**4. Pancreatic metastases from renal cell carcinoma**

(this subtype being the most frequently reported in the present study); therefore, among 177 patients submitted to surgery for pancreatic metastases from renal cell cancer, the median survival was 70 months, while the 2 year and 5 year overall survival rates were of 78 and 65%, respectively. These data suggest the potential benefit of pancreatic resections for metastatic lesions; it seems that the short-term outcomes are not significantly influenced by the metastatic character of the lesion, while the long-term outcomes seem to reveal significant long-

In a study conducted by Reddy et al. on 49 patients with metastatic pancreatic lesions, the main included primaries were renal cell carcinoma (in 21 cases), gallbladder cancer (in 6 cases), pulmonary cancer (in 4 cases), ovarian cancer (in 4 cases), sarcomas (in 4 cases), melanomas (in 3 cases), colorectal cancer (in 2 cases), breast cancer (in 1 case), hepatocellular carcinomas (in 1 case), seminomas (in 1 case), Langerhans cell histiocytosis (in 1 case) and nonpancreatic endocrine cancers (in one case). The study was conducted for a 38 year time period and reviewed data from 3830 patients submitted to pancreatic surgery; among these cases, the metastatic origin of the tumor was demonstrated in 1.6% of cases. The median age at the time of resection of pancreatic lesions was 60 years, while the most commonly encountered symptoms were abdominal pain (in 48% of cases), followed by jaundice (in 31% of cases). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31 cases, distal pancreatectomies in 14 cases and total pancreatectomy in 4 cases; among the 14 cases submitted to distal pancreatic resections, splenectomy was associated in 13 patients. When it comes to the short-term outcomes, the reported morbidity rates were 52% after pancreaticoduodenectomy, 46% after distal pancreatectomy and 25% after total pancreatectomy; however, the overall mortality rate was 0. The most often reported complications were wound infections, followed by delayed gastric emptying or pulmonary complications. When it comes to the histopathological findings, the most often reported lymph node metastases originated from renal cell carcinomas, gallbladder carcinomas, lung, colorectal carcinomas, melanomas, seminomas, sarcomas and nonpancreatic endocrine tumors, while perineural and vascular invasion were reported in gallbladder, lung, renal cell cancers and melanomas. As for the longterm outcomes, the authors reported a median overall survival rate after pancreatic resection of 3.7 years. Among long-term survivors (defined as a longer than 10 year survival after pancreatic resection), the most commonly reported origins were renal cell carcinomas, followed by Langerhans histiocytosis and seminomas. When performing an univariate analysis, the most important prognostic factors affecting the long-term survival were represented by the presence of perineural invasion and vascular invasion; surprisingly, the diameter of the metastatic tumor or lymph node metastases did not significantly influence survival. Moreover, patients who experienced any type of surgical complication as well as male patients trended to report a poorer outcome. When it comes to the influence of the cancer type on the overall prognostic, a significant influence was reported. The poorest outcomes were reported in patients submitted to surgery for pancreatic metastases originating from melanomas, followed by cases with breast cancer. No patient diagnosed with pancreatic metastases from colorectal, lung cancer or sarcoma did experience an overall survival longer than 5 years. The best outcome was reported by the patient diagnosed with metastatic Langerhans cell histiocytosis and by the patient diagnosed with seminoma, both cases being alive more than 11 years after pancreatic surgery.

term survival especially in oligometastatic lesions from renal primaries [11].

134 Advances in Pancreatic Cancer

Renal cell carcinomas represent almost 2% of all malignant tumors in adults, being the third most common genitourinary tract cancer [13]. Although renal cell carcinoma is associated with an overall good prognostic, with 5-year survival rate of up to 95%, patients presenting distant metastases report a significant poorer outcome, with 5-year survival rates lower than 10%.

Pancreatic metastases with renal cell carcinoma origin can be diagnosed at the time of the diagnostic of the primary tumor (as synchronous lesions) or after a disease free interval (as metachronous lesions). In the second case, it seems that the prognostic is significantly influenced by the disease free survival interval, a longer period of time between the initial diagnostic and the diagnostic of metastatic lesions being associated with a lower biological aggressivity and better chances of long-term survival [14, 15]. However, it should not be omitted that pancreatic metastases from renal cell carcinoma can occur even at 10–32 years from the diagnostic of the primary tumor, so that differential diagnosis should be kept in mind any moment in which a patient known with previous history of renal cell carcinoma is diagnosed with a metachronous pancreatic tumor [16].

Patients with pancreatic metastases from renal cell carcinomas can remain asymptomatic for a long period of time or can develop signs and symptoms such as weight loss, abdominal pain, jaundice or even pancreatitis due to the Wirsung duct obstruction caused by tumor growth; in certain cases lesions located in the pancreatic head will lead to the apparition of upper gastrointestinal bleeding [17, 18].

Once a pancreatic metastasis with renal cell carcinoma origin is suspected at the imagistic studies, a fine needle biopsy might be needed in order to confirm the origin of the lesion and to decide which should be the therapeutic protocol. However, pancreatic metastases from renal cell carcinoma are the most common situation in which pancreatic resection for metastatic disease has been proposed.

When it comes to the most important prognostic factors after pancreatic resections for pancreatic metastases with renal cell carcinomas, it seems that the disease free survival plays a central role; patients diagnosed with pancreatic metastases with a disease free survival longer than 2 years seem to have an improved outcome. Other factors which seem to influence the long-term outcomes are represented by the diameter of the tumor (tumors larger than 5 cm being associated with poorer outcomes), stage at the initial diagnostic and the tumoral degree of differentiation [19, 20].

The largest series of cases submitted to pancreatic resections for metastatic renal cell carcinomas was conducted by Schwarz et al. and was published in 2014 in *Annals of Surgical Oncology* [21]. The study was conducted between May 1987 and June 2003 in 12 Franco-Belgian surgical centers and involved 62 patients submitted to surgery for pancreatic metastases from renal cell carcinomas. The median age at diagnostic was 54 years (range 31–75 years) while the most common reported symptoms were abdominal pain (in 24% of cases), anemia and gastrointestinal bleeding (in 13% of cases) and jaundice (in 10% of cases). The mean interval from the diagnostic of the primary tumor to the diagnostic of the pancreatic lesion was 9.8 years (range 0–25 years—two patients presenting with synchronous pancreatic lesions). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31% of cases, distal pancreatectomies in 40% of cases, total pancreatectomies in 23% of cases and enucleation in 6% of cases. In order to achieve negative resection margins, in six cases major vascular resections with reconstruction were performed, while *en bloc* visceral resections were needed in other four cases (consisting of colonic resections in three cases and omentectomy in one case); in other six patients the presence of other distant metastases imposed performing other visceral resections such as liver resection in three cases, contralateral adrenalectomy in three cases and contralateral nephrectomy in other two cases. The histopathological studies confirmed an unique pancreatic lesion in 39 cases, while in the other 23 cases, 2 or more metastatic lesions were described. Moreover lymph node involvement was reported in 27% of cases submitted to lymph node dissection. During the early postoperative period, the authors reported an overall mortality rate of 6.4%; after a median follow-up of 91 months, 32 patients were dead of disease, 11 cases died of other non-malignant causes and 15 patients were still alive (5 cases being alive with disease while the remaining 10 cases were alive with no signs of recurrent lesions). The authors reported a 3 year, a 5 and a 10 year survival rate of 72, 63 and 32%, respectively. Among the 37 patients who experienced recurrences, 9 cases presented pancreatic relapse, the median time to recurrence being of 44 months. Pancreatic relapsed presented as isolated metastases in five cases and as part of systemic relapse—in association with lung and liver metastases in other four patients; therefore four cases were submitted to pancreatic re-resection, the median survival time after re-resection being of 52.6 months (significantly higher compared to the one reported after conservative therapy—11.2 months, *p* = 0.019). When it comes to the most important prognostic factors influencing survival, it seems that the presence of extrapancreatic disease as well as the presence of lymph node metastases significantly decreased survival. Surprisingly, the study failed to demonstrate a significant influence of the disease free survival interval on the overall survival rate, this fact being explained by the authors by the limited number of patients introduced in the current study [21].

reported in 12 cases while the postoperative overall mortality was 7.5%. When it comes to the long-term outcomes, the authors reported a mean overall survival of 147.9 months; however, none of the studied factors (including body mass index, sex, time of resection, synchronous/ metachronous lesions, symptomatic/asymptomatic lesions, resection status, existence of other extrapancreatic lesions, tumor dimension or lymph node status) did not significantly influenced survival. This fact was explained by the authors by the relative small number of cases introduced in the current study [22]. Another important aspect pointed out of these authors is the one regarding the lymph node status: among the 21 patients who benefited from lymph node resection 5 patients were diagnosed with lymph node metastases; therefore the authors

underlined the necessity of association of lymph node dissection in such cases [22].

**Disease free interval**

27 patients 9.8 years PD: 19 cases

months

years

months

23 patients 8 years PD: 4 cases

years

shown in **Table 1**.

**Period of the study**

1987– 2003

1993– 2014

2000– 2011

1997– 2012

1998– 2006

1999– 2013

**No. of patients**

40 patients 125.4

8 patients 12.42

20 patients 130 ± 59

15 patients 13.4

**Name, year of the study**

Schwarz, 2014

Ruckert, 2016 [22]

Markinez, 2013 [23]

Benhaim, 2015 [24]

Zerbi, 2008 [25]

Yuasa, 2015 [26]

[21]

The outcomes after pancreatic resection for pancreatic metastases with renal cell origin are

**Type of pancreatic resection**

DP: 25 cases TP: 14 cases Enucleation: 4 cases

PD: 15 cases DP: 12 cases Enucleation: 3 cases Broad papillary resection: 1 case

TP: 6 cases DP: 1 case

PD: 6 cases DP: 5 cases TP: 3 cases

DP: 11 cases TP: 2 cases

MP: 1 case

TP: 2 cases

Atypical resection: 1 case

Metastasectomy: 6 cases

Metastasectomy: 5 cases

Metastasectomy: 13 cases

**Early postoperative** 

Pancreatic Resections for Metastatic Disease http://dx.doi.org/10.5772/intechopen.75571 137

**Long-term outcomes**

Overall survival after pancreatic resections: 52.6 months

Overall survival after pancreatic resections: 147.9 months

Survival between 6 months and 95 months

72%

Overall survival rate at 4 years:

Overall survival after pancreatic resections: 44 months

Overall survival after pancreatic resections: not reached at 3.5 year follow-up

**outcomes**

Postoperative mortality: 4 cases

Postoperative mortality: 3 cases

Postoperative mortality: 1 case

Postoperative mortality: 1 case

Postoperative mortality: 0

Postoperative mortality: 0

In a similar study conducted by Ruckert et al. and published in 2016 in the *International Journal of Surgery,* the authors reviewed data from 40 patients submitted to surgery for pancreatic metastases from renal cell carcinomas in 2 German centers between January 1993 and October 2014. These cases were submitted to surgery for pancreatic disease after a median period of 125.4 months, the most commonly performed surgical procedures consisting of pancreatoduodenectomy (in 37.5% of cases), total pancreatectomies (in 22.5% of cases), distal pancreatectomies (in 30% of cases), segmental resections (in 7.5 cases) and papillary resections (in 2.5% of cases). The most commonly encountered complication was pancreatic leak and it was reported in 12 cases while the postoperative overall mortality was 7.5%. When it comes to the long-term outcomes, the authors reported a mean overall survival of 147.9 months; however, none of the studied factors (including body mass index, sex, time of resection, synchronous/ metachronous lesions, symptomatic/asymptomatic lesions, resection status, existence of other extrapancreatic lesions, tumor dimension or lymph node status) did not significantly influenced survival. This fact was explained by the authors by the relative small number of cases introduced in the current study [22]. Another important aspect pointed out of these authors is the one regarding the lymph node status: among the 21 patients who benefited from lymph node resection 5 patients were diagnosed with lymph node metastases; therefore the authors underlined the necessity of association of lymph node dissection in such cases [22].

The largest series of cases submitted to pancreatic resections for metastatic renal cell carcinomas was conducted by Schwarz et al. and was published in 2014 in *Annals of Surgical Oncology* [21]. The study was conducted between May 1987 and June 2003 in 12 Franco-Belgian surgical centers and involved 62 patients submitted to surgery for pancreatic metastases from renal cell carcinomas. The median age at diagnostic was 54 years (range 31–75 years) while the most common reported symptoms were abdominal pain (in 24% of cases), anemia and gastrointestinal bleeding (in 13% of cases) and jaundice (in 10% of cases). The mean interval from the diagnostic of the primary tumor to the diagnostic of the pancreatic lesion was 9.8 years (range 0–25 years—two patients presenting with synchronous pancreatic lesions). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31% of cases, distal pancreatectomies in 40% of cases, total pancreatectomies in 23% of cases and enucleation in 6% of cases. In order to achieve negative resection margins, in six cases major vascular resections with reconstruction were performed, while *en bloc* visceral resections were needed in other four cases (consisting of colonic resections in three cases and omentectomy in one case); in other six patients the presence of other distant metastases imposed performing other visceral resections such as liver resection in three cases, contralateral adrenalectomy in three cases and contralateral nephrectomy in other two cases. The histopathological studies confirmed an unique pancreatic lesion in 39 cases, while in the other 23 cases, 2 or more metastatic lesions were described. Moreover lymph node involvement was reported in 27% of cases submitted to lymph node dissection. During the early postoperative period, the authors reported an overall mortality rate of 6.4%; after a median follow-up of 91 months, 32 patients were dead of disease, 11 cases died of other non-malignant causes and 15 patients were still alive (5 cases being alive with disease while the remaining 10 cases were alive with no signs of recurrent lesions). The authors reported a 3 year, a 5 and a 10 year survival rate of 72, 63 and 32%, respectively. Among the 37 patients who experienced recurrences, 9 cases presented pancreatic relapse, the median time to recurrence being of 44 months. Pancreatic relapsed presented as isolated metastases in five cases and as part of systemic relapse—in association with lung and liver metastases in other four patients; therefore four cases were submitted to pancreatic re-resection, the median survival time after re-resection being of 52.6 months (significantly higher compared to the one reported after conservative therapy—11.2 months, *p* = 0.019). When it comes to the most important prognostic factors influencing survival, it seems that the presence of extrapancreatic disease as well as the presence of lymph node metastases significantly decreased survival. Surprisingly, the study failed to demonstrate a significant influence of the disease free survival interval on the overall survival rate, this fact being explained by the

136 Advances in Pancreatic Cancer

authors by the limited number of patients introduced in the current study [21].

In a similar study conducted by Ruckert et al. and published in 2016 in the *International Journal of Surgery,* the authors reviewed data from 40 patients submitted to surgery for pancreatic metastases from renal cell carcinomas in 2 German centers between January 1993 and October 2014. These cases were submitted to surgery for pancreatic disease after a median period of 125.4 months, the most commonly performed surgical procedures consisting of pancreatoduodenectomy (in 37.5% of cases), total pancreatectomies (in 22.5% of cases), distal pancreatectomies (in 30% of cases), segmental resections (in 7.5 cases) and papillary resections (in 2.5% of cases). The most commonly encountered complication was pancreatic leak and it was The outcomes after pancreatic resection for pancreatic metastases with renal cell origin are shown in **Table 1**.



with an extremely poor prognostic. Less than 2% of patients with pancreatic metastases from melanomas will be diagnosed with oligometastatic disease, most often the primary tumor

Pancreatic Resections for Metastatic Disease http://dx.doi.org/10.5772/intechopen.75571 139

As for the long-term outcomes, patients presenting pancreatic metastases originating from melanomas with various locations seem to have a poorer prognostic when compared to other primaries due to the aggressive biological behavior of melanomas [19]. However, compared to patients treated in a conservative manner, it seems that patients submitted to surgery might benefit from a better outcome especially in cases in which complete resection of the pancreatic lesion is feasible [32, 33]. When it comes to the most important prognostic factors which might influence the long-term outcomes, it seems that a long disease free survival interval is usually associated with a lower biological aggressivity of the primary tumor, and, therefore, with a better outcome [34]. In a case series of two patients diagnosed with pancreatic metastases from melanomas at *Melbourne University*, *Austin Hospital*, *Victoria*, *Australia* published in 2003, the authors reported encouraging results; the first case was the one of a 45-year-old woman with personal history of ocular melanoma treated by transscleral resection 12 years earlier, the histopathological studies revealing at that moment a 10 mm mixed spindle and epithelioid cell melanoma; however, she experienced an early local recurrence 1 year postoperatively, laser therapy being performed at the time of relapse. About 11 years later (after the first local relapse), the patient was diagnosed with a pancreatic head tumor in association with three to four well defined hepatic nodules measuring 5–10 mm, while the fine needle biopsy confirmed the metastatic character of the tumor originating from the melanoma. The patient was submitted to a pylorus preserving pancreatoduodenectomy and segmental liver resection, the histopathological studies confirming the metastatic character of all the resected tumors. The patient was free of disease at 6 months follow-up. The second reported case from the same authors was the one of a 55-year-old patient known with a previous history of ocular melanoma enucleated 13 years earlier who complained of epigastric pain and was diagnosed with a tumoral mass at the level of the pancreatic head; intraoperatively multiple pigmented lesions were seen on the whole surface of the pancreas, so the patient was submitted to total pancreatectomy and remained free of disease 7 months later [34]. Wood's series conducted on a group of six patients with pancreatic metastases forming melanomas, complete surgical resection of the pancreatic lesion was associated with a median overall survival rate of 24 months, significantly higher than the survival rates after palliative chemotherapy (where the median overall survival rate does not surpass 12 months) [35, 36]. However, in Woods' study one of the most important prognostic factors was related to the resection margins, patients presenting with positive resection margins or incomplete resection being associated with a significantly poorer outcome (in fact in these cases the median survival rate was 8 months, similar to the one reported after palliative chemotherapy) [35]. In

conclusion incomplete resection has no benefit in terms of survival.

Intra-abdominal breast cancer metastases are usually diagnosed at the level of the liver, spleen or axial skeleton [37]. When reported, pancreatic metastases from breast cancer are

**7. Pancreatic metastases from breast cancer**

being an ocular melanoma [30, 31].

*Abbreviations*: DP, distal pancreatectomy; PD, pancreatoduodenectomy; TP, total pancreatectomy; MP, middle pancreatectomy.

**Table 1.** Outcomes after pancreatic resections for pancreatic metastases from renal cell carcinomas.
