Dr. Prasad Wagle
HPB Surgeon

INTRODUCTION:

Metastasis to the pancreas is usually associated with extensive disease and a dismal prognosis. Resection is recommended only in cases of isolated metastasis. Eighty percent of resections reported for metastasis to the pancreas result from four primary cancer types: renal cell carcinoma, colorectal carcinoma, sarcoma and melanoma1,2. Pancreatic metastasis from renal cell carcinoma presents synchronously with wide spread metastatic disease in 12% of cases and therefore surgical resection may not be favorable^2,3. However, the overall 5 year survival for a solitary metastasis in the pancreas treated with resection ranges between 43 and 88 %^1-4.

Histology revealed metastatic clear cell carcinoma, arranged in varying-sized alveolar aggregates (Figure 2). The tumour cells showed clear cytoplasm and mild to moderate nuclear pleomorphism, (Furhman’s nuclear grading I/II.) Immunohistochemistry studies confirmed a metastatic renal cell carcinoma (cytokeratin, Epithelial Membrane Antigen (EMA), vimentin and Clustered Designate (CD) 10 positive) with a proliferative index of 4%.

A final diagnosis of metastatic clear cell renal cell carcinoma in the head of the pancreas was reached. The surgical margins were free of tumor. No lymph nodal (LN) metastasis was detected. Patient has remained well till his last follow-up.

DISCUSSION:

The pancreas is a rare site of solitary metastasis but it is often involved in diffuse metastatic disease. For all sites included, synchronous metastases from RCC occur in 25-30% and metachronous metastases in about 40% of patients⁵ . The incidence of metastases from primary renal cell carcinoma to pancreas ranges from 0.5 to 3%^2-4, lung being the most common⁵ . Metastasis often presents many years after a nephrectomy^{2- 5}

A case of this nature has been previously reported from India on one occasion⁶ . In a review of

literature in 236 cases of isolated pancreatic metastasis of RCC, Sellner et al³ reported 35% of these patients to be asymptomatic with others presenting with symptoms of abdominal pain (20%), GI bleeding (20%), obstructive jaundice (9%), weight loss (9%) and pancreatitis and diabetes (3%) each. The patients are usually asymptomatic. Usually, the symptoms arise when the tumor increases in size. The median tumor diameter in the asymptomatic subgroup was reported to be 25mm (range: 14 - 48mm) as compared to 45mm in symptomatic group⁴ .

The mode of spread can either be hematogenous or via lymphatics with direct spread to the pancreas being unusual. Spread through lymphatics may occur by retrograde lymph flow secondary to tumor infiltration of the retroperitoneal lymph nodes. Haematogenous spread may occur along the collateral vein of a hyper vascular renal tumor with or without associated renal vein thrombosis⁷ .

Sellner et al³ , reported that pancreatic metastasis occurred in all parts of pancreas irrespective of whether the renal cell carcinoma was from the right or the left kidney. They were not able to find normal and abnormal lymphatics and venous communication between renal cell carcinoma and pancreas³ . They also failed to find a relationship between the site of isolated pancreatic metastasis and the site of primary renal cell carcinoma3 . This favours hematogenous systemic spread but is not able to explain a preference for pancreatic metastasis as compared to other organ metastasis. One explanation is that the tumor cell biology that had a high affinity for the parenchyma of the pancreas and supported by the finding of late metachronous metastasis in the residual pancreas³ .

Surgical resection of primary renal cell carcinoma and metastatic deposits remains the most effective treatment since the chemotherapy, radiotherapy and hormonal therapy have proven ineffective^2,8. A solitary resectable metastasis of an RCC or multiple metastases confined to one organ are the suitable surgical candidates⁵ . Resection involves a standard pancreaticoduodenectomy or a distal pancreatectomy, majority of the times, but a median or extended pancreatectomy may be carried out if indicated depending upon the location of secondary deposit with or without resection of the inferior vena cava (IVC) when the IVC is involved by the metastatic tumor^{5, 9}.

Atypical resection such as duodenum preserving pancreatic head resection, median pancreatectomy and enucleation of the tumor has been adopted on the basis of the fact that these lesions are well encapsulated. A relatively good prognosis has been observed in the absence of spread to lymph nodes and in local recurrence^2,4. Bassi et al⁴ , adopting a policy of atypical resection, observed a 29% rate of pancreatic recurrence (5 out of 17 cases). 22.3% of patients show widespread disease at surgery for suspected isolated RCC metastasis to the pancreas and 17.1% develop extra-pancreatic recurrence after resection⁵ .

However, others feel that, since the frequency of multiple metastasis is often more than 2 (average 3.2), the choice of a standard or an atypical procedure is then probably less important than a careful search for multiple metastasis² . Pancreatic metastases intraoperatively are detected by a combination of complete pancreatic mobilisation, careful manual palpation and intraoperative ultrasonography. Multifocal pancreatic metastasis

has been reported to be in the range of 20-45%^{2- 4}. Zerbi et al² reported an increase in multifocality from 17.4% to 34.8% on pathological examination of resected specimens.

Surgical treatment of isolated pancreatic metastasis from neoplasms other than renal cell carcinoma carries a poor prognosis as they signal the onset of disseminated metastatic disease³ . The outcome of isolated pancreatic metastasis from renal cell carcinoma is clearly superior with a mean 5 year survival ranging from 43 to 88% which is even better than that of primary adenocarcinoma of pancreas^{2, 3}

Tanis et al⁵ , systematically reviewed more than 400 patients with pancreatic metastases from RCC. Factors associated with favorable prognosis include a long disease-free interval, preferably more than 2 years, after resection of primary tumor, a single, asymptomatic, metastatic deposit with central necrosis and complete excision of the secondary deposit with histologically negative margins in a candidate fit to undergo pancreatic surgery. Previous surgeries to excise isolated metastasis at extra pancreatic sites should not be an exclusion criterion^{5, 7}

Some have reported that the tumor grade of pancreatic metastasis correlated with the grade of the primary renal cell carcinoma. The tumor grade was a predictor of survival with a median survival of 41 months for grade II and 10 months for grade III cancer¹ .

The overall 24 and 60 month survival probabilites are reported to be 0.84 and 0.53, respectively, in patients who underwent resection⁴ . Corresponding values of survival probability at 24 and 60 months in patients treated conservatively were 0.53 and 0.26, and the difference between the two groups was significant (p=0.040)⁴ . Reddy et al¹ noted that, the 5 year survival rate was 80% from the time of the pancreatic metastatectomy in seven out of eleven studies whereas Tanis et al, noted that the 2 and 5 year disease free survival rates after resection of pancreatic RCC metastases were 76% and 57%⁵ . The overall survival rates were 80.6% and 72.6% respectively⁵ .

Immunoreactive cytokines used for metastatic renal cell carcinoma earlier are now being replaced by systemic agents, such as bevacizumab, sunitinib, temsirolimus and sorafenib which have shown promising results in phase III trials¹⁰. Sorafenib prolonged progression free survival in patients with advanced renal cell carcinoma¹¹. However, treatment is associated with toxic effects including diarrhea, rash, fatigue, head and foot skin reaction and occasionally hypertension and cardiac events11. In the presence of extra pancreatic recurrence, improved survival rates have been achieved (5 year survival rate of 88%) by combination of pancreatic resection and use of immunotherapy² . Also, in cases showing an aggressive growth pattern i.e. a

short disease free interval from the primary RCC or a short interval between sequentially resected metastases, a probable recommendation is to start on systemic therapy and restage after a couple of months⁵ , surgery being considered in patients in remission or with stable disease. Systemic therapy may also be considered in cases of extra pancreatic disease at exploration or as a neoadjuvant therapy in locally unresectable disease⁵ .

REFERENCES:

1. Reddy S, Wolfgang CL. The role of surgery in the management of isolated metastases to the pancreas. Lancet Oncol. 2009 Mar;10(3):287- 93.
2. Zebri A, Oatolano E, Balzano G, et al. Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection? Ann Surg Oncol. 2008 Apr;15(4):1161-8.
3. Sellner F, Tykalsky N, De Santes M, et al. Solitary and multiple isolated metastasis of clear cell renal cell carcinoma to the pancreas: an indication for pancreatic surgery. Ann Surg Oncol. 2006 Jan;13(1):75-85.
4. Bassi C, Butturini G, Falconi M, et al. High recurrence rate after atypical resection for pancreatic metastasis from renal cell carcinoma. Br J Surg. 2003 May;90(5):555-9.
5. Tanis PJ, van der Gaag NA, Busch OR, et al. Systematic review of pancreatic surgery for metastatic renal cell carcinoma. Br J Surg. 2009 Jun;96(6):579-92.
6. Shukla RC, Pathak R, Senthil S. Pancreatic metastases of renal cell carcinoma--case report. Nepal Med Coll J. 2008 Dec;10(4):275-7
7. Law CH, Wei AC, Hanna SS, et al. Pancreatic resection for metastatic renal cell carcinoma: presentation, treatment and outcome. Ann Surg Oncol. 2003 Oct;10(8) :922-6.
8. David AW, Samuel R, Eapen A, et al. Pancreatic metastasis from renal cell carcinoma 16 years after nephrectomy: a case report and review of the literature. Trop Gastroenterol. 2006 Oct-Dec;27(4):175-6.
9. Tuech JJ, Lefebure B, Bridoux V, et al. Combined resection of the pancreas and inferior vena cava for pancreatic metastasis from renal cell carcinoma. J Gastrointestinal Surg. 2008 Mar;12(3):612-5.
10. Ravaud A, Wallerand H, Culine S, et al. Update on the medical treatment of metastatic renal cell carcinoma. Eur Urol. 2008 Aug;54(2):315-25.
11. Escudier B, Eisen T, Stadler WM,et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan;356(2):125-34.