2. Case report
A 70-year-old male patient who
was referred to our hospital, for the treatment of obstructive jaundice
was diagnosed with pancreatic head cancer. He was 168 cm tall, weighed
71.6 kg, had a body mass index of 25.4 kg/m2, did not
smoke or drink alcohol, and had no history of chronic pancreatitis or
diabetes. His blood test results
were as follows: total bilirubin, 15.0 mg/dL (0.3–1.2); direct
bilirubin, 11.4 mg/dL (<0.4); aspartate aminotransferase, 125
U/L (10–40); alanine aminotransferase, 218 U/L (5–40); carbohydrate
antigen 19–9 (CA19-9), 38.2 U/mL (<37.0); carcinoembryonic
antigen (CEA), 4.4 ng/mL (5.0); duke pancreatic monoclonal antigen type
2 (DUPAN-2), >1600 U/mL (<150); and s-pancreas-1
antigen (SPan1), 240 U/mL (<30). Computed tomography (CT)
revealed a low-density mass (27 mm in diameter) with no major vessel
involvement in the pancreatic head (Fig. 1) and no distant metastases.
Endoscopic retrograde cholangiopancreatography was performed for biliary
drainage, and the pancreatic tumor was pathologically diagnosed as a
PDAC. The clinical stage was T3N1M0, stage IIB, according to the eighth
edition of the TNM classification of the American Joint Committee on
Cancer (AJCC) /Union for International Cancer Control (UICC). The tumor
was considered resectable and the patient underwent PpPD. Because tumor
invasion was observed in the superior mesenteric vein (SMV), combined
resection and reconstruction of the SMV was performed. No postoperative
complications were observed and the patient was discharged on the 21st
postoperative day.
Macroscopic examination revealed a whitish solid mass, 50×40×30 mm in
size, located in the pancreatic head (Fig. 2A and 2B ). The mass
was histologically diagnosed as a well-differentiated adenocarcinoma, T3
N1(7/38) M0, stage IIB, according to the eighth edition of the TNM
classification of the AJCC/UICC (Fig. 2C ). The lymphatic
invasion was severe, vascular invasion was moderate, and neural invasion
was severe. Biliary, duodenal, anterior tissue, retoroperitoneal tissue,
superior mesenteric vein, and extrapancreatic nerve plexus invasions
were observed.
One month after surgery, the patient received gemcitabine and S-1 (GS:
gemcitabine at a dose of 800 mg/m2 on days 1 and 8
plus S-1 at a dose of 100 mg/body
twice daily on days 1–14 of a 21-day cycle) as postoperative adjuvant
chemotherapy.
At
the time, only gemcitabine was recommended for adjuvant chemotherapy
after PDAC surgery in Japan, and S1 was not yet recommended7. In addition, since there have been some reports
that GS therapy is effective as adjuvant chemotherapy89, GS therapy
was not standard clinical treatment at that time, but selected after
providing sufficient explanation to the patient and obtaining informed
consent. Eleven months post-PpPD, multiple microscopic bilateral
pulmonary metastases were suspected on CT.
Since the lesions suspected to be
multiple lung metastases remained almost unchanged in size and only
gemcitabine was the chemotherapy medication recommended for unresectable
PDAC in Japan at that time 7, GS therapy was continued
with sufficient informed consent for an extended period, even after lung
metastasis recurrence.
At 4 years and 6 months post-PpPD, only one lesion in the right lower
lung grew rapidly (Fig. 3A ), and bronchoscopy revealed class V
cytopathology (Fig. 3B ). Whole-body dynamic CT showed no
metastasis except in the lung, and since the possibility of primary lung
cancer could not be ruled out, the bottom portion of the right lung was
thoracoscopically resected 5 years and 5 months post-PpPD.
Other pulmonary lesions showed
almost no change in size; therefore, we concluded that chemotherapy was
effective. In addition, they were not resected because they were
numerous and complete resection was impossible.
The lesion was pathologically diagnosed as an adenocarcinoma, similar to
the primary lesion (Fig. 4A ). Immunostaining was positive for
CK7 (Fig. 4B ), and negative for CK20 (Fig. 4C ) and
TTF-1 (Fig. 4D ). This indicated a low likelihood of primary
lung cancer. Based on these findings, metastatic PDAC was diagnosed. In
addition, multiple lung lesions were obscured, and after obtaining
sufficient informed consent from the patient, he was followed up without
chemotherapy. However, 6 months after the second surgery (5 years and 10
months after PpPD), CT revealed a nodule in the upper lobe of the right
lung. Although GS was resumed, the number of lung metastases increased.
Seven years and five months post-PpPD, the treatment regimen was
switched to a combination therapy of gemcitabine plus nab-paclitaxel
(GEM + nab-PTX: gemcitabine at a dose of 450 mg/m2 and
nab-PTX at a dose of 115 mg/m2 on days 1 and 8 of a
21-day cycle). Eleven years and one month post-PpPD, FOLFIRINOX (a
combination of folinic acid, fluorouracil, irinotecan hydrochloride, and
oxaliplatin) was required to stem the growth of the lung metastases.
However, the resulting adverse effects compelled the physicians to
discontinue the treatment after only one course, and the patient was
subsequently treated with S-1 alone (at a dose of 80 mg/body twice daily
on days 1–14 of a 21-day cycle).
11 years and 2 months post-PpPD, the patient was readmitted because of
dizziness and left hemiplegia. Contrast-enhanced magnetic resonance
imaging (MRI) revealed a 23×22×20-mm neoplasm in the right inferior
parietal lobule. A strong contrast effect was evident at the edges and
center, and mulberry-like papillary structures were observed within the
lesion (Fig. 5A ). A 5-mm ring-shaped contrast effect was also
observed in the right cingulate gyrus. Metastatic brain tumors were
suspected in the right inferior parietal lobule and right cingulate
gyrus. Only the right inferior parietal lobe lesion was resected to
relieve symptoms at 11 years and 4 months post-PpPD.
Histopathological analysis revealed metastatic PDAC in the brain
(Fig. 5B ). Six weeks after the third surgery, S-1 treatment was
resumed (at a dose of 100 mg/body twice daily on days 1–14 of a 21-day
cycle).
MRI performed at this time demonstrated numerous small lesions in the
brain, and a tumor appeared in the meninges at the site of the previous
surgery. Subsequently, the patient underwent whole-brain irradiation,
and his condition improved to the point where he was able to walk
without assistance. However,
the
patient died of PDAC recurrence 6 months after the craniotomy (11 years
and 8 months after the first surgery).
The CA19-9, CEA, SPan1, and
DUPAN-2 levels were measured monthly. CA19-9 was slightly elevated only
at the first visit but remained low throughout the observation period,
and CEA only spiked just before death. SPan1 and DUPAN-2 levels
increased as metastasis increased and decreased as the chemotherapy
regimen was changed (Fig. 6 ).