Why Did This Cancer Metastasize to the Pancreas?

— Although very aggressive, regular CT follow-up can make a difference

by Kate Kneisel, Contributing Writer, MedPage Today January 19, 2021

A 63-year-old woman presents to a hospital urology clinic in Dammam, Saudi Arabia, for her surveillance check-up, having been diagnosed 8 years previously with clear-cell renal cell carcinoma (CCRCC) of the right kidney.

At the time of her diagnosis in 2012, clinicians performed a metastatic workup including computed tomography of the chest, abdomen, and pelvis (CT-CAP) which did not identify any evidence of distant metastasis. After consultation with the hospital's multidisciplinary tumor board, clinicians successfully performed a right radical nephrectomy and there were no complications.

Now, eight years later at the patient's regular follow-up surveillance appointment, CT-CAP reveals a 1 cm, hypervascular mass in the body of the pancreas, which clinicians suspect is a metastasis.

The patient reports that she has had no symptoms, that her appetite is good and she has not lost weight, and she has had no fever, night sweats, abdominal pain, nausea, vomiting, or diarrhea.

Physical examination reveals a symmetrical abdomen with a visible right-flank scar from the previous excision of her right kidney, and palpation finds her abdomen to be soft and lax, with no tenderness.

After consultation with the surgeons, the patient undergoes a distal pancreatectomy that preserves the spleen. Final histopathology confirms that the lesion is metastatic CCRCC, with positive immunohistochemistry staining of paired-box gene 8 and CD19. The World Health Organization/International Society of Urologic Pathology nuclear grade is 2, and clinicians find no evidence of lymphovascular or perineural invasion and the resection margins are negative.

The patient recovers well, with no postoperative complications, and she is discharged home in good condition. She continues to receive regular follow-up checks, and her most recent CT-CAP performed at 1 year postoperatively shows no evidence of recurrence or metastasis.

Discussion

Clinicians presenting this case of a woman who presents for her surveillance check-up 8 years after a right radical nephrectomy for RCC with asymptomatic metastasis to the pancreas note that metastasis to this site is extremely rare. When invasion of the organ does occur, however, it is usually aggressive, with survival dependent on the stage of the tumor; extended regular follow-up with CT scan is recommended.

RCC is an aggressive tumor that originates within the renal cortex and accounts for about 3% of all malignancies, with CCRCC among the most common subtypes. Because patients are often asymptomatic or have nonspecific symptoms, about 25%–30% of RCC patients are diagnosed incidentally when patients are undergoing imaging studies for other reasons.

RCC's dynamic lymphatic drainage makes it difficult to predict the likely location of metastases, which may involve virtually any organ site, the case authors explain. For example, one review suggests that the most common distant RCC metastasis sites are the lungs (50%-60%), bone (30-40%), liver (30%-40%), and brain (5%), followed less often by the head, gastrointestinal viscera, lymph nodes, and adrenal glands.

Primary metastasis of RCC to the pancreas accounts for only about 2%-5% of all metastases, with females slightly more likely to be affected, the case authors note. The cancer's typical slow growth means that metastasis to the pancreas may occur up to a decade after radical nephrectomy -- hematogenous metastasis of the original RCC lesion is known to occur through drainage of the collateral veins. Retrograde lymphatic spread can occur through the retroperitoneal nodes.

RCC metastases may occur as a solitary or multifocal lesion. Since positron emission tomography scan during the surveillance period may miss a multifocal lesion, the case authors advise maintaining a high index of suspicion even in the absence of radiological findings suggesting multifocality.

In most patients, RCC metastases to the pancreas are slow growing and remain asymptomatic until the late stages, although presentation of large tumors may be marked by abdominal pain, weight loss, bleeding, and obstructive symptoms in cases of duodenal invasion. As well, 40% of symptomatic patients have paraneoplastic syndrome.

Physical exam findings are generally unremarkable, although a palpable abdominal mass may be detected in some patients. Thus, as noted, most of metastases to the pancreas are found incidentally or during radiological follow-up, which may lead to misdiagnosis in patients with no clinical signs or symptoms.

The case authors cite the following RCC diagnostic imaging modalities:

• Endoscopic ultrasound: able to detect small isodense lesions that may not be evident on CT scan and magnetic resonance imaging (MRI)

• Ultrasound: may show lesions as hypoechoic or cystic

• CT scan: the most accurate modality for assessing the extent of metastasis

• MRI: optimizes the ability to differentiate between primary and secondary metastatic tumors, as does CT scan

Because the pancreas is hypervascular, interpretation of pathological biopsies is difficult and therefore rarely contribute to diagnosis of RCC metastatic to the pancreas, although a biopsy may be required when surgical intervention is not possible, the authors note.

While data have linked pancreatic resection with high rates of postoperative complications such as acute pancreatitis and pancreatic leak, recent advances in pancreatic surgeries and postoperative care have helped decrease surgical complications. Outcomes depend on the origin and isolation of the tumor, and isolated pancreatic lesions should be resected whenever technically possible, the authors advise.

Recommended surgical approaches are based primarily on whether the metastasis is solitary or diffuse and on the lesion's location on the pancreas, as well as the patient's performance status, comorbidities, and preferences.

A report cited by the case authors that included 19 patients with RCC metastatic to the pancreas found a mean time to diagnosis of 10.2 ± 27.1 years after the resection of the primary tumor using the Whipple procedure, distal pancreatectomy, or total pancreatectomy.

Almost half of the patients in that study had a mean survival of 46.7 ± 36 months, while 55.6% were alive at 52.2 ± 26.3 months, with overall survival rates at 1, 3, and 5 years of 89%, 80%, and 71%, respectively; surgical resection is associated with a 5-year survival rate of 54%-75%.

The case authors note that the past response of RCC metastases to chemotherapy and radiation therapy has improved since treatment with tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin inhibitors and vascular endothelial growth factor inhibitors have replaced the previous generation of standard therapies, and while this has contributed to a 10% positive response rate, the development of resistance to these therapies is still high.

The Memorial Sloan Kettering Cancer Center model for risk stratification of cancer advises that treatment selection be based on the type of malignancy, whether it is a CCRCC or non-CCRCC, and whether the patient did or did not receive treatment.

The recommended first-line treatment for previously untreated patients with favorable or intermediate prognosis is sunitinib or bevacizumab plus interferon alpha, while those for whom first-line treatment failed can receive high-dose interleukin-2 and those with poor prognosis can have temsirolimus as first-line therapy or sunitinib as second-line.

Moreover, patients who received previous treatment of cytokines can have sorafenib as first-line or sunitinib as second-line, and those who had multitargeted therapy can have everolimus as first-line therapy and TKI as second-line, the authors said.

Conclusion

They conclude that while RCC metastasis to the pancreas is extremely rare given its typically aggressive nature, regular long-term follow-up with CT scan is advised. Survival is highly dependent on tumor stage, and surgical intervention results in a good outcome in most cases.