A Newly Developed Pancreatic Adenocarcinoma in a Patient with Advanced Thyroid Cancer under Long-Term Sorafenib Use

Min Ji Kim; Han-Sang Baek; Sung Hak Lee; Dong-Jun Lim

doi:10.11106/ijt.2021.14.2.175

Int J Thyroidol 2021;14(2):175-179

Published online November 30, 2021; https://doi.org/10.11106/ijt.2021.14.2.175

Min Ji Kim¹, Han-Sang Baek², Sung Hak Lee³ and Dong-Jun Lim²

Division of Endocrinology and Metabolism, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea¹, Incheon, Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea², Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea³, Seoul, Korea

Correspondence to: Dong-Jun Lim, MD, PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea
Tel: 82-2-2258-6009, Fax: 82-2-599-3589, E-mail: ldj6026@catholic.ac.kr

Received June 10, 2021; Revised August 4, 2021; Accepted August 5, 2021.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract: Sorafenib, an oral multi-target tyrosine kinase inhibitor (MTKI) for treatment of radioiodine-refractory differentiated thyroid cancer can induce acute or chronic pancreatitis as an adverse event. However, there have been no reports of pancreatic cancer associated with MTKI, especially among long-term MTKI user. A 60-year-old male patient visited our outpatient cancer clinic due to aggravated abdominal and back pain. He had been taking sorafenib for over five years for advanced thyroid cancer with multiple lung metastases, without any adverse events except mild hand-foot syndrome and slightly increased liver enzymes at the initial phase. Laboratory findings showed increasing serum amylase and lipase levels. An abdominal CT scan showed a 5.2 cm heterogeneous hypointense mass-like lesion on the pancreas distal body area. Under suspicion of pancreatic cancer, extensive surgery of distal pancreatectomy, unilateral nephrectomy, and unilateral adrenalectomy confirmed moderately differentiated adenocarcinoma with a background of chronic pancreatitis accompanying fibrosis and fat necrosis. Pancreatic cancer should be considered as well as pancreatitis in long-term MTKI users who show abrupt increases in serum pancreatic enzymes, although a causal relationship between long-term MTKI use and pancreatic cancer has not been elucidated.; Keywords : Thyroid carcinoma, Sorafenib, Pancreatic carcinoma, Adverse drug event

Introduction

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.

Case Report

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.

Fig. 1. Chest CT scan shows partial response of multiple lung metastases from advanced papillary thyroid carcinoma five and a half years after treatment with sorafenib.

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).

Table 1

Serial follow-up of serum amylase, lipase, thyroglobulin/anti-thyroglobulin antibody, and TSH levels from 16 months before pancreatectomy and to 3 months after pancreatectomy

	Reference range	16 ms before surgery	12 ms before surgery	8 ms before surgery	3 ms before surgery^*	2 ms before surgery^**	At the time of surgery	3 ms after surgery
Amylase (U/L)	28-100	37	52	60	98	171	357	68
Lipase (U/L)	13.0-60.0	NA	NA	NA	224	396	NA	95.8
Tg (ng/ml)	<50.0	21.8	19.9	19.4	25.6	25.5	15.9	25.6
Anti-Tg Ab (IU/L)	<70.0	<8.4	9.1	21.3	19.9	17.9	15.8	18.5
TSH (μIU/ml)	0.55-4.78	0.02	0.01	0.01	0.017	0.031	0.025	0.01

ms: months, Tg: thyroglobulin

*At the time of suspicion of pancreatitis.

**At the time of diagnosis of pancreatic cancer.

Fig. 2. Abdominal CT scan shows a non-enhanced hypointense lesion in the distal body of the pancreas (solid arrow), with an accompanying slightly enhanced area (open arrow) in the pancreatic tail, suspicious of pancreatic cancer with surrounding inflammation (A). PET/CT scan reveals a focal hypermetabolic uptake in the distal body of the pancreas (arrow) (B).

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).

Fig. 3. Gross images of radical antegrade modular pancreatosplenectomy (RAMP), left nephrectomy, and left adrenalec-tomy. The RAMP specimen reveals an irregular whitish lesion suspicious for invasive tumor accompanying inflammation (A). The left kidney shows a pale yellow to whitish area near the Gerota’s fascia, suggesting fat necrosis (B).

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).

Fig. 4. Microscopic images of pancreatic ductal adenocarcinoma with underlying chronic pancreatitis. Microscopic findings show infiltrating well-to-moderately differentiated ductal adenocarcinoma with desmoplastic stroma (A) and perineural invasion (B). Background pancreatic tissue revealed advanced chronic pancreatitis replacing acinar parenchyma with fibrosis (C) and focal necrotic areas (D). Kidney tissue showed chronic inflammation with fibrosis near the Gerota’s fascia (E). The adjacent perirenal adipose tissue indicated fat necrosis (F).

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.

Discussion

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.

Conflicts of Interest: No potential conflict of interest relevant to this article was reported.

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