Thyroid cancer has a good prognosis, with 10-year disease-specific survival approaching 98% in Korea.¹⁾ However, a small proportion of patients show poor prognosis with radioiodine refractoriness. Sorafenib, an oral multi-target tyrosine kinase inhibitor (MTKI), has been approved and used in radioiodine refractory differentiated thyroid cancer (RR-DTC).²⁾ However, like other MTKIs, sorafenib causes many adverse events and decrease quality of life. Although most patients’ symptoms of adverse events resolved after the initial stage of MTKI therapy, the longer is the patient exposure to sorafenib for advanced thyroid cancer, the more likely are chronic adverse events.³⁾

Among adverse events associated with sorafenib, acute pancreatitis is rare but sometimes detectable due to symptoms such as abdominal or back pain and concomitantly increased serum amylase and lipase levels.⁴⁾ Sorafenib might induce pancreatitis by inhibiting vascular endothelial growth factor receptor (VEGFR), exposing the pancreas to ischemia and affecting acinar cells in the pancreas.

Several cases of acute pancreatitis induced by sorafenib during cancer treatment are known,⁵⁾ but there have been no cases of secondary pancreatic cancer, in thyroid cancer patients on sorafenib.

Here we present the case of a long-term sorafenib user with thyroid cancer who newly developed pancreatic adenocarcinoma accompanied by background chronic pancreatitis. Clinicians should remain alert for potential occurrence of secondary pancreatic cancer, a deadly disease, associated with sorafenib use.

A 60-year-old male patient visited our outpatient cancer clinic due to aggravated abdominal and back pain, which began two months prior. Twenty years ago he was diagnosed with 5-cm sized papillary thyroid carcinoma on right lobe with extensive lymph node metastasis. After total thyroidectomy and lymph node dissection (stage IVa [T3N1bM0] on AJCC TNM stage 7th edition), he received radioiodine remnant ablation. Seven years later, recurrent neck lymph node metastases were found, along with scattered lung metastasis. Postoperative pathology of large recurrent neck lymph nodes invading jugular vein showed papillary thyroid carcinoma, classic type with hobnail features. Despite repeated high-dose radioiodine therapies (totally 530 mCi), his metastatic lung nodules were on progression, suggesting radioiodine-refractory differentiated thyroid carcinoma. Since then, he had been on sorafenib 400 mg twice per day (total, 800 mg per day) for five and a half years, showing partial response of metastatic lung tumors (Fig. 1). He had tolerated the medication well without serious adverse events during long-term sorafenib use. There was no specific disease history except dyslipidemia, which had been controlled by one tablet of 10 mg pitavastatin per day. The patient has no family history of cancer or inflammatory disease other than type 2 diabetes (mother). He denied drinking alcohol and smoking.

At the time of presentation, serum amylase and lipase levels were 98 U/L (reference range, 28-100 U/L) and 224 U/L (13.0-60.0 U/L), respectively, and white cell count was normal (Table 1). Enhanced abdominal computed tomography (CT) revealed a 5.2 cm focal, non-enhancing, mass-like lesion in the pancreatic distal body area (Fig. 2A), and positron emission tomography (PET)/CT showed focal hypermetabolic uptake in the same area (Fig. 2B). An endoscopic biopsy confirmed pancreatic adenocarcinoma. Upon reviewing yearly serial follow-up abdominal CT under sorafenib, we confirmed that there was no evidence of remarkable inflammation or a mass-like lesion in the pancreas until nine months before presentation. However, a slight increase in serum amylase within the reference was detected 3 months before surgery (Table 1).

The patient underwent radical antegrade modular pancreatosplenectomy (RAMP), and left nephrectomy, and left adrenalectomy for suspicious invasive lesions and accompanying inflammation in the left kidney and left adrenal gland to treat the newly developed pancreatic mass (Fig. 3).

The postoperative pathology showed the pancreatic mass to be a moderately differentiated adenocarcinoma on the background of chronic pancreatitis with fibrosis and fat necrosis (Fig. 4A-4D), indicating pancreatic cancer with chronic pancreatitis. The removed left kidney showed chronic inflammation with fibrosis and fat necrosis from Gerota’s fascia to the perirenal fat (Fig. 4E, 4F).

Two months after surgery, the patient underwent adjuvant chemotherapy with gemcitabine and capecitabine, which he tolerated well. No further treatment was applied for the slowly progressive metastatic papillary thyroid carcinoma, although we planned regular follow-up imaging.

This is the first report of newly developed pancreatic adenocarcinoma in a patient with radioiodine-refractory metastatic thyroid cancer treated with standard-dose sorafenib for more than five years. We readily recognized that the pancreatic mass was not a secondary metastatic tumor derived from progression of advanced papillary thyroid carcinoma due to the patient’s stable serum thyroglobulin level, a reliable serum tumor marker of thyroid cancer. However, it is difficult to confirm whether this pancreatic adenocarcinoma was induced by long-term sorafenib use or occurred as a double primary cancer due to the predisposing genetic background without connection to sorafenib. Acute and chronic pancreatitis have been reported during MTKI therapy in many cancers,⁵⁾ but pancreatic cancer is noted only sporadically as a secondary malignancy.

Pancreatic cancer usually shows aggressive behavior with an overall 5-year survival rate of less than 5%, although 20% of patients present with localized or potentially resectable tumors.⁶⁾ Therefore, early detection of secondary malignancy like pancreatic cancer is crucial to improve prognosis without interference due to underlying primary malignancy.

Acute pancreatitis, a rare adverse event induced by sorafenib, usually occurs within several weeks to months after initiation of sorafenib, so the long-term effects of sorafenib on the pancreas remain unknown. One previous report suggested that sorafenib induces atrophic changes of the pancreas, with a mean pancreatic volume loss of 25% in 95% of patients with hepatocellular carcinoma.⁷⁾ Such atrophic change might be due to the anti-angiogenic properties of sorafenib, leading to reduced microvasculature in both tumor and normal tissue.⁸⁾ However, our patient did not show atrophic changes of the pancreas due to sorafenib in follow-up serial CT scans several years before the occurrence of pancreatic cancer. Therefore, acute or subacute pancreatitis can occur in a relatively short period under sorafenib treatment, and new pancreatic cancer might follow this event. The postoperative pathology confirmed widespread peripancreatic inflammation in other organs, including the kidney and spleen, which suggests that newly developed pancreatic cancer can occur under the indirect influences of sorafenib.

However, another study of resected primary pancreatic cancer showed that thyroid cancer (mostly papillary carcinoma) is the fourth most common metachronous cancer of primary pancreatic cancer, after stomach, colorectal, and lung cancers.⁹⁾ Therefore, the newly developed pancreatic cancer in our case might present a double primary cancer comparable to primary thyroid cancer rather than the long-term effects of sorafenib. As for prognosis, metachronous pancreatic cancer patients have similar survival time to those diagnosed with pancreatic cancer only.⁹⁾ Additionally, several previous studies confirmed that sorafenib is not effective as a single agent or combination therapy with other antitumor agents to treat pancreatic cancers.^10,11)

We cannot identify a causal relationship between use of MTKI, such as sorafenib and newly developed pancreatic cancer, based on contradictory evidence described above. As a single case report cannot confirm this hypothesis, further mechanistic study will be needed to clarify this association.

Our patient has been under active surveillance due to multiple lung metastases of thyroid cancer. One of the most challenging treatment issues is whether to use sorafenib again in a patient with secondary pancreatic cancer, which was excised entirely and further treated by adjuvant intravenous combinatorial chemo-therapy.

If a patient with thyroid cancer under long-term use of sorafenib shows elevated serum pancreatic enzymes with symptomatic abdominal pain or back pain, clinicians should keep in mind that a rare but fatal pancreatic cancer with background pancreatitis is one of the possible clinical events.