4.1 Key findings
Although novel findings and innovations are made in clinical treatments, surgery for PmmRCC is still part of mainstream treatment. The following problems are still encountered in PmmRCC treatment: (1) difficulty in a precise preoperative diagnosis of PmmRCCs, distinguishing them from pNETs using the current diagnostic techniques; (2) choices of treatment methods: radical surgery or targeted therapy; (3) difficulties in deciding whether to perform lymphadenectomy; and (4) whether minimally invasive, especially robot-assisted, surgeries and local excisions can confer beneficial outcomes. The outcomes of PmmRCC cases are dependent the clinical experience of the physician; therefore, different physicians performing different treatments will lead to different outcomes (Table 4) (4, 11, 18-23). In our cohort, we employed surgical methods for treating PmmRCC. Our study showed satisfactory long-term overall survival outcomes and presented our perspective of lymphadenectomy.
4.2 Comparison with similar research
An accurate preoperative diagnosis is essential to determining a suitable treatment method. Considering the lower prevalence of pancreatic metastasis of liver, lung, bone, or brain metastasis and the long metastatic time between the primary nephrectomy and the metastatic site resection (4, 11, 18–23), accurate diagnoses can be challenging. Enhanced CT is the preferred imaging technique in abdominal examinations, as it can provide detailed information about the tumour's anatomical structure as well as its surrounding area, including the condition of the vasculature. According to our results, most pNETs and PmmRCCs appeared hyper-vascular on CT images, leading to difficulty in distinguishing between them (Figures 1a and 5). Furthermore, there are no specific tumour markers that can be used to aid in differential diagnoses. Therefore, the combined use of enhanced CT and tumour markers cannot completely overcome the above problems. Our results suggest that previous nephrectomy, hyper-vascular appearance on imagining, multiple lesions in the pancreas, and a larger tumour size could further support the diagnosis of RCC metastasis. Moreover, from the experiences of our imaging specialists, pNETs develop slowly, and even those which are small can be easily detected if patients receive regular follow-up CT examinations after primary nephrectomy, which is also consistent with the significantly older age of PmmRCC patients.
Furthermore, several other diagnostic techniques and methods have seen recent use. Some researchers report that biochemical markers such as chromogranin A and NSE can help diagnose neuroendocrine tumours (24, 25). However, our results regarding NSE are contrary to this, and chromogranin A is not a routine preoperative examination item in our centre. In addition, the relative percentage of washout in CT may be helpful (26). Furthermore, pNETs are more conspicuous in earlier phases of enhancement in enhanced CT compared to enhancement appearing in the venous and balance phases in PmmRCCs (27). Fine-needle biopsy is also recommended as a pathological diagnostic standard in many large centres globally (28), and it may be the most direct and accurate method we can apply to the current clinical diagnosis. Positron emission tomography CT (PET-CT) is another imaging diagnostic tool that can help identify the tumours’ properties and systematic metastasis. 68Ga-DOTATATE PET-CT is often used in diagnosing pNETs. Although some studies have reported differences in the molecular imaging of somatostatin receptors between the pNETs and PmmRCC (29), they still share many similarities and are difficult to distinguish (30). Consequently, there are few direct diagnostic guidelines, and a medical history of renal malignancies continues to be clinically significant.
Patients could benefit from surgery for PmmRCC with an acceptable surgical co-mortality. According to EAU guidelines (5), RCC surgery is curative if the entire tumour burden can be removed; this goal is achievable for PmmRCC treatments if patients present with single or oligometastatic diseases and are amenable to surgery. Therefore, based on the findings of our current study and some previous studies, we believe that resection may be a viable option for long-term survival (Table 4). Conversely, a recent systematic review (31) also showed encouraging 3-year and 5-year survival rates. Some studies, however, suggest that targeted therapy is preferable (7), and surgical resection only leads to a low percentage of disease-free patients with no improved survival compared with that of tyrosine kinase inhibitor therapy. As a result, further research should be carried out to identify the role of surgery in treating PmmRCC.
From our perspective, surgical resection is most often performed because it is difficult to properly identify the tumour characteristics preoperatively, and some patients present with symptoms such as jaundice and abdominal discomfort. Considering the pancreatic anatomy and the symptoms caused by tumours, such as bile drainage disorders, surgery is likely to be more effective than drug therapy alone for PmmRCC. In contrast, in many countries, such as China, tyrosine kinase inhibitors and immune checkpoint inhibitors are still not fully covered by medical insurance, and radical surgery can provide progression-free periods and reduce patients’ economic burdens.
PmmRCC is not a typical pancreatic tumour type; thus, there are few guidelines available regarding the standard scope and methods of surgery. No data have clearly demonstrated which candidates should undergo lymphadenectomy for RCC, and many urologists have abandoned lymph node dissection for its lack of proven benefit (32, 33). In PmmRCC, some studies demonstrate the same lymph node result of a low rate of lymph node involvement (4, 11, 19), while others show contrasting results (20, 22, 23). In Schwarz’s report, lymph node involvement was statistically associated with poor overall survival, and Tosoian’s study showed no significant lymph node findings, with only increased hazard ratios for mortality (4, 22). However, in Lee’s study, the result is contrary to this, with neither hazard ratio nor statistical differences (11).
In view of the low prevalence of lymph node metastasis in RCC (33), we suspect it may not be the leading cause of mRCC formation, and further investigation is required. In line with the management of localized diseases in the EAU guidelines, our previous approach included lymphadenectomy supported by preoperative imaging and intraoperative detection of lymph node metastases (5). In our centre, the results of lymph node involvement and long-term survival further support the feasibility of our previous treatment strategy, and we are more inclined to forego lymphadenectomy to reduce surgical risks if there is no suspicion of lymph node metastasis. However, different centres have different points of view. Although several previous studies reported no oncological benefits regarding lymphadenectomy, lymph nodes are an independent location of the disease, and lymph node metastasis should be evaluated before surgery, as it has a negative prognostic impact. Thus, diagnosing enlarged lymph nodes using CT or MRI scans is important. Preoperative pathological confirmations, such as using biopsies for enlarged lymph nodes, may be the most useful method. However, considering the deep location of abdominal lymph nodes and the complicated anatomy of the pancreas, many oncological results are hard to achieve, and biopsies are sometimes dangerous, especially for the No.16 lymph nodes. Furthermore, different routes of spreading have been discussed, and according to our results and those of previous reports (4, 9), there has been no established relationship between the primary nephrectomy (right or left) and the location of the metastatic lesion within the pancreas, which can help explain the regional lymphatic route and support extended lymphadenectomy. Therefore, hematogenous spread is more probable, and the high frequency of extra-pancreatic tumours at the time of diagnosis (31) further supports this theory. Tumour cells have a high affinity for the pancreatic parenchyma in which they mature and form metastases. Thus, no matter what theory is determined, the necessity of extended lymph node dissection remains controversial; further large-cohort studies are required to investigate whether lymphadenectomy for PmmRCC can be beneficial to increase overall survival.
The issue of surgical methods is of primary importance to surgeons once PmmRCC resections have been determined. Our centre employed open and minimally invasive surgical approaches, especially robot-assisted, to treat PmmRCC. Several studies regarding robotic-assisted versus open surgeries have been published to point out postoperative outcomes for typical pancreatic tumours in our centre (34, 35). Our cohort also included cases of atypical excisions for malignant PmmRCC, such as enucleation; according to one study, these have similar effects to partial surgeries in T1 RCC (36). Furthermore, some researchers believe the use of standard or atypical resection was also not a determining factor (31), and they had been applied at a high rate in some centres (18, 31). Whether such atypical resection methods share similar survival outcomes in metastatic RCC deserves further investigation. However, due to the limited sample size we have not reached a final consensus.
4.3 Limitations
There are some limitations to this study. First, preoperative assessment was limited to the accuracy in preoperative diagnosis of PmmRCC, especially as it is challenging to distinguish this rare tumour type from other tumours. New technologies and guidelines are likely to be introduced in the near future. Second, this study was designed as an observational study. The incidence of pancreatic mRCC is extremely low, and although this study was one of the largest single-centre studies, the sample size was still small, and the endpoints were insufficient to allow further statistical analysis. Previous studies noted that risk factors such as symptoms at diagnosis, a short metastatic interval after primary nephrectomy, and extra-pancreatic tumours could lead to increased recurrence and a poorer prognosis (9). However, the tumour number and size in the pancreas did not influence long-term survival outcomes (9, 37). Finally, this was a single-centre, retrospective study. However, as surgery is not mentioned in PmmRCC treatment guidelines, it has not been widely accepted for clinical application. Therefore, we conducted this retrospective study to determine the early results. We found low postoperative mortality rates, and long-term survival was foreseeable. Based on these satisfactory results, multicentre, prospective clinical studies are ongoing.
4.4 Implications and actions needed
Although many studies have suggested that mRCC leads to poor prognosis and the effects of surgery are questionable, a recent study (38) pointed out that pancreatic metastasis appeared to be an indolent factor in mRCC behaviour as demonstrated by a statistically higher median overall survival, which is in accordance with our patients’ outcomes. These findings suggest that PmmRCC may represent a less aggressive tumour phenotype in all mRCC. Furthermore, two new groups should be added to improve the study and identify the surgical role: (1) PmmRCC vs. other metachronous mRCCs whose primary sites have been resected, and (2) only surgeries vs. only drug therapies in treating PmmRCC. Alternatively, the study baseline should be unified and based on data from centres in the same area to reduce confounding factors and avoid selection bias.