Next Article in Journal
Age-Related Alterations in Immune Contexture Are Associated with Aggressiveness in Rhabdomyosarcoma
Next Article in Special Issue
P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis
Previous Article in Journal
CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis
Previous Article in Special Issue
Local Treatment of Breast Cancer Liver Metastasis
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism?

Surgical Department, Kaiser-Franz-Josef-Hospital, 1100 Wien, Austria
Cancers 2019, 11(9), 1379;
Submission received: 5 August 2019 / Revised: 2 September 2019 / Accepted: 4 September 2019 / Published: 17 September 2019
(This article belongs to the Special Issue Cancer Invasion and Metastasis)


Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic–haematogenic metastasis route (uniform distribution of the metastases across the pancreas and independence of the metastatic localization in the pancreas of the side of the renal carcinoma); and (b) postulate a high impact of a seed and soil mechanism (SSM) on isolated pancreatic metastasis of renal cell carcinoma (isPM) as an explanation for exclusive pancreatic metastases, despite a systemic haematogenous tumor cell embolization. The objective of the study presented was to search for further arguments in favor of an SSM with isPM. For that purpose, the factor’s histology, grading, and singular/multiple pancreas metastases were analyzed on the basis of 814 observations published up to 2018. While histology and grading allowed for no conclusions regarding the importance of an SSM, the comparison of singular/multiple pancreas metastases produced arguments in favor of an SSM: 1. The multiple pancreas metastases observed in 38.1% prove that multiple tumor cell embolisms occur with isPM, the exclusive “maturation” of which in the pancreas requires an SSM; 2. The survival rates (SVR), which are consistent with singular and multiple pancreas metastases (despite the higher total tumor load with the latter), prove that the metastasized tumor cells are not able to survive in all other organs because of an SSM, which results in identical SVR when the pancreatic foci are treated adequately.

1. Introduction

Two fundamental mechanisms determine and regulate the metastatic potential of solid carcinomas. On the one hand, it is the imperatively necessary invasion of blood and lymph vessels by tumor cells: there can be no metastasis without circulating tumor cells or tumor cell clusters. The fate of the embolized tumor cells is just as significant, however, since clinical experience shows that not every tumor cell embolism inevitably results in clinically manifest metastasis. That is rather the result of a multi-stage interaction of tumor cells and host organ (seed and soil), since neither each tumor cell nor each host organ can provide all necessary properties required for successful interaction. Large-scale studies determined the complexity of this mechanism, which takes place in five main steps [1,2,3]: 1. The invasion of tumor cells in the vascular system “intravasion”; 2. The transport of the tumor cells in the vascular system; 3. The docking of the tumor cells, mechanically or by way of organ–tumor cell-specific adhesion to the vascular wall [1,2,3,4,5,6]; 4. The extravasion of tumor cells through the capillary wall in the extracellular matrix (ECM)—after distraction or death of endothelial cells [2,3,6,7,8,9,10,11,12], and 5. After previous dormancy [3,13,14,15,16] or without it, the maturation of the cells into metastasis (colonization); a process which requires the formation of a vessel network [17] and the overwhelming of the immune system of the host (interaction with ECM components [18] and stroma cells [2,19,20]).
In the light of recent studies, a pre-stage “0” still has to be added: the influence of the primary tumor on potential target organs, which takes place a long time before tumor cell embolization in order to prepare them for the subsequent metastatic settlement: the development of a pre-metastatic niche [3].
Paget recognized the essential significance of an interaction between circulating tumor cells and host organ in 1889 and concisely termed it the seed and soil mechanism (SSM) [21]. The main argument for his thoughts was the clinical observation that the individual malignant tumors do not spread the metastases diffusely in all host organs following an even distribution of the tumor cells with the bloodstream, but apparently have points of predilection (e.g., breast carcinoma and bone metastases). The second argument for a seed and soil mechanism is the relative resistance of individual organs and organ systems, respectively, to metastases, such as muscles or spleen. This behavior gives rise to the suspicion that local factors which can prevent the attack of metastases take effect in these organs [5]. Another clinical phenomenon could only be added to these two main arguments in favor of the effectiveness of an SSM in human medicine decades later; the absence of diffuse lung metastases after the placement of a peritoneo-venous shunt in the treatment of malignant ascites [22,23].
For that reason, it was all the more surprising that two studies [24,25] delivered substantial evidence indicating that, with isolated pancreas metastases in renal cell carcinoma (isPM), another clinical entity exists, the development and progression of which can be explained by an SSM.
The assumed great significance of an SSM with isPM [25] was based on the sole chain of proof presuming that the epidemiological studies favored a systemic-haematogenic metastasis route. That again calls for an SSM with isPM, since the exclusive growth of metastases in the pancreas despite a diffuse haematogenous tumor cell spreading requires a tumor cell selection. The objective of the study presented here was therefore to pursue the question as to whether no other unusual behavior patterns could be discovered among the numerous parameters presented for the characterization of isPM, which deliver arguments in favor of an SSM.

2. Results

2.1. History and Literature Compilation

The first description of a singular isPM is from Jenssen [26] from the year 1952; multiple pancreatic metastases in isPM patients were reported for the first time in 1984 [27,28]. In the time following, isPM were observed in very rare cases. Up until 1996, only 66 cases could be found in the literature [29]. That only changed with the progress that was made in pancreas diagnostics, which allowed the more frequent diagnosing of these tumors: In 2006, our working group was able to find as many as 239 reports [24], and 666 by 2016 [25]. By the end of 2018, 148 additional reports were added, which increased the total to 814 reports [24,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195] (440 case records and 374 cases from summaries), which were used for the search for arguments in favor of an SSM.

2.2. Epidemiology and Pathology of isPM

Taken together, it produced the following results: 1. mean age 63.1 years; 2. 46% female, 54% male; 3. metachronous metastases in 93%; 4. interval from tumornephrectomy to manifest pancreatic metastasis 10.1 years (maximum 33 years [104]; 5. multiple metastases 38.1%; 6. Localization: head of pancreas 48%, body 22%, and tail 30%; 7. Grading: G1 16%, 2 64%, G3 20%, G4 0%; 8. cumulative five year survival rate (SVR) 72%.

2.2.1. Histology

Since a standardized histological WHO classification gained acceptance only late in the observation period of over 65 years, only the cases of the last 20 years were analyzed. According to that, isPM are not strictly limited to clear cell renal carcinoma, but were occasionally also reported with the rarer renal carcinoma types: papillary renal carcinoma (N = 3) [172] and chromophobe carcinoma (N = 1) [172]. For that reason, an exclusive preference for one histological type for the occurrence of isPM cannot be deduced from the reports in hand, even though a frequent occurrence of isPM with clear cell renal carcinoma with 96% [172,178] is calculated on the basis of the reports up until now.

2.2.2. Grading

The problem of the observation, the description, and the classification of individual tumor parameters varying across a long period of observation is also true for the grading of isPM. This is aggravated by the fact that a modification of the grading system for the WHO/International Society of Urological Pathology (ISUP) system [196,197] as carried out in 2013. In order to obtain comparable collectives, only those reports for which the classification according to Fuhrman which has been used most frequently in the past years were accepted for the analysis [198]. That was the case with only 137 cases reported in literature. The result of this analysis is shown in Table 1. There are 22 G1 cases compared with 88 G2, 27 G3 cases, and no G4 cases [172,175,183,186] (an undoubtedly G4 case was only reported for the first time in 2019 after completion of the literature research at the end of 2018 [199]).

2.2.3. Singular-Multiple Pancreas Metastases

Since out of 456 sufficiently documented cases (322 case reports and 134 cases in summaries), at least 174 cases (38.1%) were described where multiple metastases developed in the pancreas from the beginning (case reports: N = 127 [24,26,39,44,45,50,52,55,57,60,62,65,67,70,74,79,81,82,86,88,90,92,93,96,97,99,101,102,104,105,106,107,112,113,115,119,120,124,127,131,133,139,141,144,145,146,147,153,158,159,163,166,170,171,182,188,190]; summaries: N = 47 [149,152,155,168,172,175]), this allows for a comparative examination of the multiple with the singular cases.
An average number of 3.1 (SD 1.5) pancreatic foci was determined based on the multiple reports, with up to 7 foci being reported [120,147], and even 14 in an individual case [168]. The results of the comparative analysis (Table 2) show that the two collectives of singular and multiple metastases do not differ significantly with regard to age, frequency of synchronous/metachronous metastases, interval until development of metastases, distribution of the grading levels, and cumulative 5-year SVR (Figure 1).
That is not surprising for factors such as age, synchronous/metachronous, and interval. But this behavior is unexpected and in need of explanation for the parameters of tumor grading and even more for the SVR.
The results of this literature analysis are already confirmed, at least regarding the SVR, by some single-institution reports which analyzed large collectives (N ≥ 20) by risk factors for survival; the four studies [152,172,174,175] confirmed that the presence of singular or multiple pancreas metastases has no significant impact on the SVR.

2.3. Arguments for a SSM in isPM

2.3.1. Metastasis Route and SSM

Since the results in that regard were already previously presented in detail [24,25], the results updated with the new included cases [130,134,143,153,159,165,167,169,170,173,176,182,184,185,186,187,188,189,190,191,192,193,194] are listed here in the form of a summary.
Three potential metastasis routes are specified and discussed in the literature [25]:
  • A local lymphogenic metastasis route [48,88,101,106,150,161,168], where pancreatic metastases are supposed to develop by way of pre-existent or tumor-induced local lymph routes between kidney and pancreas after blockage of the regional lymph nodes by a retrograde lymphatic flow.
  • A local venous spread route, where pre-existent, porto-renal anastomoses [106,157,200,201], or draining, collateral veins of hyper-vascularized tumors [27,48,88,101,106,168]—enabling a tumor cell embolism in the pancreas—and that independently of whether there is a renal vein thrombosis or not [48].
  • The systemic haematogenic metastasis route
An analysis of the literature data produces the following results relevant for the issue of the metastasis route:
(a) Distribution inside the pancreas (Table 3)
Out of 210 sufficiently documented reported cases, 100 (48%) were described in the head, and 110 in the body and the tail area (52%). When that observed distribution is brought in relation to the volume distribution of the pancreas (46% in the head and 54% in the body and the tail [202]), no preference for one side can be found (p = 0.344). The distribution of isPM in the pancreas only correlates with the volume distribution and, consequently, with the blood flow.
(b) Distribution in the pancreas and renal carcinoma side (Table 4)
The distribution pattern of metastases inside the pancreas (head, body, or tail) indicates no dependency on left- or right-side renal carcinoma (p = 0.797), a result which was pointed out by our research as early as 2006 [24], and is now also confirmed by the collective of the casuistic reports published until 2018, and which is meanwhile also confirmed by several single institution reports [150,152,174,175,193].
Both results contradict a high significance of a local metastasis route and, in contrast, support the systemic haematogenic metastasis route. After all, the local-lymphatic route, as well as the local-venous route, should more frequently result in metastases in the nearby head of the pancreas after a right-side renal carcinoma and more frequently in the nearer body and tail area after a left-side renal carcinoma, from which a dependency of the distribution pattern in the pancreas from the location of the primary tumor should result. However, the contrary is the case. The detectable uniform distribution inside the pancreas—and especially its independence from the side of the primary tumor—can only be plausibly explained by a systemic-haematogenous metastatic pathway [24,25,88,147,161,168], since the risk of the development of metastases in all parts of the pancreas is equally high only there.
In addition to this main argument, we found more indications in the literature which argue against a high significance of the local-lymphatic and local-venous metastasis route, but in favor of the systemic route:
a. In general, the lymphatic system is rarely involved with isPM. Regional lymph node metastases were only present at the time of renal carcinoma surgery in 7.1% of the reports communicated [74,150,160,175,176], and at the time of pancreas metastases surgery, paraaortal lymph nodes were reported only once [142], and peripancreatic lymph nodes were found in only 18 of 309 reports (5.8%) [124,152,163,172,174,177]. That makes a great significance of a lymphatic tumor cell transport with isPM seem unlikely. b. A tumorous infiltration of the renal vein stems (category IIIb), condition for a flow reversal in the direction of the pancreas, was only reported in 9.6% [129,145,148,150], which argues against a great significance of tumor infiltration or tumor occlusion of the renal veins, respectively, in the development of isPM. c. Porto-renal anastomoses [200,201] which drain blood from the kidney region in the portal vascular system of the pancreas would, following the hepatopedal bloodstream in the portal vein system, also have to drain this blood with the tumor cells contained in it in the liver—with subsequent liver metastases. That is not the case, since no clustering of metachronous liver metastases is detectable epidemiologically. d. A high significance of a systemic-haematogenic metastatic route, however, emphasises that out of 27 extra-pancreatic, resectable metastases which developed time-wise between renal carcinoma surgery and diagnosis of pancreas metastases, 20 (72%) were undoubtedly of a haematogenic, systemic origin [25,153], and out of the 94 metastases which developed after the resection of the pancreas metastases, 70 (74.1%) were also undoubtedly of a haematogenic-systemic origin [25,130,167,169,170]. Consequently, the predominant number of metastases which were occasionally observed before the development or after the removal of pancreatic metastases are of a systemic haematogenic origin.
In sum, these data make a particular significance of the lymphogenic and local-venous route appear unlikely. By contrast, the systemic-haematogenic route seems to be more significant, since it correlates well with the epidemiological data. This comes, however, at the price that the question as to why—despite systemic-haematogenic spread—clinical manifest metastases develop exclusively in the pancreas remains unanswered [148,154,161,175].

2.3.2. Histology, Grading, and SSM

The study found two relevant peculiarities. On the one hand, the highly specific metastatic pathway is not strictly linked to clear cell renal carcinoma, but was also occasionally observed with the rarer, histological forms [172]. On the other hand, the study shows that this highly specific metastatic behavior of the tumor cells gets lost with the degree of tumor cell de-differentiation; until the end of 2018, there was no G4 observation [172,175,183,186].
Particularities which indicate a special importance of an SSM cannot be deduced from the literature data for histology and grading.

2.3.3. Multiple Pancreas Metastases and SSM

The comparative study of singular and multiple pancreas metastases presented here produced three results which are remarkable for the influence of an SSM:
1. The risk of multiple metastases in the pancreas, which is only 120–180 g, is high at 38.1%—with a simultaneous absence of metastases in other organs.
It shows that multiple tumor cell embolisms undoubtedly occur in the case of isPM. If manifested metastases remain limited to the pancreas despite multiple cell embolisms in the vascular system, however, that can only be explained by an SSM.
2. No different SVR for singular and multiple isPM.
That the SVR with metastasising renal cell carcinoma is influenced by the total tumor mass and therefore also by the number of metastases is to be expected, but it was only examined later in studies. When an effective drug treatment for metastasising renal cell carcinoma became available for the first time with the establishment of targeted therapies [169,203,204,205,206], the question as to prognostic factors gained clinical importance and resulted in corresponding studies. These studies [207,208,209,210], which differ little with regard to patient selection, determination of the tumor burden, and drug treatment show concordantly that the baseline tumor burden correlates significantly negatively with the overall survival time. Regarding the question asked here, this means that shorter SVR are to be expected for patients with multiple pancreas metastases and, consequently, a greater tumor load. However, the literature analysis presented shows—just like five major institution reports [150,152,172,174,175]—a diametrically opposite behavior; singularity or multiplicity of pancreatic metastases has no influence on the SVR.
3. A grading level distribution identical for singular and multiple metastases.
It is a known fact that the risk of tumor cell embolization and the subsequent number of metastases is co-determined by the degree of cell degeneration, i.e., the grading, in case of solid tumors, and that is the methodical reason for the grading of solid tumors. Regarding our question, however, this means that a shift to the higher grading levels should be detectable in the case of multiple metastases. However, the analysis revealed no such shift.
For that reason, the absence of the expected results for grading, and even more for SVR when comparing singular/multiple metastases, requires an explanation. However, the unusual clinical behavior can easily be reconciled with the effect of an exquisite SSM which is maintained over a longer period of time, often over several years. On the one hand, the embolised renal carcinoma cells with isPM have properties which make metastasis of them in the pancreas particularly easy, resulting in multiple metastases, while they cannot settle in the other organs on the other hand. Then, the high 38.1% rate of multiple pancreas metastases are not the consequence of more aggressive primary tumor cells with a larger number of embolized tumor cells, which cannot be reconciled with the non-different grading. The high rate is rather the consequence of a share of tumor cells able to settle in the pancreas which is exquisitely high with isPM. It is not the cell aggressiveness which determines the clinical course, but the exquisite cell adaptation to the pancreas, which is often maintained for years—consequently, a SSM. This SSM makes the non-different SVR plausible as well. In the case of singular as well as multiple metastases, the effect of the high organ specificity is that these cells are not able to metastasise outside of the pancreas and die. Since this mechanism affects tumor cells of singular metastases just like cells of multiple pancreatic metastases, a pattern of metastasis which is strictly limited to the pancreas persists for a prolonged period of time with both types of progression, which explains the consistent SVR after adequate treatment of the pancreatic foci.

3. Discussion

With over 330,000 cases world-wide, renal cell carcinoma is the ninth most common malignant tumor [211], which is already in a stage of generalisation in 20–30% of the patients at the time of diagnosis [171,172,175,211], and even after supposedly radical surgery, 15–25% of the patients develop a stage of generalisation [171,172,183,203] with metastases in lungs, bones, liver, and brain later on [157,178,183,212]. A special characteristic of renal carcinomas is that the disease is characterised by a protracted course in about 20%, with periods of slow tumor growth or stability for many years [144,171,181,212,213]. The exquisitely rare entity of isPM, of which approximatively 800 cases were reported world-wide, is also part of this last-mentioned group. The clinical presentation is typically characterised by a late onset (10 years after primary tumor), often multiple occurrence (38%), and a good prognosis. The only therapeutic option for a long period of time was surgical resection—depending on the metastatic site in the pancreas in the form of duodenopancreatectomy (DP) [26,116,148,171,175,186,193], pylorus preserving DP [120,121,127,131,132,135,137,140,150,174,179,183], distal pancreatectomy [29,116,145,157,181], total pancreatectomy [32,33,139,144,151,186,188], central (midsegment) pancreatectomy [68,121,131,146,147,152,171,175,186,193], or local tumor resections, the role of which is still controversial [25,121,125,146,150,152,158,160,163,172]. With cumulative 5-year survival rates of 43–100% (Table 5) (surgical treatment produced extraordinarily good results for metastasis surgery.
Over the last fifteen years, the medical treatment of metastatic renal cell carcinoma (RCC) has been revolutionized with the introduction of highly effective targeted therapies with multi-tyrosine kinase and mTor inhibitors, and monoclonal antibodies like angiogenesis and immune checkpoint inhibitors [154,169,203,204,205,206,214,215,216]. With these therapeutics, very positive results were achieved with isPM as well [160,178,217,218,219], which were even a match for surgical treatment in a retrospective study [178]. For that reason, the definition of the significance of surgical treatment, drug treatment, and the combination of both in isPM patients has to be the task of future prospective studies [154,160,175,179]. Only a few reports state that no anti-tumor treatment was carried out after the diagnosis “isPM”, and thus reflect the spontaneous progress, were reported. In 2018, a cumulative 3-year SVR of 42% [25] could be determined based on 16 cases. That was significantly worse than the SVR of the patients on whom curative resection was performed, but it is nevertheless an extraordinarily good result for an organ metastasis stage.
The generally good prognosis for patients with isPM clearly emphasises that this entity is not the accidental first manifestation of a directly upcoming stage of generalisation, but a separate, very special type of progression of metastasising renal cell carcinoma.
As the analysis of the literature overview shows, the reported epidemiological regularities (diffuse distribution inside the pancreas, no dependency on the side of the primary tumor, frequent development of undoubtedly haematogenic metastases in reports with extra-pancreatic metastases before or after the development of isPM) can ultimately only be rendered probable by way of a high significance of a systemic, haematogenic metastasis route.
However, the great significance of a systemic, haematogenic metastasis route with isPM deduced from the epidemiological data inevitably brings up the question of why, despite of a systemic haematogenous mode of cell spread manifest, metastases are strictly restricted to the pancreas. After all, the exclusive intravasion of the pancreas, which weighs only 120–180 g, by metastasised renal carcinoma cells by chance is highly unlikely, with the repeated cell embolisms in the scope of multiple metastases to boot. The only currently known mechanism which can explain that in a plausible manner is a SSM, which lets mature metastasising renal carcinoma cells into manifest metastases only in the pancreas, while they cannot develop to metastasis in all other organs.
With the theory of the local lymphogenic/haematogenic metastasis route as well—to which epidemiology assigns only little significance, however—isolated pancreas metastases can, with the simultaneously very rare presence of metastases in the complete tissue crossed by the tumor cells between renal tumor and pancreas (one paraaortal lymph node involvement [142]; only in 7% infiltrated peripancreatic lymph nodes [124,152,163,172,174,177]), also only be explained by a highly specific interaction between tumor cells and pancreas, which allows a maturation into metastases exclusively in the pancreas.
To date, the argumentation for the existence of an SSM for isPM was limited exclusively to conclusions drawn from the systemic-haematogenic metastasis route, which was rendered probable. The presented comparative studies of solitary and multiple metastases deliver a second chain of argumentation independent of the metastasis route for an SSM with isPM: the multiple pancreas metastases observed in 38%, the consistent grading level distribution for isPM with solitary and multiple metastases, and above all, the SVR, which are also consistent. That behavior can also only be plausibly explained by a highly specific SSM, which makes it much easier for these tumor cells to settle in the pancreas and makes it almost impossible in all other organs. Consequently, the disease remains strictly limited to the pancreas with solitary as well as multiple metastases, which results in equally good SVR with multiple as well as singular pancreatic metastases following an adequate “radical” treatment of the pancreas metastases (In context with the unusual clinical behavior of isPM it is noteworthy that a recent clinical investigation [220] revealed a second unexpected behavior of pancreatic metastases from renal cell carcinoma. In patients with multi-organ metastasis from RCC those seem to have an unexpected better outcome, in which the pancreas was affected from metastasis too, when compared with patients with multiorgan metastases but without pancreatic metastases—although the pancreatic metastasis group had a higher median number of affected organ sites than the non-pancreatic metastasis group. This indicates that RCC capable of metastasizing into the pancreas represent a special subgroup of RCC and that detailed molecular studies may provide valuable information on the molecular drivers of tumor progression [220]).
In summary, the study delivers another argument for considering isPM a model entity for the taking effect of an SSM, since the reports about singular and multiple metastases deliver an additional, second chain of argumentation. According to the current state of knowledge, several arguments consequently suggest that this type of metastasis should not exclusively be considered a mechanical tumor cell transport phenomenon, but to regard it as a biochemical tumor cell settlement phenomenon [3].
Limits of the study
It is a retrospective study of casuistic reports, and a hidden bias in the published casuistic reports cannot be excluded on principle. The methodical limitation of an analysis of casuistic reports is already compensated, however—at least as far as the SVR with singular/multiple metastases is concerned—by various high volume single institution reports [152,172,174,175] which confirm the results of the casuistic reports.

3.1. Pathomechanism

The precise biochemical processes involved in the development of isPM are not yet investigated and therefore unknown. Even in extensive overviews, detailed investigations concerning pancreatic metastasis of RCC could not be found [221]. There are, however, studies of more frequent tumor entities that identified some biochemical mechanisms that may also be at work in isPM.

3.1.1. Genetic/Epigenetic Alterations and isPM

Due to the scarcity of isPM, detailed systematic studies on the genetic/epigenetic profile of isPM have, to our best knowledge, not yet been presented. A MEDLINE (PubMed) based literature research thus revealed only one single presentation [222], reporting on two cases of pancreatic metastasis in RCC in which mutation analysis was performed, in order to evaluate the use of moleculary targeted therapies. There are, however, a few publications comparing non-metastatic with metastatic RCC, however these report on metastatic RCC as one group without taking into consideration different distant metastasis sites or the inclusion of pancreatic metastasis. On the one hand, a recent investigation [223] did not address variability between matched primary tumors and metastasis or changes in the genomic of RCC. On the other hand, in a few publications [224,225,226,227,228], reporting on metastatic RCC as one group, it could be proved that the microRNA profile in metastatic RCC differs from non metastatic RCC [225,229], as well as the epithelial-mesenchymal transition associated microRNA/mRNA signature [230] (The number of differently expressed miRNA in metastatic RCC was determined to be 12 [229], 14 [224], 15 [230], 20 [227], and 21 [225], respectively; 11 of these miRNAs were mentioned just in one report: miRNA 10a–p5, 21, 30c–5p, 30e, 31, 130b, 149, 199–5p, 200b, 429, 455; and 10 in two or more reports: miRNA 10b–5p, 30a–3p, 30a–5p, 139–5p, 144, 200a, 200c, 204, 223–3p, 451). In addition, the microRNA expression in distant RCC metastasis differed according to the site of metastasis in lung, bone, and brain [224]. These results reveal a relation between microRNA signature and metastatic potential and distant metastatic site. Whether analogous a special microRNA signature is involved in the isPM phenomenon remains, of course, uncertain, and will have to be established by further investigations.
Furthermore, several investigations have shown the great number of altered miRNA involved in renal cell carcinoma also [228,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248]. These miRNA regulate cancer metastasis also, because of their capacity to inhibit numerous target genes involved in different steps of the metastatic cascade, e.g., EMT [233,241,244,245], migration [234,236,238,240,241,246], and metastasis settlement [231,235,239,242,243]. The variable interactions of all these miRNS in various tumor cells brings about manifold different capabilities for metastasis, which increases the odds that one of the embolized tumor cell exactly “fits” the properties of the target organ (soil)—a necessary prerequisite for the metastatic process.

3.1.2. Organotropism and SSM

The genetic mechanism responsible for this extreme organotropism of the metastatic pattern can naturally not be determined at present. In general, there will be an organ preference during metastasis if steps which require a precisely fitting interaction of tumor cell-specific properties with organ-specific properties occur in the scope of the early multi-stage process of metastasis. At least three such mechanisms are already known:
1. The pre-metastatic niche (PMN) [3,249,250,251,252]. PMN conceptualized as a fertile “soil” conducive to the survival and outgrowth of metastatic seed results from the interaction of three components: (a) Primary tumor derived components (such as tumor-derived secreted factors or tumor-derived exosomes/microvesicles [253,254]), (b) Tumor mobilized bone marrow derived cells (such as myeloid derived suppressor cells [255]), and (c) Organ components of the future host organ, (such as cellular and molecular factors, fibroblasts, endothelium cells of vascular structures, and extracellular matrix) [256,257]. Since properties of the primary tumor, as well as of the host organ, are involved in PMN formation, this results in an organotropism during niche formation, which facilitates later metastasis in the target organ and prevents it in non-target organs, respectively. The ability to provide a PMN is documented for RCC also, by the proof of a PMN in the lung [256]. This study also pointed out the complexity of the process, as only CD105+ tumor stem cells were capable of doing so. The ability to form a PMN in the pancreas, however, is so far not documented for RCC.
2. A successful interaction of a chemokine receptor on the tumor cell surface and a suitable ligand is the prerequisite for the activation of numerous signal transducing pathways, which are critical in cell proliferation, migration, angiogenesis, invasion, and proliferation [1,258]. Since the equipment of the individual tumor cells with chemokine receptors is tumor cell-specific and the type and the level of the ligand are organ-specific, successful interaction is only possible in tissues where cell receptors and ligand match precisely [1,2,3]. For example, breast cancer was found to express the chemokine receptors CXCR4 and CCR7 at high levels. The corresponding ligands on the other hand, CXCL12 and CCL21, are present at elevated levels in lymph nodes, lung, liver, and bone marrow—preferred distant metastatic sites of breast cancer [1,3].
3. Due to the lack of qualified investigations on pancreatic metastasis considerations on the impact of different immunoediting [259] in different distant metastasis sites, creating an organotropism leading to isPM must remain speculative, although conceivable, if one interprets the above-mentioned different miRNA profile at different distant metastatic organ sites as a consequence of cell selectioning process. It is therefore tempting to assume that in isPM in all host organs except the pancreas immune-surveillance detects and correctly eliminates the metastasized tumor cells by natural tumor specific T-cell mediated immune response, or keeps them in a dormant “equilibrium” state [259]. Only in the pancreas (soil) is an immunosuppression present which enables the carcinomas cells to evade immune control and to mature to manifest metastasis. IsPM would thus represent a “single organ deficiency of immune response”. The reasons for this immunosuppression in the pancreas are of course not yet known. In this context, it is worth recalling that the pancreas consists of two different components, an exocrine and an endocrine, and that at the moment it remains unknown whether the metastasis settlement commences in the vascular structures of the exocrine or endocrine component.
Currently, the question as to whether and how these biochemical processes, but also other phenomena still unknown to date, are involved in isPM remains unanswered, and has to remain the task of future research.

4. Materials and Methods

A literature compilation concerning isPM dating up to the end of 2018 was evaluated as to whether 1. The lines of argumentation presented so far are still tenable, and 2. Whether further epidemiological particularities and phenomena which can be explained by an SSM can be proven. Histology, grading, and a comparison of singular versus multiple metastases in isPM were examined and analyzed for correlations with the SSM for that purpose.

4.1. Data Sources

The literature research was based on MEDLINE (PubMed) registry and data on the epidemiology, pathology, and clinical variables i.e., age, sex, site of primary RCC, time to onset of metastatic disease, number, size, and site of metastases and survival time, were collected and analyzed.

4.2. Inclusion and Exclusion Criteria

For the analysis we considered as isPM the very rare observations of metastasising renal carcinoma where solitary or multiple metastases definitely, or at least across a period of years, synchronously, as well as metachronously to RCC, developed exclusively in the pancreas. For the selection of the individual reports, the criterions defined in 2006 (24) were used; e.g., for rating metastases as solitary or multiple, only those reports were considered that specified the number of lesions or that used wording clearly indicative of singularity or multiplicity. For defining the site of the metastatic lesions (head, body, or tail), only solitary isPMs that were unequivocally assignable to a specific part of the pancreas by preoperative imaging, the surgeons report, or the resected specimen were considered. It goes without saying that in a retrospective review, not every report contained data on all variables investigated, thus reducing the number of observations for subset analysis. The actual number of observations that provided information on a given variable was specified [24].

4.3. Statistics

Continuous data are presented as means (standard deviation). Differences were evaluated with the X2test, Fisher’s exact test, and Student’s t-test. Survival was calculated according to the Kaplan–Meier method and differences among subgroups were compared by log-rank test. P < 0.05 was considered significant.

5. Conclusions

IsPM constitute a very rare, well-defined tumor entity, for the development of which a highly developed SSM is responsible with a high probability. Furthermore, the uniform clinical course gives rise to the suspicion that the phenomenon is based on a uniform pathomechanism which remains constant for years. That indicates that genetic investigations would be meaningful to examine the mechanism which causes the exclusive presence of metastases in the pancreas and their absence in other organs, respectively. A clarification of these factors can contribute to a more profound understanding of the complex metastatic process, which is the fundamental requirement for the development of therapeutics which can block the metastatic process.


This research received no external funding.

Conflicts of Interest

The author declares that there is no conflict of interest. There was no funding source for this study.


  1. Chambers, A.F.; Groom, A.C.; McDonald, I.C. Metastasis: Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002, 2, 563–572. [Google Scholar] [CrossRef] [PubMed]
  2. Shibue, T.; Weinberg, R.A. Metastatic colonization: Settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin. Cancer Biol. 2011, 21, 99–106. [Google Scholar] [CrossRef] [PubMed]
  3. Talmadge, J.E.; Fidler, I.J. AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 2010, 70, 5649–5669. [Google Scholar] [CrossRef]
  4. Schluter, K.; Gassmann, P.; Enns, A.; Korb, T.; Hemping-Bovenkerk, A.; Hölzen, J.; Haier, J. Organ specific tumor cell adhesion and extravasion of colon carcinoma cells with different metastatic potential. Am. J. Pathol. 2006, 169, 1064–1073. [Google Scholar] [CrossRef] [PubMed]
  5. Nicolson, G.L. Organ specificity of tumor metastasis: Role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev. 1988, 7, 143–188. [Google Scholar] [CrossRef] [PubMed]
  6. Strell, C.; Entschladen, F. Extravasation of leukocytes in comparison to tumor cells. Cell. Commun. Signal. 2008, 6, 10. [Google Scholar] [CrossRef] [PubMed]
  7. Miles, F.L.; Pruitt, F.L.; van Golen, K.L.; Cooper, C.R. Stepping out the flow: Capillary extravasion in cancer metastasis. Clin. Exp. Metastasis 2008, 25, 305–324. [Google Scholar] [CrossRef] [PubMed]
  8. Gandalovičová, A.; Rosel, D.; Fernandes, M.; Veselý, P.; Heneberg, P.; Čermák, V.; Petruželka, L.; Kumar, S.; Sanz-Moreno, V.; Brábek, J. Migrastatics—Anti-Metastatic and anti-invasion drugs: Promises and challenges. Trends Cancer 2017, 3, 391–406. [Google Scholar] [CrossRef]
  9. Zhang, Q.; Yang, M.; Shen, J.; Gerhold, L.M.; Hoffman, R.M.; Xing, H.R. The role of the intravascular microenvironment in spontaneous metastasis development. Int. J. Cancer 2010, 126, 2534–2541. [Google Scholar] [CrossRef]
  10. Clark, A.; Vignjevic, D. Modes of cancer cell invasion and the role of the microenvironment. Curr. Opin. Cell Biol. 2015, 36, 13–22. [Google Scholar] [CrossRef] [Green Version]
  11. Friedl, P.; Wolf, K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat. Rev. Cancer 2003, 3, 362–374. [Google Scholar] [CrossRef] [PubMed]
  12. Wong, M.S.; Sidik, S.M.; Mahmud, R.; Stanlas, J. Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects. Clin. Exp. Pharmacol. Physiol. 2013, 40, 307–319. [Google Scholar] [CrossRef] [PubMed]
  13. Hedley, B.D.; Chambers, A.F. Tumor dormancy and metastasis. Cancer Res. 2009, 102, 67–101. [Google Scholar]
  14. Luzzi, K.J.; MacDonald, I.C.; Schmidt, E.E.; Kerkvliet, N.; Morris, V.L.; Chambers, A.F.; Groom, A.C. Multistep nature of metastatic efficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastasis. Am. J. Pathol. 1998, 153, 865–873. [Google Scholar] [CrossRef]
  15. Naumov, G.N.; MacDonald, I.C.; Weinmeister, P.M.; Kerkvliet, N.; Nadkarni, K.V.; Wilson, S.M.; Morris, V.L.; Groom, A.C.; Chambers, A.F. Persistence of solitary mammary carcinoma cells in a secondary site: A possible contributor to dormancy. Cancer Res. 2002, 62, 2162–2168. [Google Scholar] [PubMed]
  16. Goss, P.; Allan, A.L.; Rodenhiser, D.I.; Foster, P.J.; Chambers, A.F. New clinical and experimental approaches for studying tumor dormancy: Does tumor dormancy offer a therapeutic target? APMIS 2008, 116, 552–568. [Google Scholar] [CrossRef] [PubMed]
  17. Folkman, J. Angiogenesis. Annu. Rev. Med. 2006, 57, 1–18. [Google Scholar] [CrossRef]
  18. Hynes, R.O. The extracellular matrix: Not just pretty fibrils. Science 2009, 326, 1216–1219. [Google Scholar] [CrossRef]
  19. Killion, J.J.; Fidler, I.J. Therapy of cancer metastasis by tumoricidal activation of tissue macrophages using liposome-encapsulated immunomodulators. Pharmacol. Ther. 1998, 78, 141–154. [Google Scholar] [CrossRef]
  20. Fidler, I.J.; Gersten, D.M.; Hart, I.R. The biology of cancer invasion and metastasis. Adv. Cancer Res. 1978, 28, 149–250. [Google Scholar]
  21. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1889, 1, 99–101. [Google Scholar] [CrossRef]
  22. Gassmann, P.; Haier, J. The tumor cell-host interface in the early onset of metastatic organ colonisation. Clin. Exp. Metastasis 2008, 25, 171–181. [Google Scholar] [CrossRef] [PubMed]
  23. Tarin, D.; Price, J.E.; Kettlewell, M.G.; Souter, R.G.; Vass, A.C.; Crossley, B. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunt. Cancer Res. 1984, 44, 3584–3592. [Google Scholar] [PubMed]
  24. Sellner, F.; Tykalsky, N.; De Santis, M.; Pont, J.; Klimpfinger, M. Solitary and multiple isolated metastases of clear cell renal carcinoma to the pancreas: An indication for pancreatic surgery. Ann. Surg. Oncol. 2006, 13, 75–85. [Google Scholar] [CrossRef] [PubMed]
  25. Sellner, F. Isolated pancreatic metastases from renal cell carcinoma: An outcome of a special metastatic pathway or of a specific tumor cell selection? Clin. Exp. Metastasis 2018, 35, 91–102. [Google Scholar] [CrossRef] [PubMed]
  26. Jenssen, E.A. Metastatic hypernephroma to the pancreas. Acta Chir. Scand. 1952, 104, 177–180. [Google Scholar] [PubMed]
  27. Py, J.M.; Arnaud, J.P.; Cinqualbre, J.; Adloff, M.; Bollack, C. Pancreatic metastases of nephro-epitheliomas. Apropos of 2 cases. Acta Chir. Belg. 1984, 84, 117–121. [Google Scholar] [PubMed]
  28. Skaarup, P.; Jorgensen, T.; Larsen, S. Asynchronous metastasizing renal cell carcinoma associated with progressive immune complex glomerulonephritis and proteinuria. Scand. J. Urol. Nephrol. 1984, 18, 351–356. [Google Scholar] [CrossRef] [PubMed]
  29. Hirota, T.; Tomida, T.; Iwasa, M.; Takahashi, K.; Kaneda, M.; Tamaki, H. Solitary pancreatic metastasis, occuring 8 years after nephrectomy for renal cell carcinoma. Inter. J. Pancreatol. 1996, 19, 145–153. [Google Scholar]
  30. Lawson, L.I.; Holt, L.P.; Rooke, H.W. Recurrent duodenal haemorrhage from renal carcinoma. Br. J. Urol. 1966, 38, 133–137. [Google Scholar] [CrossRef]
  31. Franciosi, R.A.; Russo, J. Renal cell carcinoma metastatic to the pancreas thirteen years following nephrectomy. Mil. Med. 1969, 134, 200–203. [Google Scholar] [CrossRef]
  32. Marquand, J.; Giraud, B.; Maliakas, S. Pancreatic metastasis revealing a kidney neoplasm. J. Urol. Nephrol. 1971, 77, 595–601. [Google Scholar]
  33. Guttman, F.M.; Ross, M.; Lachance, C. Pancreatic metastasis of renal cell carcinoma treated by total pancreatectomy. Arch. Surg. 1972, 105, 782–784. [Google Scholar] [CrossRef] [PubMed]
  34. Gillet, M.; Camelit, G.; Runser, G.; Clement, D. Duodenopancreatic metastasis from a carcinoma of the kidney revealed by digestive haemorrhage treated by cephalic duodeno-pancreatectomy. Chirurgie 1974, 100, 226–230. [Google Scholar] [PubMed]
  35. Hermanutz, K.D.; Sonnenberg, G.E. Late metastasis of a hypernephroid kidney carcinoma to the pancreas with tumor invasion to the duodenum. Fortschr. Röntgenstr. 1977, 127, 595–597. [Google Scholar] [CrossRef] [PubMed]
  36. Saxon, A.; Gottesman, J.; Doolas, A. Bilateral hypernephroma with solitary pancreatic metastasis. J. Surg. Oncol. 1980, 13, 317–322. [Google Scholar] [CrossRef]
  37. Yazaki, T.; Ishikawa, S.; Ogawa, Y.; Takahashi, S.; Nemoto, S.; Rinsho, K.; Kanoh, S.; Kitagawa, R. Silent pancreatic metastasis from renal cell carcinoma. Acta Urol. Jpn. 1981, 27, 1517–1522. [Google Scholar]
  38. Audisio, R.A.; La Monica, G. Solitary pancreatic metastasis occuring 20 years after nephrectomy for carcinoma of the kidney. Tumori J. 1985, 71, 197–200. [Google Scholar] [CrossRef]
  39. Kishimoto, H.; Niumra, Y.; Okamoto, K.; Tsuchie, K.; Yamase, H.; Maeda, S.; Kamija, J.; Hasegawa, H.; Hayakawa, N.; Yamamoto, M. A case of resected renal cell carcinoma with massive pancreatic metastasis. Jpn. J. Cancer Clin. 1985, 31, 91–96. [Google Scholar]
  40. Amamiya, H.; Iizumi, T.; Yazaki, T.; Waku, M.; Yasuda, H.; Takada, T.; Shikata, J.; Nagai, J. A solitary pancreatic metastasis from renal cell carcinoma. Hinyouki Geka 1988, 2, 167–170. [Google Scholar]
  41. Carini, M.; Selli, C.; Barbanti, G.; Bianchi, S.; Muraro, G. Pancreatic late recurrence of bilateral renal cell carcinoma after conservative surgery. Eur. Urol. 1988, 14, 258–260. [Google Scholar] [CrossRef] [PubMed]
  42. Hirano, M.; Douden, K.; Bantou, H.; Sakatoku, M.; Saitoh, H.; Tachikawa, H.; Takizawa, T.; Horigami, K.; Kameya, T.; Nagai, T.; et al. Solitary pancreatic metastasis occuring 10 years after nephrectomy for carcinoma of the kidney. Tan Sui 1988, 9, 233–237. [Google Scholar]
  43. Sharma, S.K.; Kumar, A.; Madhusoodnan, P.; Banerjee, C.; Suri, S.; Dhar, M. Solitary pancreatic metastasis from renal cell carcinoma. A rare metastatic site. Indian J. Cancer 1988, 25, 29–32. [Google Scholar] [PubMed]
  44. Guyenne, C.; Rat, P.; Haas, O.; Baudet, J.G.; Favre, J.P. Triple metastase pancreatique d´un cancer du rein traitee par duodenopancreatectomie subtotale. Presse Med. 1989, 18, 231. [Google Scholar] [PubMed]
  45. Iwanami, M.; Nakayoshi, A.; Yagi, H.; Shimizu, K.; Kimura, K.; Suzuki, K.; Matsumoto, K.; Kai, Y.; Ueno, M.; Sagawa, F. A resected case of the asymptomatic pancreatic metastasis in the body and tail of the pancreas from renal cell carcinoma. J. Jpn. Panc. Soc. 1989, 4, 100–106. [Google Scholar]
  46. Roland, C.F.; Van Heerden, J.A. Nonpancreatic primary tumors with metastasis to the pancreas. Surg. Gynec. Obstet. 1989, 168, 345–347. [Google Scholar]
  47. Simpson, N.S.; Mulholland, C.; Lioe, T.; Spence, R. Late solitary metastatic renal carcinoma in the pancreas. Ulst. Med. J. 1989, 58, 198–199. [Google Scholar]
  48. Strijk, S.P. Pancreatic metastases of renal cell carcinoma: Report of two cases. Gastrointest. Radiol. 1989, 14, 123–126. [Google Scholar] [CrossRef]
  49. Temellini, F.; Bavosi, M.; Lamarra, M.; Quagliarini, P.; Giuliani, F. Pancreatic metastasis 25 years after nephrectomy for renal cancer. Tumori J. 1989, 75, 503–504. [Google Scholar] [CrossRef]
  50. Gohji, K.; Matsumoto, O.; Kamidono, S. Solitary pancreatic metastasis from renal cell carcinoma. Hinyokika Kiyo 1990, 36, 677–681. [Google Scholar]
  51. Terashima, M.; Abe, H.; Suga, K.; Matsuya, F.; Kobayashi, K.; Itoh, S.; Sasaki, R.; Kanno, S.; Tomichi, N. Two cases of renal cell carcinoma metastasized to the pancreas and to the gallbladder. Jpn. J. Gastroenterol. Surg. 1990, 23, 1952–1956. [Google Scholar] [CrossRef]
  52. Furukawa, T.; Hattori, R.; Ohtake, H.; Souma, T.; Kinukawa, T.; Hirai, A.; Kimura, J.; Sakata, T.; Ishii, M.; Hayashi, N.; et al. A resectable case of pancreatic head metastasis from renal cell carcinoma. Hinyouki Geka 1991, 4, 111–114. [Google Scholar]
  53. Kubo, K.; Morita, J.; Mizoe, J.; Ogawa, H.; Irie, G. Renal cell carcinoma metastatic to the pancreas 8 years following nephrectomy. Jpn. J. Clin. Radiol. 1991, 36, 509–512. [Google Scholar]
  54. Nishida, O.; Matsunaga, Y.; Dekigai, H.; Um, S.H.; Hsieh, C.C.; Kimura, F.; Yoshioka, H.; Murakami, M.; Inoue, R.; Murai, A. Three elderly cases of renal cell carcinoma with pancreatic metastasis. Jpn. J. Geriatr. 1991, 28, 392–396. [Google Scholar] [CrossRef] [PubMed]
  55. Oka, H.; Hatayama, T.; Taki, Y.; Ueyama, H.; Hida, S.; Noguchi, M. A resected case of renal cell carcinoma with metastasis to pancreas. Hinyokika Kiyo 1991, 37, 1531–1534. [Google Scholar] [PubMed]
  56. Tabata, T.; Kuroda, Y.; Nishimatsu, S.; Satoh, Y. A resected case of pancreatic tumor metastasized from renal cell carcinoma. J. Jpn. Panc. Soc. 1991, 6, 245–250. [Google Scholar]
  57. Yamamoto, S.; Tobinaga, K.; Taketomi, K.; Kimino, K.; Ashizuka, S.; Kishikawa, M. Pancreatic metastasis of renal cell carcinoma occuring 17 years after nephrectomy. J. Jpn. Soc. Clin. Surg. 1991, 52, 3006–3011. [Google Scholar]
  58. Fujii, M.; Kogawa, T.; Matsuyama, K.; Yamamoto, H.; Kawahito, Y.; Iinuma, S.; Kokura, S.; Takemura, S.; Yoshikawa, T.; Kondo, M.; et al. A case of metastatic renal cell carcinoma to pancreas ten years after nephrectomy. J. Kyoto Pref. Univ. Med. 1992, 101, 589–596. [Google Scholar]
  59. Melo, C.R.; Melo, I.S.; Monteiro, A.Z.; de Mello, E.S. Pancreatic metastasis from renal cell carcinoma. Arq. Gastroenterol. 1992, 29, 110–112. [Google Scholar]
  60. Nakagawa, K.; Tsuchiya, T.M.; Momono, S.; Sasaki, Y.; Sato, T. A case of pancreatic metastasis of renal cell carcinoma. Jpn. J. Gastroenterol. Surg. 1992, 25, 2200–2204. [Google Scholar] [CrossRef]
  61. Rypens, F.; Gansbeke, V.; Lambiliotte, J.; Regemorter, V.; Verhesi, A.; Struyven, J. Pancreatic metastasis from renal cell carcinoma. Br. J. Radiol. 1992, 65, 547–548. [Google Scholar] [CrossRef] [PubMed]
  62. Stankard, C.E.; Karl, R.C. The treatment of isolated pancreatic metastases from renal cell carcinoma: A surgical review. Am. J. Gastroenterol. 1992, 87, 1658–1660. [Google Scholar] [PubMed]
  63. Aikou, S.; Tokura, Y.; Yamafuji, K.; Takahashi, T.; Yoshihide, O.; Kishii, K.; Fujii, S.; Katsumata, K.; Tamiya, M. A resected case of pancreatic metastasis from renal cell carcinoma presenting with acute duodenal bleeding. J. Jpn. Soc. Clin. Surg. 1993, 54, 2666–2672. [Google Scholar] [CrossRef]
  64. Calmes, J.M.; Meyer, A. Pancreatic hypernephroma manifested by a duodenal hemorrhage. Rev. Med. Suisse Romande 1993, 113, 629–631. [Google Scholar] [PubMed]
  65. Ishikawa, T.; Horimi, T.; Majima, K. A resected case of pancreatic tumor metastasized from renal cell carcinoma. A review of 11 cases in the Japanese and 13 cases in the foreign literature. J. Jpn. Soc. Clin. Surg. 1993, 51, 1642–1647. [Google Scholar]
  66. Marcote-Valdivieso, E.; Arlandis, F.; Baltasar, A.; Martinez-Castro, R.; Vierna-Garcia, J. Synchronous pancreatic metastasis of renal carcinoma. Rev. Esp. Enferm. Dig. 1993, 83, 471–473. [Google Scholar] [PubMed]
  67. Nan, Y.; Kuno, N.; Kurimoto, K.; Nakamura, T.; Kobayashi, S. A resected case of pancreatic tumor metastasized from renal cell carcinoma diagnosed by endoscopic biopsy through the main pancreatic duct. Gastroenterol. Endosc. 1993, 35, 1380–1385. [Google Scholar]
  68. Sauvanet, A.; Barthes, T.; Levy, P.; Flejou, J.F.; Delcenserie, R.; Bernades, P.; Belghiti, J. Late pancreatic metastasis from renal cell carcinoma. Pancreas 1993, 8, 742–744. [Google Scholar] [CrossRef] [PubMed]
  69. Takeuchi, H.; Konaga, E.; Harano, M.; Watanabe, K.; Takeuchi, Y.; Hara, M.; Mano, S. Solitary pancreatic metastasis from renal cell carcinoma. Acta Med. Okayama 1993, 47, 63–66. [Google Scholar] [PubMed]
  70. Vergara, V.; Marucci, M.; Marcarino, C.; Brunello, F.; Capussotti, L. Metastatic involvement of the pancreas from renal cell carcinoma treated by surgery. Ital. J. Gastroenterol. 1993, 25, 388–390. [Google Scholar]
  71. Yanagisawa, T.; Nakayama, K.; Kashiwagi, M.; Tanaka, J.; Kashiwagi, T.; Mizusaki, K.; Itoh, A.; Akimoto, H.; Takahashi, T.; Aoki, T.; et al. Three cases of resectable pancreatic metastases from renal cell carcinoma. Geka Shinryo 1993, 35, 651–655. [Google Scholar]
  72. Zugel, N.; Leipprand, F.; Weckermann, D.; Witte, J. Solitary metastasis to the head of the pancreas in hypernephroid carcinoma. Fortschr. Med. 1994, 112, 388–390. [Google Scholar] [PubMed]
  73. Dousset, B.; Andant, C.; Guimbaud, R.; Roseau, G.; Tulliez, M.; Gaudric, M.; Palazzo, L.; Chaussade, S.; Chapuis, Y. Late pancreatic metastasis from renal cell carcinoma diagnosed by endoscopic ultrasonography. Surgery 1995, 117, 591–594. [Google Scholar] [CrossRef]
  74. Fabre, J.M.; Rouanet, P.; Dagues, F.; Blanc, F.; Baumel, H.; Domergue, J. Various features and surgical approach of solitary pancreatic metastasis from renal cell carcinoma. Eur. J. Surg. Oncol. 1995, 21, 683–686. [Google Scholar] [CrossRef]
  75. Onishi, T.; Ohishi, Y.; Iizuka, N.; Suzuki, Y.; Shirakawa, H.; Hatano, T.; Tom, M. Clinical characteristics of 7 renal cell carcinoma patients developing a solitary pancreatic metastasis after nephrectomy. Jpn. J. Urol. 1995, 86, 1538–1542. [Google Scholar] [CrossRef] [PubMed]
  76. Orita, M.; Morita, N.; Hiraoka, H.; Noshima, S.; Takaimashi, T.; Esato, K. A case of resected pancreatic metastasis from renal cell carcinoma 14 years after radical nephrectomy. J. Jpn. Pancreas Soc. 1995, 10, 63–68. [Google Scholar]
  77. Takashi, M.; Takagi, Y.; Sakata, T.; Shimoji, T.; Miyake, K. Surgical treatment of renal cell carcinoma metastases: Prognostic significance. Int. Urol. Nephrol. 1995, 27, 1–8. [Google Scholar] [CrossRef] [PubMed]
  78. Barras, J.P.; Baer, H.; Stenzl, A.; Czerniak, A. Isolated late metastasis of a renal cell cancer treated by radical distal pancreatectomy. HPB Surg. 1996, 10, 51–53. [Google Scholar] [CrossRef]
  79. Palazzo, L.; Borotto, E.; Cellier, C.; Roseau, G.; Chaussade, S.; Couturier, D.; Paolaggi, J. Endosonographic features of pancreatic metastases. Gastrointest. Endosc. 1996, 44, 433–436. [Google Scholar] [CrossRef]
  80. Paz, A.; Koren, R.; Gal, R.; Wolloch, Y. Late solitary pancreatic metastasis from renal cell carcinoma. Isr. J. Med. Sci. 1996, 32, 1319–1321. [Google Scholar]
  81. Chambers, T.P.; Fishman, E.K.; Hruban, R.H. Pancreatic metastases from renal cell carcinoma in von Hippel-Lindau disease. Clin. Imaging 1997, 21, 40–42. [Google Scholar] [CrossRef]
  82. Robbins, E.G.; Franceschi, D.; Barkin, J.S. Solitary metastatic tumors to the pancreas: A case report and review of the literature. Am. J. Gastroenterol. 1996, 91, 2414–2417. [Google Scholar]
  83. Harrison, L.; Merchant, N.; Cohen, A.; Brennan, M. Pancreaticoduodenectomy for nonperiampullary primary tumors. Am. J. Surg. 1997, 174, 393–395. [Google Scholar] [CrossRef]
  84. Adem, C.; Chetritt, J.; Guymar, S.; Bellil, K.; Ladouch-Badre, A.; Benlagha, N.; Bedossa, P. Pancreatic metastasis of a renal adenocarcinoma. Apropos on 2 cases. Ann. Pathol. 1998, 18, 481–483. [Google Scholar]
  85. Altschuler, E.L.; Ray, A. Spontaneous regression of a pancreatic metastasis of a renal cell carcinoma. Arch. Fam. Med. 1998, 7, 516–517. [Google Scholar] [CrossRef]
  86. Butturini, G.; Bassi, C.; Falconi, M.; Salvia, R.; Caldiron, E.; Iannucci, A.; Zamboni, G.; Graziani, R.; Procacci, C.; Pederzoli, P. Surgical treatment of pancreatic metastases from renal cell carcinomas. Dig. Surg. 1998, 15, 241–246. [Google Scholar] [CrossRef]
  87. Gupta, R.K.; Lallu, S.; Delahunt, B. Fine-needle aspiration cytology of metastatic clear-cell renal carcinoma presenting as a solitary mass in the head of the pancreas. Diagn. Cytopathol. 1998, 19, 194–197. [Google Scholar] [CrossRef]
  88. Hashimoto, M.; Watanabe, G.; Matsuda, M.; Dohi, T.; Tsurumaru, M. Management of the pancreatic metastases from renal cell carcinoma: Report of four resected cases. Hepatogastroenterology 1998, 45, 1150–1154. [Google Scholar]
  89. Jingu, K.; Watanabe, K.; Yamamoto, H.; Fujita, Y.; Honda, I.; Watanabe, S.; Nagata, M.; Sugimoto, K.; Watanabe, Y. Surgical treatment of a solitary pancreatic metastasis from renal cell carcinoma: Report of a case. Surg. Today 1998, 28, 91–94. [Google Scholar] [CrossRef]
  90. Merkle, E.M.; Boaz, T.; Kolokythas, O.; Haaga, J.R.; Lewin, J.S.; Brambs, H.J. Metastases to the pancreas. Br. J. Radiol. 1998, 71, 1208–1214. [Google Scholar] [CrossRef]
  91. Sahin, M.; Foulis, A.A.; Poon, F.W.; Imrie, C.W. Late focal pancreatic metastasis of renal cell carcinoma. Dig. Surg. 1998, 15, 72–74. [Google Scholar] [CrossRef]
  92. Z’graggen, K.; Fernandez-del Castillo, C.; Rattner, D.W.; Sigala, H.; Warshaw, A.L. Metastases to the pancreas and their surgical extirpation. Arch. Surg. 1998, 133, 418–419. [Google Scholar]
  93. Augustin, H.; Bacher, H.; Uggowitzer, M.; Ott, A.; Hubmer, G.; Mischinger, H.J. Pancreatic metastases from renal cell carcinoma mimicking insulinomas. BJU Int. 1999, 83, 140–141. [Google Scholar] [CrossRef]
  94. Carucci, L.R.; Siegelman, E.S.; Feldman, M.D. Pancreatic metastasis from clear cell renal carcinoma: Diagnosis with chemical shift MRI. J. Comput. Assist. Tomogr. 1999, 23, 934–936. [Google Scholar] [CrossRef]
  95. Erigushi, N.; Aoyagi, S.; Hara, M.; Miyazaki, T.; Hashino, K.; Imamura, I.; Jimi, A.; Naito, H. A resected case of pancreatic metastasis from primary renal cell carcinoma. Kurume Med. J. 1999, 46, 119–122. [Google Scholar] [CrossRef]
  96. Ng, C.S.; Loyer, E.M.; Iyer, R.B.; David, C.L.; DuBrow, R.A.; Charnsangavej, C. Metastases to the pancreas from renal cell carcinoma: Findings on three-phase contrast-enhanced CT. Am. J. Roentgenol. 1999, 172, 1555–1559. [Google Scholar] [CrossRef]
  97. Sugiyama, M.; Katsura, M.; Yamamoto, K.; Nouchi, W.; Abe, N.; Hatano, N.; Atomi, Y. Pancreatic metastasis from renal cell carcinoma causing massive gastrointestinal bleeding in von Hippel-Lindau disease. Hepatogastroenterology 1999, 46, 1199–1201. [Google Scholar]
  98. Yavascaoglu, I.; Korun, N.; Oktay, B.; Simsek, U.; Ozyurt, M. Renal cell carcinoma with solitary synchronous pancreaticoduodenal and metachronous periprostatic metastases: Report of a case. Surg. Today 1999, 29, 364–366. [Google Scholar] [CrossRef]
  99. Fricke, P.; Schulz, H.U.; Buhtz, P.; Lippert, H. The pancreas as a site of multiple metastases from renal cell carcinoma. Report of one case and review of the literature. Chirurg 2000, 71, 575–579. [Google Scholar] [CrossRef]
  100. Ghavamian, R.; Klein, K.A.; Stephens, D.H.; Welch, T.J.; LeRoy, A.J.; Richards, R.L.; Burch, P.A.; Zincke, H. Renal cell carcinoma metastatic to the pancreas: Clinical and radiological features. Mayo Clin. Proc. 2000, 75, 581–585. [Google Scholar] [CrossRef]
  101. Kassabian, A.; Stein, J.; Jabbour, N.; Parsa, K.; Skinner, B.; Parekh, D.; Cosenza, C.; Selby, R. Renal cell carcinoma metastatic to the pancreas: A single institution series and review of the literature. Urology 2000, 56, 211–215. [Google Scholar] [CrossRef]
  102. Le Borgne, J.; Partensky, C.; Glemain, P.; Dupas, B.; de Kerviller, B. Pancreaticoduodenectomy for metastatic ampullary and pancreatic tumors. Hepatogastroenterology 2000, 47, 540–544. [Google Scholar]
  103. Mehta, N.; Volpe, C.; Haley, T.; Balos, L.; Bradley, E.L.; Doerr, R.J. Pancreaticoduodenectomy for metastatic renal cell carcinoma: Report of a case. Surg. Today 2000, 30, 94–97. [Google Scholar] [CrossRef]
  104. Thompson, L.D.; Heffess, C.S. Renal cell carcinoma to the pancreas in surgical pathology material. Cancer 2000, 89, 1076–1089. [Google Scholar] [CrossRef]
  105. Espinoza, R.; Rossi, R.; Rossi, R.; Rosenberg, H. Metachronous pancreatic metastasis of a renal cell carcinoma: 3 new cases. Rev. Med. Chile 2001, 129, 86–90. [Google Scholar]
  106. Faure, J.P.; Tuech, J.J.; Richer, J.P.; Pessaux, P.; Arnaud, J.P.; Carretier, M. Pancreatic metastasis of renal cell carcinoma: Presentation, treatment and survival. J. Urol. 2001, 165, 20–22. [Google Scholar] [CrossRef]
  107. Hashimoto, M.; Miura, Y.; Matsuda, M.; Watanabe, G. Concomitant duodenal and pancreatic metastases from renal cell carcinoma: Report of a case. Surg. Today 2001, 31, 180–183. [Google Scholar] [CrossRef]
  108. Marusch, F.; Koch, A.; Dietrich, F.; Hoschke, B.; Gastinger, I. A singular late metastasis of renal cell carcinoma in the pancreas. An uncommon pancreatic tumor. Zentralbl. Chir. 2001, 126, 391–395. [Google Scholar] [CrossRef]
  109. Ruibal Moldes, M.; Quintana de la Rosa, J.L.; Farina Perez, L.A.; Tardaguila, F.; Ortiz Rey, J.A.; Zungri Telo, E. Late pancreatic metastasis from renal carcinoma. Acta Urol. Esp. 2001, 25, 122–124. [Google Scholar] [CrossRef]
  110. Scatarige, J.C.; Horton, K.M.; Sheth, S.; Fishman, E.K. Pancreatic parenchymal metastases. Am. J. Roentgenol. 2001, 176, 695–699. [Google Scholar] [CrossRef]
  111. Sohn, T.A.; Yeo, C.J.; Cameron, Y.L.; Nakeeb, A.; Lillemoe, K.D. Renal cell carcinoma metastatic to the pancreas: Results of surgical management. J. Gastrointest. Surg. 2001, 5, 346–351. [Google Scholar] [CrossRef]
  112. Tada, T.; Kobayashi, G.; Noda, Y.; Kimura, K.; Ito, K.; Fujita, N. A resected case with multiple pancreatic metastasis of renal cell carcinoma. Jpn. J. Gastro Enterol. 2001, 98, 1368–1373. [Google Scholar]
  113. Bechade, D.; Palazzo, I.; Desrame, J.; Duvic, C.; Herody, M.; Didelot, F.; Coutant, G.; Algayres, J.P. Pancreatic metastasis of renal carcinoma: Report of three cases. Rev. Med. Intern. 2002, 23, 862–866. [Google Scholar]
  114. Chou, Y.H.; Chiou, H.J.; Hong, T.M.; Tiu, C.M.; Chiou, S.Y.; Su, C.H.; Tsay, S.H. Solitary metastasis from renal cell carcinoma presenting as diffuse pancreatic enlargement. J. Clin. Ultrasound 2002, 30, 499–502. [Google Scholar] [CrossRef] [PubMed]
  115. Eloubeidi, M.A.; Jhala, D.; Chhieng, D.C.; Jhala, N.; Eltoum, I.; Wilcox, C.M. Multiple late asymptomatic pancreatic metastases from renal cell carcinoma: Diagnosis by endoscopic ultrasound-guided fine needle aspiration biopsy with immunocytochemical correlation. Dig. Dis. Sci. 2002, 47, 1839–1842. [Google Scholar] [CrossRef] [PubMed]
  116. Hiotis, S.P.; Klimstra, D.S.; Conlon, K.C.; Brennan, M.F. Results after pancreatic resection for metastatic lesions. Ann. Surg. Oncol. 2002, 9, 675–679. [Google Scholar] [CrossRef] [PubMed]
  117. Lisii, D.; Gaimant, A.; Sautereau, D.; Paraf, F.; Maubon, A. Duodenal bleeding revealing a renal cell carcinoma. Gastroenterol. Clin. Biol. 2002, 26, 1044–1046. [Google Scholar] [PubMed]
  118. Peschaud, F.; Cheynel, N.; Hagry, O.; Tremeaux, J.C.; Rat, P.; Favre, J.P. Surgical treatment of pancreatic metastases from renal carcinoma. Ann. Chir. 2002, 127, 527–531. [Google Scholar] [CrossRef]
  119. Roviello, F.; Nastri, G.; Hako, L.; Marrelli, D.; De Stefano, A.; Cioppa, T.; Pinto, E. Pancreatic metastasis from clear cell carcinoma. Chir. Ital. 2002, 54, 873–877. [Google Scholar]
  120. Yachida, S.; Fukushima, N.; Kanai, Y.; Nimura, S.; Shimada, K.; Yamamoto, J.; Sakamoto, M. Pancreatic metastasis from renal cell carcinoma extending into the main pancreatic duct: A case report. Jpn. J. Clin. Oncol. 2002, 32, 315–317. [Google Scholar] [CrossRef]
  121. Bassi, C.; Butturini, G.; Falconi, M.; Sargenti, W.; Mantovavi, W.; Pederzoli, P. High recurrence rate after atypical resection for pancreatic metastases from renal cell carcinoma. Br. J. Surg. 2003, 90, 555–559. [Google Scholar] [CrossRef] [PubMed]
  122. Giulini, S.; Portolani, N.; Bonardelli, S.; Baiocchi, G.; Zampatti, M.; Coniglio, A.; Baronchelli, C. Distal pancreatic resection with splenic preservation for metastasis of renal carcinoma diagnosed 24 years later from nephrectomy. Ann. Ital. Chir. 2003, 74, 93–96. [Google Scholar] [PubMed]
  123. Hermandez, D.J.; Kavoussi, L.R.; Ellison, L.M. Laparoscopic pancreatectomy for metastatic renal cell carcinoma. Urology 2003, 62, 551. [Google Scholar] [CrossRef]
  124. Law, C.H.; Wei, A.C.; Hanna, S.S.; Al-Zahrani, M.; Taylor, B.R.; Greig, P.D.; Langer, B.; Gallinger, S. Pancreatic resection for metastatic renal carcinoma: Presentation, treatment and outcome. Ann. Surg. Oncol. 2003, 10, 922–926. [Google Scholar] [CrossRef] [PubMed]
  125. Nakagohri, T.; Konishi, M.; Inoue, K.; Nakamura, T.; Kinoshita, T. Partial pancreatic head resection for pancreatic metastasis from renal cell carcinoma. Hepatogastroenterology 2003, 50, 2236–2238. [Google Scholar] [PubMed]
  126. Pecchi, A.; Cesinaro, A.; Torricelli, P. Solitary pancreatic metastasis from renal cell carcinoma. Radiol. Med. 2003, 105, 386–390. [Google Scholar]
  127. Zacharoulis, D.; Asopa, V.; Karvounis, E.; Williamson, R. Resection of renal metastases to the pancreas: A surgical challenge. HPB 2003, 5, 137–141. [Google Scholar] [CrossRef]
  128. Moussa, A.; Mitry, E.; Hammel, P.; Sauvanet, A.; Nassif, T.; Palazzo, L. Pancreatic metastasis: A multicentric study of 22 patients. Gastroenterol. Clin. Biol. 2004, 28, 872–876. [Google Scholar] [CrossRef]
  129. Ninan, S.; Jain, P.; Paul, A.; Menon, K. Synchronous pancreatic metastases from asymptomatic renal cell carcinoma. JOP 2005, 6, 26–28. [Google Scholar]
  130. Sotiropoulos, G.C.; Lang, H.; Liu, C.; Brokalaki, E.I.; Molmenti, E.I.; Broelsch, C.E. Surgical treatment of pancreatic metastases of renal cell carcinoma. JOP 2005, 6, 339–343. [Google Scholar]
  131. Wente, M.N.; Kleeff, J.; Esposito, I.; Hartel, M.; Müller, M.W.; Fröhlich, B.E.; Büchler, M.W.; Friess, H. Renal cancer cell metastasis into the pancreas: A single center experience and overview of the literature. Pancreas 2005, 30, 218–222. [Google Scholar] [CrossRef] [PubMed]
  132. Crippa, S.; Angelini, C.; Mussi, C.; Bonardi, C.; Romano, F.; Sartori, P.; Uggeri, F.; Bovo, G. Surgical treatment of metastatic tumors to the pancreas: A single center experience and review of the literature. World J. Surg. 2006, 30, 1536–1542. [Google Scholar] [CrossRef] [PubMed]
  133. Köhler, K.; Haroske, G.; Ludwig, K. Management of pancreatic metastases from renal cell carcinoma. Report of five cases. Zentralbl. Chir. 2006, 131, 425–428. [Google Scholar] [CrossRef] [PubMed]
  134. Shrikhande, S.V.; Büchler, P.; Esposito, I.; Loos, M.; Büchler, M.W.; Friess, H. Splenic and portal vein thrombosis in pancreatic metastasis from renal cell carcinoma. World J. Surg. Oncol. 2006, 4, 25. [Google Scholar] [CrossRef] [PubMed]
  135. Eidt, S.; Jergas, M.; Schmidt, R.; Siedek, M. Metastasis to the pancreas—An indication for pancreatic resection? Langenbecks Arch. Surg. 2007, 392, 539–542. [Google Scholar] [CrossRef] [PubMed]
  136. Karimi, K.M.; McFadden, D.W. Pancreatic resection for metastatic renal cell cancer to the pancreas. Am. Surg. 2007, 73, 58–60. [Google Scholar]
  137. Maeda, H.; Okabayashi, T.; Nishimori, I.; Kobayashi, M.; Sugimoto, T.; Kohsaki, T.; Onishi, S.; Hanazaki, K. Duodenum-preserving pancreatic head resection for pancreatic metastasis from renal cell carcinoma: A case report. Langenbecks Arch. Surg. 2007, 392, 649–652. [Google Scholar] [CrossRef]
  138. Varker, K.A.; Muscarella, P.; Wall, K.; Ellison, C.; Bloomston, M. Pancreatectomy for non-pancreatic malignancies results in improved survival after R0 resection. World J. Surg. Oncol. 2007, 5, 145. [Google Scholar] [CrossRef]
  139. Aimoto, T.; Uchida, E.; Yamahatsu, K.; Yoshida, H.; Hiroi, M.; Tajiri, T. Surgical treatment for isolated multiple pancreatic metastases from renal cell carcinoma: Report of a case. J. Nippon Med. Sch. 2008, 75, 221–224. [Google Scholar] [CrossRef]
  140. Bahra, M.; Jacob, D.; Langrehr, J.M.; Glanemann, M.; Schumacher, G.; Lopez-Hänninen, E.; Neuhaus, P. Metastatic lesions to the pancreas. When is resection reasonable? Chirurg 2008, 79, 241–248. [Google Scholar] [CrossRef]
  141. Kawakami, H.; Kuwatani, M.; Yamato, H.; Shinada, K.; Hirano, S.; Kondo, S.; Yonemori, A.; Matsuno, Y.; Asaka, M. Pancreatic metastasis from renal cell carcinoma with intraportal tumor thrombus. Inter. Med. 2008, 47, 1967–1970. [Google Scholar] [CrossRef]
  142. Koide, N.; Yokoyama, Y.; Oda, K.; Nishio, H.; Ebata, T.; Abe, T.; Igami, T.; Nimura, Y.; Nagino, M. Pancreatic metastasis from renal cell carcinoma. Results of the surgical management and pathologic findings. Pancreas 2008, 37, 104–107. [Google Scholar] [CrossRef]
  143. Matsutani, T.; Sasajima, K.; Miyamoto, M.; Yokoyama, T.; Maruyama, H.; Yanagi, K.; Matsuda, A.; Kashiwabara, M.; Suzuki, S.; Tajiri, T. Resection of pancreatic metastasis from renal cell carcinoma and an early gastric cancer. J. Nippon Med. Sch. 2008, 75, 41–45. [Google Scholar] [CrossRef]
  144. Schauer, M.; Vogelsang, H.; Siewert, J.R. Pancreatic resection for metastatic renal cell carcinoma: A single center experience and review of the literature. Anticancer Res. 2008, 28, 361–366. [Google Scholar]
  145. Tuech, J.J.; Lefebure, R.; Bridoux, V.; Albouy, B.; Lermite, E.; Le Pessot, F.; Le Blanc-Louvry, I.; Michot, F. Combined resection of the pancreas and inferior vena cava for pancreatic metastasis from renal cell carcinoma. J. Gastrointest. Surg. 2008, 12, 612–615. [Google Scholar] [CrossRef]
  146. Zerbi, A.; Ortolano, E.; Balzano, G.; Borri, A.; Beneduce, A.; Di Carlo, V. Pancreatic metastasis from renal cell carcinoma: Which patients benefit from surgical resection? Ann. Surg. Oncol. 2008, 15, 1161–1168. [Google Scholar] [CrossRef]
  147. Deguchi, Y.; Shimada, K.; Nara, S.; Esaki, M.; Sakamoto, Y.; Kosuge, T.; Hiraoka, N. Pancreaticojejunostomy with invagination of the punched pancreatic remnant after medial pancreatectomy and enucleation for multiple metastases of renal cell carcinoma: Report of a case. Surg. Today 2009, 39, 1086–1090. [Google Scholar] [CrossRef]
  148. Machado, N.O.; Chopra, P. Pancreatic metastasis from renal carcinoma managed by Whipple resection. A case report and literature review of metastatic pattern, surgical management and outcome. J. Pancreas 2009, 10, 13–18. [Google Scholar]
  149. Tanis, P.J.; van der Gaag, N.A.; Busch, O.R.; van Gulik, T.M.; Gouma, D.J. Systematic review of pancreatic surgery for metastatic renal cell carcinoma. Br. J. Surg. 2009, 96, 579–592. [Google Scholar] [CrossRef]
  150. Volk, A.; Kersting, S.; Konopke, R.; Dobowolski, F.; Franzen, S.; Ockert, D.; Grützmann, R.; Saeger, H.D.; Bergert, H. Surgical therapy of intrapancreatic metastasis from renal cell carcinoma. Pancreatology 2009, 9, 392–397. [Google Scholar] [CrossRef]
  151. Hijioka, S.; Hifumi, M.; Mekky, M.; Takekuma, Y.; Kawaguchi, T.; Yokomizo, H.; Sato, T. Total pancreatectomy for metastatic renal carcinoma with marked extension into the main pancreatic duct. Inter. Med. 2010, 49, 557–562. [Google Scholar] [CrossRef]
  152. Konstantinidis, I.; Dursun, A.; Zheng, H.; Wargo, J.; Thayer, S.P.; Fernandez-del Castillo, C.; Warshaw, A.L.; Ferrone, C.R. Metastatic tumors in the pancreas in the modern era. J. Am. Coll. Surg. 2010, 211, 749–753. [Google Scholar] [CrossRef]
  153. Mourra, N.; Arrive, L.; Balladur, P.; Flejou, J.F.; Tiret, E.; Paye, F. Isolated metastatic tumors to the pancreas: Hôpital St-Antoine experience. Pancreas 2010, 39, 577–580. [Google Scholar] [CrossRef]
  154. Ballarin, R.; Spaggiari, M.; Cautero, N.; De Ruvo, N.; Montalti, R.; Longo, C.; Pecchi, A.; Giacobazzi, P.; De Marco, G.; D’Amico, G.; et al. Pancreatic metastases from renal cell carcinoma: The state of the art. World J. Gastroenterol. 2011, 17, 4747–4756. [Google Scholar] [CrossRef]
  155. D’Ambra, M.; Ricci, C.; Casadei, R.; Minni, F. Pancreatic metastasis from renal cell carcinoma. Urologia 2011, 78, 5–8. [Google Scholar] [CrossRef]
  156. Miyao, M.; Naito, S.; Ozono, S.; Shinohara, N.; Masumori, N.; Igarashi, T.; Nakao, M.; Tsushima, T.; Senga, Y.; Horie, S.; et al. Late recurrence of renal cell carcinoma: Retrospective and collaborative study of the japanese society of renal cancer. Urology 2011, 77, 379–384. [Google Scholar] [CrossRef]
  157. Thadani, A.; Pais, S.; Savino, J. Metastasis of renal cell carcinoma to the pancreas 13 years postnephrectomy. Gastroenterol. Hepatol. 2011, 7, 697–699. [Google Scholar]
  158. You, D.; Choi, D.; Choi, S.; Heo, J.; Kim, W.; Ho, C.; Lee, H. Surgical resection of metastasis to the pancreas. J. Korean Surg. 2011, 80, 278–282. [Google Scholar] [CrossRef]
  159. Alzahrani, M.A.; Schmulewitz, N.; Grewal, S.; Lucas, F.V.; Turner, K.O.; McKenzie, J.T.; Sussman, J.J.; Ahmad, S.A. Metastases to the pancreas: The experience of a high volume center and a review of the literature. J. Surg. Oncol. 2012, 105, 156–161. [Google Scholar] [CrossRef]
  160. Firek, P.; Richter, S.; Jaekel, J.; Brehmer, B.; Heidenreich, A. Metastasectomy in renal cell cancer after neoadjuvant therapy with multi-tyrosine kinase inhibitors. Urologe 2012, 51, 398–402. [Google Scholar] [CrossRef]
  161. Hung, J.; Wang, S.; Shyr, Y.; Su, C.; Chen, T.; Wu, C. Resection for secondary malignancy of the pancreas. Pancreas 2012, 41, 121–129. [Google Scholar] [CrossRef]
  162. Katsourakis, A.; Noussios, G.; Hadjis, I.; Alatsakis, M.; Chatzitheoklitos, E. Late solitary pancreatic metastasis from renal cell carcinoma: A case report. Case Rep. Med. 2012, 2012, 464808. [Google Scholar] [CrossRef]
  163. Yazbek, T.; Gayet, B. The place of enucleation and enucleo-resection in the treatment of pancreatic metastasis of renal cell carcinoma. JOP 2012, 13, 433–438. [Google Scholar]
  164. Hata, T.; Sakata, N.; Aoki, T.; Yoshida, H.; Kanno, A.; Fujishima, F.; Motoi, F.; Masamune, A.; Shimosegawa, T.; Unno, M. Repeated pancreatectomy for metachronous duodenal and pancreatic metastases of renal cell carcinoma. Case Rep. Gastroenterol. 2013, 7, 442–448. [Google Scholar] [CrossRef]
  165. Mqirage, M.; Zabala Egurrola, J.; Rodríguez, J.G.; Peña, C.P. Metachronous pancreatic metastasis of renal cell carcinoma: A case report. Can. Urol. Assoc. J. 2013, 7, e460–e461. [Google Scholar] [CrossRef]
  166. Niess, H.; Conrad, C.; Kleespies, A.; Haas, F.; Bao, Q.; Jauch, K.W.; Graeb, C.; Bruns, C. Surgery for metastasis to the pancreas: Is it safe and effective? J. Surg. Oncol. 2013, 107, 859–864. [Google Scholar] [CrossRef]
  167. Espinoza, E.; Hassani, A.; Vaishampayan, U.; Shi, D.; Pontes, J.E.; Weaver, D.W. Surgical excision of duodenal/pancreatic metastatic renal cell carcinoma. Front. Oncol. 2014, 4, 218. [Google Scholar] [CrossRef]
  168. Kimura, Y.; Keira, Y.; Imamura, M.; Ito, T.; Nobuoka, T.; Mizuguchi, T.; Masumori, N.; Hasegawa, T.; Hirata, K. Histopathological aspects of pancreatic metastases in renal cell carcinoma: Does the mode of invasion permit limited resections? Pancreat. Disord. Ther. 2014, 4, 2. [Google Scholar]
  169. Lauro, S.; Onesti, E.C.; Righini, R.; Carbonetti, F.; Cremona, A.; Marchetti, P. A synchronous pancreatic metastasis from renal clear cell carcinoma, with unusual CT characteristics, completely regressed after therapy with sunitinib. Case Rep. Med. 2014, 2014, 473431. [Google Scholar] [CrossRef]
  170. Minni, F.; Casadei, R.; Perence, B.; Greco, V.; Marrano, N.; Margiotta, A.; Marrano, D. Pancreatic metastasis: Observations of three cases and review of the literature. Pancreatology 2014, 4, 509–520. [Google Scholar] [CrossRef]
  171. Moletta, L.; Milanetto, A.C.; Vincenzi, V.; Alaggio, R.; Pedrazzoli, S.; Pasquali, C. Pancreatic secondary lesions from renal cell carcinoma. World J. Surg. 2014, 38, 3002–3006. [Google Scholar] [CrossRef]
  172. Schwarz, L.; Sauvanet, A.; Regenet, N.; Mabrut, J.Y.; Gigot, J.F.; Housseau, E.; Millat, B.; Ouaissi, M.; Gayet, B.; Fuks, D.; et al. Long-term survival after pancreatic resection for renal cell carcinoma metastasis. Ann. Surg. Oncol. 2014, 21, 4007–4013. [Google Scholar] [CrossRef]
  173. Takeshi, A.; Mitsuhiro, I.; Hiromitsu, A.; Naoyuki, Y.; Taiichiro, S.; Hiroki, S.; Takeaki, K.; Tatsuya, S.; Futoshi, O.; Hiroharu, S.; et al. Middle segment-preserving pancreatectomy for recurrent metastasis of renal cell carcinoma after pancreatoduodenectomy: A case report. Case Rep. Surg. 2014, 2014, 3. [Google Scholar] [CrossRef]
  174. Tosoian, J.J.; Cameron, J.L.; Allaf, M.E.; Hruban, R.H.; Nahime, C.B.; Pawlik, T.M.; Pierorazio, P.M.; Reddy, S.; Wolfgang, C.L. Resection of isolated renal cell carcinoma metastases of the pancreas: Outcomes from the Johns Hopkins Hospital. J. Gastrointest. Surg. 2014, 18, 542–548. [Google Scholar] [CrossRef]
  175. Benhaim, R.; Oussoultzoglou, E.; Saeedi, Y.; Mouracade, P.; Bachellier, P.; Lang, H. Pancreatic metastasis from clear cell renal cell carcinoma: Outcome of an aggressive approach. Urology 2015, 85, 135–140. [Google Scholar] [CrossRef]
  176. Chang, Y.H.; Liaw, C.; Chuang, C.K. The role of surgery in renal cell carcinoma with pancreatic metastasis. Biomed. J. 2015, 38, 173–176. [Google Scholar]
  177. Gajendra, S.; Sachdew, R.; Mohapatra, I.; Goel, R.; Goel, S. Metastatic renal cell carcinoma: An unusual cause of bleeding pancreatic mass. J. Clin. Diagn. Res. 2015, 9, 15–17. [Google Scholar] [CrossRef]
  178. Santoni, M.; Conti, A.; Partelli, S.; Porta, C.; Sternberg, C.N.; Procopio, G.; Bracarda, S.; Basso, U.; De Giorgi, U.; Derosa, L.; et al. Surgical resection does not improve survival in patients with renal metastases to the pancreas in the era of tyrosine kinase inhibitors. Ann. Surg. Oncol. 2015, 22, 2094–2100. [Google Scholar] [CrossRef]
  179. Wiltberger, G.; Bucher, J.N.; Krenzien, F.; Benzing, C.; Atanasov, G.; Schmelzle, M.; Hau, H.M.; Bartels, M. Extended resection in pancreatic metastases: Feasibility, frequency, and long-term outcome: A retrospective analysis. BMC Surg. 2015, 15, 126. [Google Scholar] [CrossRef]
  180. Yuasa, T.; Inoshita, N.; Saiura, A.; Yamamoto, S.; Urakami, S.; Masuda, H.; Fujii, Y.; Fukui, I.; Ishikawa, Y.; Yonese, J. Clinical outcome of patients with pancreatic metastases from renal cell cancer. BMC Cancer 2015, 15, 46. [Google Scholar] [CrossRef]
  181. Boussios, S.; Zerdes, J.; Batsi, O.; Papakostas, V.P.; Seraj, E.; Pentheroudakis, G.; Glantzounis, G. Pancreatic resection for renal cell carcinoma metastasis: An exceptionally rare coexistence. Int. J. Surg. Case Rep. 2016, 27, 198–201. [Google Scholar] [CrossRef] [Green Version]
  182. Dong, J.; Cong, L.; Zhang, T.P.; Zhao, Y.P. Pancreatic metastasis of renal cell carcinoma. Hepatobiliary Pancreat. Dis. Int. 2016, 15, 30–38. [Google Scholar] [CrossRef]
  183. Fikatas, P.; Klein, F.; Andreou, A.; Schmuck, R.B.; Pratschke, J.; Bahra, M. Long-term survival after surgical treatment of renal cell carcinoma metastasis within the pancreas. Anticancer Res. 2016, 36, 4273–4278. [Google Scholar]
  184. Miura, T.; Nakamura, N.; Ogawa, K.; Watanabe, Y.; Yonekura, K.; Sanada, T.; Kuwabara, H.; Goseki, N. Resection of pancreatic metastasis from renal cell carcinoma 21 years after nephrectomy. Cancer Chemother. 2016, 43, 2187–2189. [Google Scholar]
  185. Nihei, K.; Sakamoto, K.; Suzuki, S.; Mishina, T.; Otaki, M. A case of pancreatic metastasis of renal cell carcinoma. Cancer Chemother. 2016, 43, 2274–2276. [Google Scholar]
  186. Rückert, F.; Distler, M.; Ollmann, D.; Lietzmann, A.; Birgin, E.; Teoule, P.; Grützmann, R.; Wilhelm, T.J. Retrospective analysis of survival after resection of pancreatic renal cell carcinoma metastases. Int. J. Surg. 2016, 26, 64–68. [Google Scholar] [CrossRef]
  187. Chatzizacharias, N.A.; Rosich-Medina, A.; Dajani, K.; Harper, S.; Huguet, E.; Liau, S.S.; Praseedom, R.K.; Jah, A. Surgical management of hepato-pancreatic metastasis from renal cell carcinoma. World J. Gastrontest. Oncol. 2017, 15, 70–77. [Google Scholar] [CrossRef]
  188. Choi, Y.J.; Lee, J.H.; Lee, C.R.; Han, W.K.; Kang, C.M.; Lee, W.J. Laparoscopic total pancreatectomy for multiple metastasis of renal cell carcinoma of the pancreas: A case report and literature review. Ann. Hepatobiliary Pancreat. Surg. 2017, 21, 96–100. [Google Scholar] [CrossRef]
  189. Ko, S.; Yun, S.; Kim, S.; Kim, T.N.; Seo, H. Pancreatic resection for renal cell carcinoma metastasis: A case review. Ann. Hepatobiliary Pancreat. Surg. 2017, 21, 176–179. [Google Scholar] [CrossRef]
  190. Zianne, M.; Takahashi, N.; Tsujibata, A.; Miwa, K.; Goto, Y.; Matano, Y. Asymptomatic pancreatic metastasis from renal cell carcinoma diagnosed 21 years after nephrectomy. Case Rep. Gastrointest. Med. 2017, 2017, 8765264. [Google Scholar] [CrossRef]
  191. Boni, A.; Cochetti, G.; Ascani, S.; Del Zingaro, M.; Quadrini, F.; Paladini, A.; Diego Cocca, D.; Mearini, E. Robotic treatment of oligometastatic kidney tumor with synchronous pancreatic metastasis: Case report and review of the literature. BMC Surg. 2018, 18, 40. [Google Scholar] [CrossRef]
  192. Limaiem, F.; Bouraoui, S. Metastasis of renal cell carcinoma to the pancreas 11 years post nephrectomy. Pan Afr. Med. J. 2018, 30, 53. [Google Scholar] [CrossRef]
  193. Madkhali, A.A.; Shin, S.; Song, K.B.; Lee, J.H.; Hwang, D.W.; Park, K.M.; Lee, Y.J.; Kim, S.C. Pancreatectomy for secondary metastasis of the pancreas. Medicine 2018, 97, e12653. [Google Scholar] [CrossRef]
  194. Nogueira, M.; Dias, S.C.; Silva, A.C.; Pinto, J.; Machado, J. Solitary pancreatic renal cell carcinoma metastasis. Autopsy Case Rep. 2018, 8, e2018023. [Google Scholar] [CrossRef] [Green Version]
  195. Yamashita, H.; Toyama, H.; Terai, S.; Mukubou, H.; Shirakawa, S.; Ishida, J.; Asakura, Y.; Shimizu, T.; Lee, D.; Tanaka, M.; et al. A patient with multiple pancreatic metastases undergoing total pancreatectomy 18 years after renal cell carcinoma resection. Cancer Chemother. 2018, 45, 2214–2216. [Google Scholar]
  196. Delahunt, B.; Cheville, J.C.; Martignoni, G.; Humphrey, P.A.; Magi-Galluzzi, C.; McKenney, J.; Egevad, L.; Algaba, F.; Moch, H.; Grignon, D.J.; et al. The international society of urological pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am. J. Surg. Pathol. 2013, 37, 1490–1504. [Google Scholar] [CrossRef]
  197. Moch, H. WHO classification 2016 and first S3 guidelines on renal cell cancer: What is important in practice? Pathologe 2016, 37, 127–133. [Google Scholar] [CrossRef]
  198. Fuhrman, S.; Lasky, L.; Limas, C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am. J. Surg. Pathol. 1982, 6, 655–663. [Google Scholar] [CrossRef]
  199. Brozzetti, S.; Sterpetti, A.V. Unexpected prolonged survival after extended and emergent resection of pancreatic metastases from renal cell carcinoma. J. Gastrointest. Cancer 2019. [Google Scholar] [CrossRef]
  200. Loré, J.M.; Madden, J.L.; Gerold, F.P. Pre-existing portocaval shunts. A hypothesis for the bizarre metastases of some carcinomas. Cancer 1958, 11, 24–27. [Google Scholar] [CrossRef]
  201. Saitoh, H.; Yoshida, K.; Uchijima, Y.; Kobayashi, N.; Suwata, J.; Nakame, Y. Possible metastatic routes via portocaval shunts in renal adenocarcinoma with liver metastasis. Urology 1991, 37, 598–601. [Google Scholar] [CrossRef]
  202. Allen-Mersh, T. Significance of the site of origin of pancreatic exocrine adenocarcinoma. J. Clin. Pathol. 1982, 35, 544–546. [Google Scholar] [CrossRef]
  203. Motzer, R.J.; Hutson, T.E.; Tomczak, P.; Michaelson, M.D.; Bukowski, R.M.; Oudard, S.; Negrier, S.; Szczylik, C.; Pili, R.; Bjarnason, G.A.; et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cancer. J. Clin. Oncol. 2009, 27, 3584–3590. [Google Scholar] [CrossRef]
  204. Escudier, B.; Bellmunt, J.; Négrier, S.; Bajetta, E.; Melichar, B.; Bracarda, S.; Ravaud, A.; Golding, S.; Jethwa, S.; Sneller, V. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J. Clin. Oncol. 2010, 28, 2144–2150. [Google Scholar] [CrossRef]
  205. Beck, J.; Bellmunt, J.; Escudier, B. Long-term stable disease in metastatic renal cell carcinoma: Sorafenib sequenced to sunitinib and everolimus: A case study. Med. Oncol. 2011, 28, 1379–1383. [Google Scholar] [CrossRef]
  206. Rini, B.; Escudier, B.; Tomczak, P.; Kaprin, A.; Szczyloik, C.; Hutson, T.E.; Michaelson, M.D.; Gorbunova, V.; Gore, M.E.; Rusakov, I.G.; et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell caarcinoma (AXIS): A randomized phase III trial. Lancet 2012, 378, 1931–1939. [Google Scholar] [CrossRef]
  207. Ishikara, H.; Kondo, T.; Yoshida, K.; Omae, K.; Takagi, T.; Iizuka, H.; Kobayashi, H.; Tanabe, K. Evaluation of tumor burden after sequential molecular-targeted therapy in patients with metastatic renal cancer. Jpn. J. Clin. Oncol. 2017, 47, 226–232. [Google Scholar] [CrossRef]
  208. Iacovelli, R.; Lanoy, E.; Albiges, L.; Escudier, B. Tumour burden is an independent prognosic factor in metastatic renal cell carcinoma. BJU Int. 2012, 110, 1747–1754. [Google Scholar] [CrossRef]
  209. Basappa, N.S.; Elson, P.; Golshayan, A.R.; Wood, L.; Garcia, J.A.; Dreicer, R.; Rini, B.I. The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib. Cancer 2011, 117, 1183–1189. [Google Scholar] [CrossRef]
  210. Stein, W.D.; Huang, H.; Menefee, M.; Edgerly, M.; Kotz, H.; Dwyer, A.; Yang, J.; Bates, S.E. Other paradigms: Growth rate constants and tumor burden determinated using computed tomography data correlate strongly with the overall survival of patients with renal cell carcinoma. Cancer J. 2009, 15, 441–447. [Google Scholar] [CrossRef]
  211. Jonasch, E.; Gao, J.; Rathmell, K.W. Renal cell carcoinoma. BMJ 2014, 349, g4797. [Google Scholar] [CrossRef]
  212. McNichols, D.W.; Segura, J.W.; DeWeerd, J.H. Renal cell carcinoma: Long-term survival and late recurrence. J. Urol. 1981, 126, 17–23. [Google Scholar] [CrossRef]
  213. Dekernion, J.B.; Ramming, K.P.; Smith, R.B. The natural history of metastatic renal cell carcinoma—A computer analysis. J. Urol. 1978, 120, 148–152. [Google Scholar] [CrossRef]
  214. Chara, L.; Rodriguez, B.; Holgado, E.; Ramirez, N.; Fernández-Rañada, I.; Mohedano, N.; Arcediano, A.; García, I.; Cassinello, J. An unusual metastatic renal cell carcinoma with maintained complete response to sunitinib treatment. Case Rep. Oncol. 2011, 4, 583–586. [Google Scholar] [CrossRef]
  215. Mazza, C.; Escudier, B.; Albiges, L. Nivolumab in renal cell carcinoma: Latest evidence and clinical potential. Ther. Adv. Med. Oncol. 2017, 9, 171–181. [Google Scholar] [CrossRef]
  216. Flippot, R.; Escuduer, B.; Albiges, L. Immune checkpoint inhibitors: Toward new paradigms in renal cell carcinoma. Drugs 2018, 78, 1443–1457. [Google Scholar] [CrossRef]
  217. Shatveryan, G.A.; Chardarov, N.K.; Bagmet, N.N.; Ratnikova, N.P.; Bedzhanyan, A.L.; Petrenko, K.N.; Polishchuk, L.O.; Karagyozyan, G.A. Isolated pancreatic metastases of renal cell carcinoma. Khirurgiia 2017, 12, 36–40. [Google Scholar] [CrossRef]
  218. Sbitti, Y.; Debbagh, A.; Slimani, K.; Mahi, M.; Errihani, H.; Ichou, M. When tyrosine kinase inhibitor sunitinib can be discontinued in metastatic renal cell carcinoma to pancreas: A case report. J. Med. Case Rep. 2018, 20, 80. [Google Scholar] [CrossRef]
  219. Medioni, J.; Choueiri, T.K.; Zinzindohoue, F.; Cho, D.; Fournier, L.; Oudard, S. Response of renal cell carcinoma pancreatic metastasis to Sunitinib treatment: A retrospective analysis. J. Urol. 2009, 181, 2470–2475. [Google Scholar] [CrossRef]
  220. Kalra, S.; Atkinson, B.J.; Matrana, M.R.; Matin, S.F.; Wood, C.G.; Karam, J.A.; Tamboli, P.; Sircar, K.; Rao, P.; Corn, P.G.; et al. Prognosis of patients with metastatic cell carcinoma and pancreatic metastases. BJU Int. 2016, 117, 761–765. [Google Scholar] [CrossRef]
  221. Liu, Q.; Zhang, H.; Jiang, C.; Qian, C.; Liu, Z.; Luo, D. Factors involved in cancer metastasis: A better understanding to “seed and soil” hypothesis. Mol. Cancer 2017, 16, 176. [Google Scholar] [CrossRef]
  222. Li, Y.; Zhang, Z.; Zhang, Y.; Yang, J.; Zhu, D.; Li, D.; Zhou, J. Clinical diagnosis and detection of genetic mutations of pancreatic metastases: A report of four cases and review of the literature. Oncol. Lett. 2017, 14, 1017–1024. [Google Scholar] [CrossRef] [Green Version]
  223. De Velasco, G.; Wankowicz, S.A.; Madison, R.; Ali, S.M.; Norton, C.; Duquette, A.; Ross, J.S.; Bosśe, D.; Lalani, A.A.; Miller, V.A.; et al. Targeted genomic landscape of metastases compasred to primary tumours in clear cell metastatic renal carcinoma. Br. J. Cancer 2018, 118, 1238–1242. [Google Scholar] [CrossRef]
  224. Heinzelmann, J.; Unrein, A.; Wickmann, U.; Baumgart, S.; Stapf, M.; Szendroi, A.; Grimm, M.O.; Gajda, M.; Wunderlich, H.; Junker, K. MicroRNAs with prognostic potential for metastasis in clear cell renal cell carcinoma: A comparison of primary tumors and distant metastasis. Ann. Surg. Oncol. 2014, 21, 1046–1054. [Google Scholar] [CrossRef]
  225. Wu, X.; Weng, L.; Li, X.; Guo, C.; Pal, S.K.; Jin, J.M.; Li, Y.; Nelson, R.A.; Mu, B.; Onami, S.H.; et al. Identification of a 4-microRNA signature for clear cell renal carcinoma metastasis and prognosis. PLoS ONE 2012, 7, e35661. [Google Scholar] [CrossRef]
  226. Qi, Y.; Wang, L.; Wang, K.; Peng, Z.; Ma, Y.; Zheng, Z.; Shang, D.; Xu, W.; Zheng, J. New mechanistic insights of clear cell renal carcinoma from integrated miRNA and mRNA expression profiling studies. Biomed. Pharmacother. 2019, 111, 821–834. [Google Scholar] [CrossRef]
  227. Kowalik, C.G.; Palmer, D.A.; Sullivan, T.B.; Teebagy, P.A.; Dugan, J.M.; Libertino, J.A.; Burks, E.J.; Canes, D.; Rieger-Christ, K.M. Profiling microRNA from nephrectomy and biopsy specimens: Predictors of progression and survival in clear cell renal cell carcinoma. BJU Int. 2017, 128, 428–440. [Google Scholar] [CrossRef]
  228. Heinzelmann, J.; Arndt, M.; Pleyers, R.; Fehlmann, T.; Hoelters, S.; Zeuschner, P.; Vogt, A.; Pryalukhin, A.; Schaeffeler, E.; Bohle, R.M.; et al. 4-miRNA score predicts the individual metastatic risk of renal cell carcinoma patients. Ann. Surg. Oncol. 2019. [Google Scholar] [CrossRef]
  229. Yu, L.; Xiang, L.; Feng, J.; Li, B.; Zhou, Z.; Li, J.; Lin, Y.; Lv, Y.; Zou, D.; Lei, Z.; et al. miRNA-21 and miRNA-223 expression singnature as a predictor for lymph node metastasis, distant metastasis and survival in kidney renal clear cell carcinoma. J. Cancer 2018, 9, 3651–3659. [Google Scholar] [CrossRef]
  230. Mlcochova, H.; Machakova, T.; Rabien, A.; Radova, L.; Fabian, P.; Iliev, R.; Slaba, K.; Poprach, A.; Kilic, E.; Stanik, M.; et al. Epithelial-mesenchymal transition associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma. Sci. Rep. 2016, 6, 31852. [Google Scholar] [CrossRef]
  231. Shiomi, E.; Sugai, T.; Ishida, K.; Osakabe, M.; Tsuyukubo, T.; Kato, Y.; Takata, R.; Obara, W. Analysis of expression patterns of microRNAs that are closely associated with renal carcinogenesis. Front. Oncol. 2019, 9, 431. [Google Scholar] [CrossRef]
  232. Yuan, J.; Dong, R.; Liu, F.; Zhan, L.; Liu, Y.; Wei, J.; Wang, N. The miR-183/182/96 cluster functions as a potential carcinogenic factor and prognostic factor in kidney renal clear cell carcinoma. Exp. Ther. Med. 2019, 17, 2457–2464. [Google Scholar] [CrossRef]
  233. Dasgupta, P.; Kulkarni, P.; Majid, S.; Varahram, S.; Hashimoto, Y.; Bhat, N.S.; Shiina, M.; Deng, G.; Saini, S.; Tabatabai, Z.L.; et al. MicroRNA-203 inhibits long noncoding RNA HOTAIR and regulates tumorigenesis through epithelial-to-mesenchymal transition pathway in renal cell carcinoma. Mol. Cancer Ther. 2018, 17, 1061–1069. [Google Scholar] [CrossRef]
  234. Li, Y.; Chen, D.; Su, Z.; Li, Y.; Liu, J.; Jin, L.; Shi, M.; Jiang, Z.; Qi, Z.; Gui, Y.; et al. MicroRNA-106b functions as an oncogene in renal cell carcinoma by affecting cell proliferation, migration and apoptosis. Mol. Med. Rep. 2016, 13, 1420–1426. [Google Scholar] [CrossRef]
  235. Xiao, W.; Wang, X.; Wang, T.; Xing, J. Mir-223-3p promotes cell proliferation and metastasis by downregulating SLC4A4 in clear cell renal cell carcinoma. Aging 2019, 11, 615–631. [Google Scholar] [CrossRef]
  236. Su, Z.; Chen, D.; Zhang, E.; Li, Y.; Yu, Z.; Shi, M.; Jiang, Z.; Ni, L.; Yang, S.; Gui, Y.; et al. MicroRNA-509-3p inhibits cancer cell proliferation and migration by targeting the mitogen- activated protein kinase kinase kinase 8 oncogene in renal cell carcinoma. Mol. Med. Rep. 2015, 12, 1535–1543. [Google Scholar] [CrossRef]
  237. Tong, Z.; Meng, X.; Wang, J.; Wang, L. MicroRNA-212 inhibits the proliferation and invasion of human renal cell carcinoma by targeting FOXA1. Mol. Med. Rep. 2018, 17, 1361–1367. [Google Scholar] [CrossRef]
  238. Gu, C.; Wang, Z.; Jin, Z.; Li, G.; Kou, Y.; Jia, Z.; Yang, J.; Tian, F. MicroRNA-212 inhibits the proliferation, migration ad invasion of renal cell carcinoma by targeting X-linked inhibitor of apoptosis protein (XIAP). Oncotarget 2017, 8, 92119–92133. [Google Scholar] [CrossRef]
  239. He, C.; Chen, Z.Y.; Li, Y.; Yang, Z.Q.; Zeng, F.; Cui, Y.; He, Y.; Chen, J.B.; Chen, H.Q. miR-10b suppresses cell invasion and metastasis through targeting HOXA3 regulated by FAK/YAP signalling pathway in clear-cell renal cell carcinoma. BMC Nephrol. 2019, 20, 127. [Google Scholar] [CrossRef]
  240. Yamasaki, T.; Seki, N.; Yoshino, H.; Itesako, T.; Hidaka, H.; Yamada, Y.; Tatarano, S.; Yonezawa, T.; Kinoshita, T.; Nakagawa, M.; et al. MicroRNA-218 inhibits cell migration and invasion in renal cell carcinoma through targeting caveolin-2 involved in focal adhesion pathway. J. Urol. 2013, 190, 1059–1068. [Google Scholar] [CrossRef]
  241. Ji, S.; Su, X.; Zhang, X.; Han, Z.; Zhao, Y.; Liu, Q. MicroRNA-372 functions as a tumor suppressor in cell invasion, migration and epithelial-mesenchymal transition by targeting ATAD2 in renal cell carcinoma. Oncol. Lett. 2019, 17, 2400–2408. [Google Scholar] [CrossRef]
  242. Li, Y.; Guan, B.; Liu, J.; Zhang, Z.; He, S.; Zhan, Y.; Su, B.; Han, H.; Zhang, X.; Wang, B.; et al. MicroRNA-200b is downregulated and suppresses metastasis by targeting LAMA4 in renal cell carcinoma. EBioMedicine 2019, 44, 439–451. [Google Scholar] [CrossRef] [Green Version]
  243. Zhou, H.; Tang, K.; Liu, H.; Zeng, J.; Li, H.; Yan, L.; Hu, J.; Guan, W.; Chen, K.; Xu, H.; et al. Regulatory network of two tumor-suppressive noncoding RNAs interferes with the growth and metastasis of renal cell carcinoma. Mol. Ther. Nucleic Acids 2019, 16, 554–565. [Google Scholar] [CrossRef]
  244. Wang, M.; Sun, Y.; Xu, J.; Lu, J.; Wang, K.; Yang, D.R.; Yang, G.; Li, G.; Chang, C. Preclinical studies using miR-32-5p to suppress clear cell renal carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling. Int. J. Cancer 2018, 143, 100–112. [Google Scholar] [CrossRef]
  245. Ding, X. MicroRNAs: Regulators of cancer metastasis and epithelial-mesenchymal transition (EMT). Chin. J. Cancer 2014, 33, 140–146. [Google Scholar] [CrossRef]
  246. Wei, R.; Ye, X.; Zhao, Y.; Jia, N.; Liu, T.; Lian, W.; Wei, H.; Zhang, G.; Song, L. MicroRNA-218 inhibits the cell proliferation and migration in clear cell renal cell carcinoma through targeting cancerous inhibitor of protein phosphatase 2A. Oncol. Lett. 2019, 17, 3211–3218. [Google Scholar] [CrossRef]
  247. Chen, X. Expression of microRNA-3133 correlates with the prognosis in patients with clear cell renal cell carcinoma. Medicine 2019, 98, e16008. [Google Scholar] [CrossRef]
  248. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear renal cell carcinoma. Nature 2013, 499, 43–49. [Google Scholar] [CrossRef]
  249. Kaplan, R.N.; Riba, R.D.; Zacharoulis, S.; Bramley, A.H.; Vincent, L.; Costa, C.; MacDonald, D.D.; Jin, D.K.; Shido, K.; Kerns, S.A.; et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005, 438, 820–827. [Google Scholar] [CrossRef]
  250. Sceneay, J.; Smyth, M.J.; Möller, A. The pre-metastatic niche: Finding common ground. Cancer Metastasis Rev. 2013, 32, 449–464. [Google Scholar] [CrossRef]
  251. Liu, Y.; Cao, X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 2016, 30, 668–681. [Google Scholar] [CrossRef]
  252. Peinado, H.; Zhang, H.; Matei, I.R.; Costa-Silva, B.; Hoshino, G.; Rodrigues, G.; Psaila, B.; Kaplan, R.N.; Bromberg, J.F.; Kang, Y.; et al. Pre-metastatic niches: Organ-specific homes for metastases. Nat. Rev. Cancer 2017, 17, 302–317. [Google Scholar] [CrossRef]
  253. Grange, C.; Brossa, A.; Bussolati, B. Extracellular vesicles and carried miRNAs in the progression of renal cell carcinoma. Int. J. Mol. Sci. 2019, 20, 1832. [Google Scholar] [CrossRef]
  254. Wang, L.; Yang, G.; Zhao, D.; Wang, J.; Bai, Y.; Peng, Q.; Wang, H.; Fang, R.; Chen, G.; Wang, Z.; et al. CD103-positive CSC exosomes promotes EMT of clear cell renal carcinoma: Role of remote MiR-19b-3p. Mol. Cancer 2019, 18, 86. [Google Scholar] [CrossRef]
  255. Wang, Y.; Ding, Y.; Guo, N.; Wang, S. MDSCs: Key criminals of tumor pre-metastatic niche formation. Front. Immunol. 2019, 10, 172. [Google Scholar] [CrossRef]
  256. Grange, C.; Tapparo, M.; Collino, F.; Vitillo, L.; Damasco, C.; Deregibus, M.C.; Tetta, C.; Bussolati, B.; Camussi, G. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011, 71, 5346–5356. [Google Scholar] [CrossRef]
  257. Gai, C.; Pomatto, M.A.; Grange, C.; Deregibus, M.C.; Camussi, G. Extracellular vesicles in onco-nephrology. Exp. Mol. Med. 2019, 51, 29. [Google Scholar] [CrossRef]
  258. Walenkamp, A.M.; Lapa, C.; Herrmann, K.; Wester, H.J. CXCR4 ligands: The next big hit? J. Nucl. Med. 2017, 58, 77S–82S. [Google Scholar] [CrossRef]
  259. Münst, S.; Läubli, H.; Soysal, S.D.; Zippelius, A.; Tzankov, A.; Hoeller, S. The immune system and cancer evasion strategies: Therapeutic concepts. J. Intern. Med. 2016, 279, 541–562. [Google Scholar] [CrossRef]
Figure 1. Kaplan–Meier survival curves; solitary versus multiple isolated pancreatic metastases from renal cell carcinoma (p = 0.557).
Figure 1. Kaplan–Meier survival curves; solitary versus multiple isolated pancreatic metastases from renal cell carcinoma (p = 0.557).
Cancers 11 01379 g001
Table 1. Analysis of 814 isolated pancreatic metastases from renal cell carcinoma [24,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195]; N = number of cases with adequate documentation; (standard deviation of mean).
Table 1. Analysis of 814 isolated pancreatic metastases from renal cell carcinoma [24,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195]; N = number of cases with adequate documentation; (standard deviation of mean).
Age (years; N = 349)63.1 (9.7)
Sex (m: f)371: 31854: 46
Synchronous: Metachronous25: 3347: 93
Time to Onset (years; N = 334)10.1 (6.3)
Multiple (N = 456)17438.1
Localization (head, body, tail)99: 46: 61 48: 22: 30
Size (mm; N = 174)37.0 (21.4)
Radical Surgery (N = 477)25654
Grading 1, 2, 3, 4 (N = 137)22: 88: 27: 016: 64: 20: 0
Actuarial 3-year Survival (N = 307) 80
Actuarial 5-year Survival (N = 307) 72
Table 2. Solitary vs. multiple isolated pancreatic metastases renal cell carcinoma (standard deviation of mean).
Table 2. Solitary vs. multiple isolated pancreatic metastases renal cell carcinoma (standard deviation of mean).
Age (years; N = 180/110)63.7 (9.3)62.7 (8.8)n.s. p = 0.706
Synchronous18 (11%)6 (6%)n.s. p = 0.432
Metachronous153 (89%)98 (94%)
Time to Onset (years; N = 143/95)10.1 (6.6)10.0 (6.4)n.s. p = 0.432
Grading (N = 27/23) 17 (24%)4 (26%)n.s. p = 0.670
211 (48%)12 (41%)
39 (28%)7 (33%)
Table 3. Distribution of isPM within the pancreas. Right side = head, left side = body, and tail (N = 210).
Table 3. Distribution of isPM within the pancreas. Right side = head, left side = body, and tail (N = 210).
Side Affected by Metastan%
Right Side10047.6
Left Side11052.4
Table 4. Correlation between side of renal cell carcinoma and site of metastasis within the pancreas (N = 120; p = 0.797).
Table 4. Correlation between side of renal cell carcinoma and site of metastasis within the pancreas (N = 120; p = 0.797).
Site of Pancreatic Metastasis SiteSide Affected by Renal Cell Carcinoma
Table 5. Cumulative 5-year survival rates following surgical treatment of isPM.
Table 5. Cumulative 5-year survival rates following surgical treatment of isPM.
Author, YearN5-yr Survival (%)
Madkhali [193], 20181747
Chatzizacharias [187], 2017771
Fikatas [183], 20161971
Yuasa [180], 20152079
Tosoian [174], 20144252
Schwarz [172], 20146263
Kimura [168], 20141377
Konstandinidis [152], 20102061
Zerbi [146], 20082388
Bahra [140], 20089100
Crippa [132], 2006580
Wente [131], 20051253
Law [124], 20031475
Bassi [121], 20032253
Sohn [111], 20011075
Thomson [104], 20002143

Share and Cite

MDPI and ACS Style

Sellner, F. Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism? Cancers 2019, 11, 1379.

AMA Style

Sellner F. Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism? Cancers. 2019; 11(9):1379.

Chicago/Turabian Style

Sellner, Franz. 2019. "Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism?" Cancers 11, no. 9: 1379.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop