Renal cancer is reported to be among the top 15 most common cancer types worldwide. Even though mortality rates can vary between different countries, the average incidence is approximately 10 cases per 100,000. Fortunately, these statistics have been shown to steadily decline over the years, as a response to the development of high-quality treatment options. As mentioned above, the presence of metastatic sites can change the patient’s survival chances dramatically. Specifically, even though localized tumors can present with a survival rate of up to 90%, distant metastases and limited spread are connected with 12% and 72.5% respectively.[4]

In general, it should be noted that the presence of metastases on the pancreas are considered a rare site, which makes up less than 3% of total pancreatic malignancies.

The severity of such cases is also supported by the fact that any type of tumor is able to present a secondary malignancy on the pancreas. According to autopsy and surgical databases, primary tumors from lymphomas, carcinomas of the stomach, kidney, lung, and GI tract are more commonly responsible for pancreatic metastases.[5] Other scientific reviews that were conducted, presented detailed percentages of the different type of metastatic site origins. Specifically, the most frequent was renal cancer, at 62%, then non-small-cell lung cancer, followed by melanoma. Other, but not so common, malignancies which have been observed to give metastatic sites on the pancreas are thyroid, ovarian, hepatocellular carcinomas, and prostate.[6,7]

It should be remembered that secondary metastatic malignancies on the pancreas can be present with more than one pattern. Precisely, in 5-10% of patients, numerous small nodules, which merge occasionally into a larger mass, can be reported. The depletion of these nodules is heavily dependent on the histological type of the primary tumor. Moreover, another morphological display, present in 15-44% of patients, is observed through a diffuse infiltration of the pancreas, resulting in an indirectly enlarged organ. Finally, the third pattern, found in 50-75% of patients, is described as a singular mass with an infrequent hypodense focus on the contrast-enhanced CT.[8,9]

Diagnosis of dangerous medical entities is always characterized as crucial due to the necessity to manage and treat the abnormality as soon as possible. Thus, diagnosis of metastasis on the pancreas must be executed with carefulness and caution. In general, suspicion arises from the history of a relevant primary cancer. Majority of secondary pancreatic malignancies are observed through a CT, which takes place in patients who undergo follow-up examinations after a primary tumor. Other than the use of CT, dynamic contrast-enhanced CT, Magnetic Resonance Imaging (MRI), contrast-enhanced ultrasonography, and Endoscopic Ultrasonography (EUS), can also be helpful in discovering the metastatic site.[7] Each imaging technique presents with each own advantages, as well as display characteristics, which must be taken into consideration before analyzing each image. Thus, in Ultrasound imaging, the metastatic sites are described as hypoechogenic masses inside the pancreatic parenchyma, while cysts are not really observed. Even after a negative CT scan, EUS may be able to identify and depict the presence of secondary metastatic malignancies on the pancreas. Furthermore, EUS-guided Fine-Needle Aspiration (FNA) is also another possible diagnostic technique, which can prove helpful in locating metastases from different primary tumors.[10] The introduction of a technologically advanced imaging technique, called Contrast-Enhanced Ultrasonography (CEUS), has provided significant advancements in locating pancreatic lesion or characterizing malignancies already noticeable with the US. This imaging method offers better results, when dealing hyper-vascular tumors, such as renal cell cancer, hepatocellular carcinoma, and neuroendocrine tumors.[11] Moving on, MR imaging depicts the lesions as hypointense, when compared with normal gland tissue on T1-weighted images. On the other hand, T2-weighted images display the lesions with heterogenous or relatively hyperintense signal.[7] Appropriate imaging and careful diagnosis is extremely significant in metastases from renal cell carcinomas, since they present with strong enhancement both on the CT and MRI. This observation can be explained through the hypervascularity of the viable tumor tissue, while also being the main differential diagnostic feature from the hypo vascular pancreatic adenocarcinoma. Therefore, in such cases early scanning, after intravenous contrast administration is advised.[12] Despite the fact that solitary metastatic sites from renal cell carcinoma are the most common type, the presence of multifocal lesions is not rare, especially in cases of lung cancer or colonic cancer metastases.

Differential diagnosis is critical when managing such cases, due to the similarities with other independent diseases. Specifically, understanding and identifying the differences between secondary pancreatic tumors and primary pancreatic adenocarcinomas can be challenging. Primarily, the use of CT is not able to identify small differences in attenuation between nonnecrotic or non-cystic neoplastic tissue and normal tissue of the pancreas. This observation is considered critical when dealing with metastatic nodules, which do not modify the physiological contour of the pancreas.[9] Additionally, differentiation between non-hyperfunctioning islet cell carcinoma and other metastatic tumors that do not look similar to the common ductal type of pancreatic adenocarcinoma, can be quite demanding. In cases of renal cell carcinoma, both diseases share a lot of common elements, morphologically as well as in imaging features. Both types of malignancies are characterized as hyper-vascular, while also being subject to central necrosis and cystic degeneration.[7]

Patients may develop epigastric abdominal pain or acute pancreatitis following the ductal obstruction from the metastatic lesion, or be completely asymptomatic. Other clinical signs, such as GI bleeding or painless jaundice after biliary obstruction, can be the result of either metastatic sites or primary pancreatic tumors. In cases where patients present renal cell carcinoma, the triad of flank pain, palpable mass and gross hematuria is a classic symptom that is only present in 10% of newly diagnoses cases.[13]

As far as prognosis of the patient is concerned, statistics heavily depend on a variety of factors that can impact the survival rates. Precisely, the execution of surgical management of solitary pancreatic metastases that originate from malignancies, other that renal cell carcinoma, present with a poor prognosis. Around 2-6% of patients who are reported to have metastatic renal cell carcinoma, are also observed to have isolate metastatic sites, “susceptible” to surgical resection. This type of operation on secondary lesions, limited to the pancreas, is reported to have a 5-year survival rate of 29-35%. Moreover, the presence of an extended waiting period between the appearance of metastatic sites and the implementation of nephrectomy, typically results in a better prognosis. The fact that the involvement of lymph nodes around the pancreas is an uncommon site, radical lymph node dissection can easily be avoided.[14,15]

Treatment and management of pancreatic metastases is widely considered as an interesting medical challenge that requires attention, caution and a multifaceted approach. Precisely, there is not enough confidence in the potential benefit of surgical treatment, whereas surgical resection is considered as a safe option for patients with isolated metastatic sites. Even though long-term survival is not common, surgery should be considered in the multimodality approach to this case.[16] In specific cases of renal cell cancer as the primary tumor, complete resection of the secondary lesions can be achieved with a low complication rate. It should be noted that survival rate is a complicated topic, where not sufficient data are available at the moment. It is thought that the number of metastases, as well as the size of the lesion heavily impact the chances of survival.[7] In patients with advanced renal cell carcinoma, the provision of sunitinib showed promising results, while also being effective in pancreatic metastases. These reports create controversy, when dealing with patients with metastatic renal cell carcinoma on the pancreas, regarding the difference in benefit between anti-angiogenic agents and aggressive surgical resection. Finally, the provision of adjuvant therapy, chemotherapy, immunotherapy and radiation therapy, after the execution of surgical resection, has presented disappointing results. However, new data regarding the benefit of molecular targeted therapy for renal cell carcinoma have been promising.[17]

In a recent study, Duarte et al., combined and analyzed data regarding major characteristics of metastatic renal cell carcinoma. Among the multiple findings, great emphasis should be given on the future of treatment and management methods.

Scientists believe that the key point in developing a new treatment pathway is to take advantage of the metastatic tumor’s needs of an established blood supply. Thus, instead of inhibiting the angiogenesis of the secondary malignancy, an alternative approach is to target the existing tumor blood supply networks. Renal cell carcinoma’s metastatic sites on the pancreas have been reported to present with increased angiogenesis and enhancement for PBRM1 mutations, while also having decreased BAP1 mutations and a physiological stroma.[18] In another study, which examined patients with renal cell carcinoma metastases on multiple locations, the data supported the idea that pancreatic secondary lesions had greater PBRM1 modifications, in comparison to the other types.

The completion of another statistical analysis of 31 cases with renal cell carcinoma metastases to the pancreas depicted that these types of patients have prospective sensitivity to anti-angiogenic therapeutic agents, along with a significant resistance to Immune Checkpoint Inhibitors. Genomic analysis of the secondary malignancies on the pancreas showed augmented rates of PBRM1, ALK, and NTRK3 mutations, while also having decreased rates of BAP1, MTAP, CDKN2A mutations, low PD-L1 positivity.[19]

Therefore, the fact that metastatic sites on the pancreas have a less immunogenic phenotype, it is suggested that the inclusion of VEGFR treatment may be more beneficial compared to Immune-Oncologic therapy.[19]

Our presentation of the two case reports provides critical insight regarding the medical management of two patients who presented with metastatic renal cell carcinoma to the pancreas. As mentioned above, such medical cases are extremely uncommon and dangerous. Thus, the inclusion and description of such instances offers unique and rare medical knowledge regarding the diagnosis, treatment and outcome of these type of patients. The detailed description of the histological examinations, as well as the inclusion of imaging figures, contributes in the better understanding of the morphology, as well as the clinical display of this significant disease.