11% in autopsy studies of patients with advanced malignancy. In clinical series, the frequency of pancreatic metastases ranges from 2% to 5% of all pancreatic malignant tumors. However, the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies. The epidemiology, clinical presentation, and treatment of pancreatic metastases from renal cell carcinoma are known from single-institution case reports and literature reviews. There is currently very limited experience with the surgical resection of isolated pancreatic metastasis, and the role of surgery in the management of these patients has not been clearly defined. In fact, for many years pancreatic resections were associated with high rates of morbidity and mortality, and metastatic disease to the pancreas was considered to be a terminal-stage condition. More recently, a significant reduction in the operative risk following major pancreatic surgery has been demonstrated, thus extending the indication for these operations to patients with metastatic disease.

Renal cell carcinoma (RCC) remains an important cause of cancer death in the United States, with an estimated 58  240 new cases and approximately 13  040 deaths in 2010[1].

The natural history of RCC is characterized by a high 5-year survival (up to 95%) when the tumor is limited to the kidney (stage 1)[2-4]. Among patients with RCC, 20% to 30% have metastases at presentation, and up to 40%-50% will develop widespread metastatic disease after nephrectomy. The 5-year survival rate is < 10%-15% once metastases have spread[5,6].

Pancreatic metastases are rare, with a reported incidence varying from 1.6% to 11% in autopsy studies of patients with advanced malignancy[7,8]. In clinical series, the frequency of pancreatic metastases ranges from 2% to 5% of all pancreatic malignant tumors[9-12].

The tumors that metastasize most commonly to the pancreas are RCC, lung cancer (adenocarcinoma and non-small cell lung carcinoma), lobular breast carcinoma, and colorectal adenocarcinoma, followed by melanoma, soft-tissue sarcoma (leiomyosarcoma), and a large number of other neoplasms[7,8,13-19].

However, the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies[11,19-27]. Pancreatic metastases from RCC are frequently the only metastatic site and they typically occur a long time after nephrectomy[20,23,26].

According to Sellner et al[23], local lymphogenous or local venous spread through abnormal lymphatic or venous communications between the RCC and the pancreas[11,21,28] cannot play an important role, because this would fail to explain the lack of relationship between the site of isolated pancreatic metastases and the side affected by the primary tumor: i.e., the left or right kidney. The localization anywhere in the pancreas irrespective of the site of the RCC argues, instead, in favor of a hematogenous systemic spread. However, a systemic spread would not explain the discrepancy between the relative frequency of multiple pancreatic metastases and the absence of metastases to other organs. The most likely explanation for this unique behavior of isolated pancreatic metastases would seem to lie in the special biology of the tumor. Tumor cells apparently have a high affinity for the parenchyma of the pancreas and only there do they find the conditions they need to mature to manifest metastases. The high affinity of some renal cancer cells for the parenchyma of the pancreas is supported by some reports[23] of metachronous late metastases which again occurred solely in the residual pancreas[11,22]. The results of basic research, which is slowly unraveling the local biochemical mechanisms that underlie the development of metastases, are promising, so it is hoped that the biochemical causes of the unique spreading pattern of some RCC will perhaps be understood one day[29].

As with primary pancreatic cancer, the early signs and symptoms of isolated pancreatic metastases are often non-specific and subtle. Isolated pancreatic metastases are often found with routine surveillance imaging for primary lesions or as an incidental finding on imaging done for an unrelated indication.

Pancreatic metastasis of RCC generally occurs in the seventh decade of life and is usually asymptomatic[14,15,30], although cases of abdominal pain, gastrointestinal bleeding caused by duodenal involvement, weight loss, jaundice, and pancreatitis due to pancreatic duct obstruction have been described[14,15,26,31].

Most of the studies reviewed report mean time intervals greater than 10 years, and a period as long as 32.7 years has been described[12,19,21-24,26,32]. In fact, renal carcinoma is the primary tumor that metastasizes to the pancreas following the greatest disease-free interval. This singular feature of RCC makes long-term follow-up essential in these patients.

Multiple lesions throughout the pancreatic gland have been more frequently detected in patients with RCC than in those with other primary tumors. Other single-center series reported similar frequencies of multifocality with respect to pancreatic RCC metastases, ranging from 20% to 45%[12,22,23,26,27,33,34]. In the review by Sellner et al[23], multiple lesions occurred in 39% of the 187 patients. This issue has important clinical implications: surgical treatment of patients with suspected pancreatic metastases from RCC must take into account the high probability that the patient will have more than one pancreatic lesion.

In a recent review by Masetti et al[35], univariate survival analyses conducted in a subgroup of patients with RCC metastases (n = 157), with a median follow-up of 24 mo (range 1 to 134 mo), showed that the factors associated with worse survival were symptoms at diagnosis, and a disease-free interval less than 2 years in patients with metachronous lesions.

In the case of unresectable disease, surgical or endoscopic palliation in association with chemotherapy can improve the quality of life but not survival, even if, in rare cases of renal cell metastases, an improved survival has been reported after palliative surgery[34,64].

In the series described by Zerbi et al[12], 13 patients who did not undergo resection, because of locally advanced disease or due to the presence of extrapancreatic disease, all received immunotherapy with interferon (IFN) α as first-line treatment; 6 patients underwent other therapies (interleukin-2 in 3 cases, thalidomide in 1 case, radiotherapy in 1 case, bone marrow transplantation in 1 case). The median survival was 27 mo (range 17.5 to 50.2 mo).

In this group of patients who did not undergo surgical resection, 2- and 5-year survival rates were 59% and 47%, respectively.

No prospective randomized or case-controlled studies have been performed to evaluate the role of surgical resection. In addition, many of the existing retrospective studies are limited because of the small number of patients who were treated for prolonged periods of time.

The pooled data from the 18 studies in Table 1 do not contain adequate detail to assess features for the prediction of outcome in the context of pancreatic metastasectomy for RCC. However, analyzing the three largest series reported in the literature it can be seen firstly that in their series of 21 patients who underwent pancreatic metastasectomy for RCC, Reddy et al[54] reported that tumor size greater than 4 cm (P = 0.13) and perineural invasion (P = 0.26) were not associated with significant differences in outcome, whereas lymph node involvement (hazard ratio 24.1, P = 0.01) and vascular invasion (hazard ratio 20.4, P = 0.007) were each associated with worse overall survival. The median survival was 4.8 years (range 0.35 to 18.3 years). Metachronous RCC had a similar survival to synchronous lesions (P = 0.98).

Zerbi et al[12] addressed the question of whether or not pancreatic metastasectomy changes the progression of RCC. They assessed a non-matched control group of patients with non-operatively managed pancreatic RCC metastasis. In this study, 13 out of 36 patients with pancreatic RCC were not offered surgery on the basis of functional status or extent of disease. These 13 patients were the control group, and their outcome was compared with outcomes for patients undergoing pancreatic metastasectomy. For the entire cohort, the median survival was 27 mo (range 0.6 to 222 mo) and 5-year survival was 47%. Patients who had tumors resected had a 5-year survival of 88% compared with 47% for the non-operative group (P = 0.026), suggesting a benefit of pancreatic metastasectomy.

On the other hand, in their series of 20 patients with pancreatic metastases from RCC, Konstantinidis et al[62] reported that, on univariate analysis, the number of metastatic nodules (solitary vs multiple, P = 0.87), the size of metastases (greater or smaller than median of 3 cm, P = 0.78), the location of the metastases (P = 0.72), or an R1 resection (P = 0.62) had no prognostic significance for overall survival. Hemoglobin values below the lower level of the reference range also did not predict worse outcome (P = 0.99). Patients had median and mean follow-up of 36.8 and 38.1 mo, respectively (range 0.5 to 143 mo). Their median survival from the time of metastasectomy was 8.7 years (range 1.3 to 12 years) and 5-year actuarial survival was 61%.

However, the treatment of pancreatic metastases from RCC remains controversial because of the relatively low frequency of this localization and the complex natural history of RCC, ranging from cases with a long disease-free interval to others with early development of widespread metastases[65].

To predict the behavior of disease in patients with metastatic RCC, several prognostic models have recently been developed[66-68]. In particular, Motzer et al[68,69] from Memorial Sloan-Kettering Cancer Center (MSKCC) proposed categorizing patients with metastatic RCC into one of three classes by using a model with five prognostic factors. This prognostic score was recently validated and modified by a study from the Cleveland Clinic Foundation group[70](Table 2).

Since RCC is highly resistant to chemotherapy, interleukin-2 or IFN α have been widely used as first-line treatment of metastatic disease. These agents have limited efficacy and are associated with considerable toxic effects. Response rates with these cytokines were low (5% to 20%), the median overall survival was approximately 12 mo, and the overall survival rate at 5 years was less than 10%[71-75].

Several molecularly targeted therapies have recently shown substantial clinical efficacy in patients with advanced RCC, in particular the multitargeted tyrosine kinase inhibitors (such as sunitinib and sorafenib), anti-vascular endothelial growth factor (VEGF) antibody (such as bevacizumab), and mammalian target of rapamycin (mTOR) pathway inhibitors (such as everolimus and temsirolimus). The treatment regimen is based on the MSKCC risk stratification, on the type of the tumor (clear cell renal carcinoma or not clear cell renal carcinoma), and on the previous treatment (cytokines or multitargeted therapy). Sunitinib is chosen as first-line therapy in patients with favorable or intermediate prognosis. Two phase 2 trials on sunitinib in patients treated with cytokines as first-line therapy showed that the objective response rates (as assessed by investigators and by an independent review) were 34%-40%, better than with INF α[76,77].

The subsequent randomized phase 3 trial enrolled 750 patients. There were 375 patients in the sunitinib group and 372 in the IFN group. The median progression-free survival (PFS) was 11 mo for patients in the sunitinib group and 5 mo for patients in the IFN group (P < 0.001), with a 58% reduction in the risk of progression. Sunitinib also improved the objective response rates (47% vs 12%)[78]. Patients with this prognostic grade can also be treated with bevacizumab plus IFN. In the first phase 2 trials, bevacizumab improved PFS with respect to placebo (4.8 mo vs 2.5 mo)[79].

The AVOREN study[80], a randomized phase 3 trial, enrolled 649 patients with 327 patients on IFN plus bevacizumab and 322 patients on IFN plus placebo. Bevacizumab plus IFN showed better PFS (median 10.2 mo vs 5.4 mo; P = 0.0001) and response rate (31% vs 13%). The mortality risk fell by about 14%. An American phase 3 trial (CALGB 90206)[81] confirmed the good results of bevacizumab.

In patients with poor prognosis, temsirolimus is the first option. A phase 3 trial[82] compared 3 therapeutic regimens, temsirolimus vs IFN vs the combination of these 2 agents. Temsirolimus alone improved both PFS and overall survival (OS), with a reduction of the mortality risk (14%). It is also the first choice in patients with not clear cell renal carcinoma.

Sorafenib showed superiority as a second-line therapy over placebo in terms of PFS and OS in patients treated with cytokines. The TARGET study[83], a phase 3 trial, randomized 903 patients; there were 451 patients in the sorafenib group and 452 in the placebo group. The median overall survival was 19.3 mo for patients in the sorafenib group and 15.9 mo for patients in the placebo group (P = 0.02). PFS was also significantly prolonged with sorafenib treatment (5.5 mo vs 2.8 mo; P < 0.001), with a 49% reduction in the risk of progression. Significantly more patients in the sorafenib group than in the placebo group had partial responses or stable disease (P < 0.001).

In patients treated previously with multitargeted therapy, everolimus can be the first choice. A phase 3 trial compared everolimus vs placebo in patients treated with sorafenib and/or sunitinib. Everolimus doubled the PFS compared with placebo (4 mo vs 1.9 mo) and decreased the risk of recurrence.

Based on all the clinical trials, we can summarize all the evidence in a therapeutic algorithm (Table 3). In the future, personalized treatments will be prescribed according not only to clinical criteria, but also to biological and molecular factors such as for breast and colorectal cancer.

Pancreatic metastases are commonly treated with surgical resection. However, such a resection cannot always be performed safely, especially in elderly patients or those with diabetes mellitus. Pancreatic metastases of RCC may be treated successfully with radiation therapy (RT).

In the literature there is only one case report of four patients[84]. These patients presented with multiple pancreatic metastases of RCC and were treated with RT combined with IFN α. Radiotherapy was delivered at 2 Gy/fraction, up to 50 Gy in 25 fractions, with three-dimensional conformal radiation therapy technique and 10 MV photon beams from linear accelerators.

In three patients, stable local disease persisted for an average time of 33.6 mo (range11 to 69 mo) after RT. In one patient, a partial response was obtained, lasting 25 mo after RT.

The European Association of Urology guidelines recommend RT for the treatment of brain and bone lesions to induce symptomatic relief of metastases from RCC. To our knowledge, there are no other previous reports of radiotherapy for pancreatic metastases of RCC.

In patients with pancreatic metastases of RCC, surgical resection with or without systemic treatment, such as cytokine therapy or antiangiogenic therapy, should be considered if complete resection is possible.

On the other hand, systemic treatment with or without RT to induce symptomatic relief and to prevent disease progression can be considered for high-risk patients, such as those with a poor performance status, diabetes mellitus, and older age.

Treatment options for unresectable pancreatic metastases of RCC are limited and new therapeutic measures should be advocated. Radiofrequency ablation (RFA) is a local ablative method that can destroy the tumor by thermal coagulation and protein denaturation. RFA has been used successfully in the treatment of unresectable solid tumors in the liver, lung, kidney, brain, breast, prostate, bone, adrenal glands and spleen[85-92]. Application of RFA to the pancreas presents potential problems related to anatomical considerations and particular properties of the pancreatic parenchyma. The risk of inadvertent thermal injury to the distal common bile duct, duodenum, transverse colon and portal vein is considerable with RFA. In addition, thermal injury to normal pancreatic tissue may cause acute necrotizing pancreatitis, pancreatic fistula or pancreatic ascites[93-101].

Elias et al[94] reported two cases of multiple pancreatic metastases from RCC treated by RFA. Both patients manifested acute necrotizing pancreatitis with massive destruction of normal pancreatic parenchyma.

Hadjicostas et al[96], based on results obtained in four patients, concluded that RFA seems to be a feasible, potentially safe and promising option in patients with advanced and non-resectable pancreatic cancer. Girelli et al[102], based on results obtained in 50 patients, showed that RFA of locally advanced pancreatic cancer is feasible and relatively well tolerated, with a 24% complication rate.

Postoperative observation (clinical surveillance, laboratory tests and imaging studies) is mandatory because of the potential for major or minor, early or later complications. The most frequent complications encountered in the earlier postoperative period (within 1 wk) are fluid collection, pancreatic fistula, duodenal perforation and vascular damage. At later times, digestive or abdominal bleeding, infections or abscesses are more common. Severe acute pancreatitis is a rare complication[96]: in Girelli’s[102] study, there was only one case, and none were reported in Wu’s study[101]. Major complications are frequently present with RFA of pancreatic head tumors, mainly owing to the closeness of the duodenum. These lesions are more difficult to treat, as reported previously[101].

While waiting for other studies to clarify its role, RFA should be performed in high-volume centers by an experienced surgical team devoted to pancreatic surgery.

Thus, as suggested by Zerbi et al[12], a high index of suspicion is necessary for all patients with a history of RCC, and they should be monitored lifelong to allow the early detection of recurrence.

Because of the possibility of substantial morbidity after pancreatic resection and the questionable benefit of metastasectomy in some patients, pancreatic metastasectomy should be offered only after a thoughtful and systematic selection process. Ideally, this process would involve a multidisciplinary team that includes a medical oncologist and an experienced pancreatic surgeon. Once the decision is made to proceed with resection, evidence suggests that the procedure should be performed at a high-volume center[103,104]. In agreement with Reddy et al[54], we suggest the following criteria for the selection of patients for pancreatic metastasectomy: primary cancer type that is associated with successful outcome, control of the primary cancer site, isolated metastases, resectability of the metastasis, and patient fitness to tolerate pancreatectomy.

Prospective studies would better address the role of surgical therapy in pancreatic metastasectomy. However, because of the rarity of these lesions, such a trial can only be performed in a multi-institutional setting and possibly only for RCC metastases because of their high relative incidence compared with other cancers.