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Cite this article: Kumamoto Y, Kaizu T, Tajima H, Kawamata H, Nishiyama R, et al. (2015) Liver Metastasis from Mixed Acinar-Endocrine Carcinoma of the Pancreas: A Case Report and Review of the Literature. J Liver Clin Res 2(2): 1015.

*Corresponding authorMasahiko Watanabe, Department of Surgery, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 252-0374, Japan, Tel: 81-42-778-8111; Fax: 81-42-778-9556; Email:

Submitted: 06 April 2015

Accepted: 20 April 2015

Published: 21 April 2015

Copyright© 2015 Watanabe et al.

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Keywords•Mixed acinar-endocrine carcinoma•Liver metastasis

Case Report

Liver Metastasis from Mixed Acinar-Endocrine Carcinoma of the Pancreas: A Case Report and Review of the LiteratureYusuke Kumamoto, Takashi Kaizu, Hiroshi Tajima, Hiroshi Kawamata, Ryo Nishiyama and Masahiko Watanabe*Department of Surgery, Kitasato University School of Medicine, Japan

Abstract

Mixed acinar-endocrine carcinoma (MAEC) of the pancreas is an exceedingly rare tumor, and the clinicopathological and oncological behavior of this type of tumor is scarcely known. A 42-year-old male patient with MAEC and metachronous liver metastasis was referred to our hospital for the treatment of repeated pancreatitis. A computed tomography (CT) scan revealed a pancreatic tail mass 3x8cm in size with expansive growth into the main pancreatic duct. Endoscopic retrograde pancreatography showed a filling defect in the main pancreatic duct, and an endocrine tumor was suspected by cytology of the pancreatic juice. A distal pancreatectomy was performed, and the immunopathological diagnosis was MAEC of the pancreas. The patient received S-1 chemotherapy after the surgery. Two years later, dynamic CT showed 2 hyper vascular hepatic nodules, 14mm and 8mm in diameter, in segment 4 of the liver. Laparoscopic assisted partial hepatectomy was performed and histological findings were compatible with a metastatic MAEC. One year later, a 5-mm hepatic nodule was detected in segment 3 by magnetic resonance imaging. The hepatic tumor was resected by laparoscopic surgery and diagnosed as a metastatic MAEC. The patient is alive and disease-free 50months after the first operation.

ABBREVIATIONSMAEC: Mixed Acinar-Endocrine Carcinoma; CT: Computed

Tomography; US: Ultrasonography; MRI: Magnetic Resonance Imaging; FDG-PET: Fluorodeoxyglucose-Positron Emission Tomography

INTRODUCTIONMixed acinar-endocrine carcinoma (MAEC) of the pancreas is

exceedingly rare. To our knowledge, almost 30 cases have been previously reported in the English-language literature [1-16]. Almost all these cases showed a large tumor size and prognosis seemed to be relatively poor [1]. However, its biological and oncological behavior remains unknown. We herein report a case of a patient who is alive and disease-free 50 months after the first operation, a distal pancreatectomy, followed by repeated hepatectomies.

CASE PRESENTATIONA 42-year-old man presented with back pain and was

diagnosed as having an acute relapse of chronic pancreatitis by

a local physician because of hyperamylasemia revealed on blood tests. He was transferred to our hospital for further examination and treatment. Contrast-enhanced computed tomography (CT) revealed a pancreatic tail mass 3x8cm in size with expansive growth into the main pancreatic duct (Figure 1A). Endoscopic retrograde pancreatography showed a filling defect in the main pancreatic duct (Figure 1B). The ultrasonography (US) detected an intraductal spreading mass in the main pancreatic duct (Figure 2A). Magnetic resonance imaging (MRI) showed the tumor was isointense on both T1- and on T2-weighted images, very weak enhancement on dynamic study, and high intensity on diffusion-weighted image (Figure 2B). Fluorodeoxyglucose-positron emission tomography (FDG-PET) CT revealed that the mass showed signs of hypo metabolic activity (Figure 2C). An endocrine tumor was suspected by the cytology of the pancreatic juice.

The preoperative diagnosis was a neuroendocrine tumor with hypovascularity. A distal pancreatectomy with splenectomy was performed. Grossly, the resected tumor measured 3.1x8.0x2.9cm and was a well-demarcated, lobulated, white-yellowish soft mass

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with intraductal spreading to the neck of the main pancreatic duct (Figure 3).

Histologically, the tumor cells grew in mainly solid and trabecular structures, and partially in a rosette pattern (Figure 4A). It extended beyond the pancreas and invaded retro pancreatic adipose tissue. A lymphovascular invasion was observed, but regional lymph node metastasis was not identified. An immune histochemical analysis showed that the large parts of the tumor were immunoreactive for trypsin, acinar cell marker (Figure 4B), and some parts of the tumor showed positive for synaptophysin and neural cell adhesion molecule (NCAM), a neuroendocrine marker (Figure 4 C,D). Electron microscopic analysis revealed endocrine granules and zymogen granules in the tumor, therefore, confirming the MAEC diagnosis (Figure 5).

The patient developed a pancreatic fistula categorized as grade B by the International Study Group on Pancreatic Fistula criteria. He recovered by conservative therapy and was discharged on

postoperative day 40. He received S-1 chemotherapy after the surgery. Follow-up imaging analysis was performed every 6 months. Two hyper vascular hepatic nodules, 14mm and 8mm in diameter in segment 4 of the liver were detected on dynamic CT performed 2 years after the surgery (Figure 6 A,B). Laparoscopic assisted partial hepatectomy was performed and histological findings were compatible with metastatic tumors of MAEC. The postoperative course was uneventful. He was discharged on postoperative day 7. One year later, another hepatic nodule 5mm in diameter was detected in segment 3 on MRI examination. The tumor grew to 8mm in diameter the next 3 months (Figure 6C). The hepatic tumor was resected by laparoscopic surgery and diagnosed as a metastatic MAEC. After the operation, the patient remains disease free and is still alive 50 months after the first operation.

DISCUSSION The pancreas is composed of exocrine and endocrine gland

components, with the exocrine part comprising ductal and acinar cells and the endocrine part comprising endocrine cells. Over 80% of pancreatic malignant tumors originate from the ductal

Figure 1 Abdominal contrast-enhanced computed tomography (CT) findings. (A) A tumor 3x8cm in size with expansive growth was found in the pancreatic tail. (B) Endoscopic retrograde pancreatography showed an elliptical filling defect in the main pancreatic duct of the pancreatic body.

A B

C

Figure 2 (A) Abdominal ultrasonography showed intraductal spreading mass in the main pancreatic duct. (B) Magnetic resonance imaging (MRI) showed the tumor as high-signal intensity on the diffusion-weighted image. (C) Fluorodeoxyglucose-positron emission tomography CT revealed that the mass showed signs of hypometabolic activity.

A B

C D

Figure 4 (A) Microscopic study revealed solid nests of neoplastic cells (hematoxylin & eosin).(B) On immunohistochemical studies, the tumor cells were diffusely positive for trypsin, and (C) focally positive for synaptophysin and (D) neural cell adhesion molecule.

Figure 3 Gross appearance of the tumor in the pancreatic tail. The tumor was a well-demarcated, lobulated, white-yellowish soft mass with intraductal spreading to the neck of the main pancreatic duct.

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component. Less than 10% are neuroendocrine tumors, and acinar cell carcinomas account for only about 1% of pancreatic tumors [17]. Acinar cell carcinomas of the pancreas have been known to express neuroendocrine markers in some cases, but the volume of this part was limited to only a few cells [9]. However, the neuroendocrine cells may comprise over 30% of the tumor in which case the tumor is referred to as MAEC [18].

MAECs are exceedingly rare tumors. Since Ulich et al. reported the first case of MAEC in 1982 [19], sporadically reported cases and 3 short series of MAECs have been published so far [1-16]. In the review of these reports, several characteristic behaviors of MAECs were pointed out. Ohike et al. compared 37 cases of acinar cell carcinomas and 6 cases of MAECs in a report in which they stated that MAECs and acinar cell carcinomas shared most clinicopathological features (mean age, tumor size, pathological pattern, hormone receptors and p53 expression) except for

the sex ratio, concluding that MAEC of the pancreas is likely a subtype of acinar cell carcinoma [9]. On the other hand, Yu et al. reported on 5 cases of MAECs in which they proposed that MAECs affect both sexes roughly equally and explained that MAECs are pathogenetically more closely related to neuroendocrine tumors than they are to acinar cell carcinomas [15].

We summarized 13 case reports and 3 short series of MAECs in Table1. The median age of the patients was 61.5 years and the male to female ratio was 2:1. The mean diameter of the tumors was 8.0cm. The tumors can develop in any part of the pancreas but were relatively common in the pancreatic head (head to body-tail ratio, 13:10). Acinar cell predominant cases are major compared to endocrine cell predominant cases (acinar predominant to endocrine predominant ratio, 13:9). Three cases contained both components equally. Although acinar cell carcinoma is known to be a more aggressive disease than endocrine carcinoma in the pancreas, there is no tendency of prognosis depending on the predominant component of the MAEC.

The recent studies reported the data of Ki-67 expression, which is one of the indicators for the malignant potential of these tumors. MAECs showed high levels of Ki-67 expressions in general and high tumor recurrence rates, for which the most frequent metastatic site was the liver [1-16].

In most cases, the primary treatment was surgical resection, and an R0 resection with an adequate safety margin was essential for achieving long-term survival. However, one case underwent chemotherapy with FOLFOX (oxaliplatin/5-fluorouacil/leucovrin) after palliative surgery and survived longer than 36months. This result suggests that chemotherapy has some positive effects for survival in cases of MAECs. But the recommended regimen has not yet been confirmed. There were few reports of resection for liver metastasis of MAECs. The present study shows that repeated hepatic resections also have positive effects for survival if the tumors were resectable.

The survival rate at 1 year of patients with acinar cell carcinoma has been reported to be 56.5% [20]. On the other hand, that of MAECs was 69.0%, calculated from the reported cases [1-16]. As the prognosis for neuroendocrine tumors was reported better than acinar cell carcinomas, MAECs were suspected to have both characteristics and located between acinar cell carcinomas and neuroendocrine tumors [21].

The present case report is a very rare case of MAEC in the pancreas of a patient who is alive and disease free, now 50 months after the first operation, distal pancreatectomy followed by repeated hepatectomies, and a review of the literature on this malignancy. Due to the small number of MAEC cases reported and the lack of large-scale follow-up data, there are still many controversies on the matter of the optimal course of treatment. However, complete surgical resection of the primary tumor and the metastatic site with an adequate safety margin to accomplish an R0 resection is the treatment most often recommended. The roles of chemotherapy and radiotherapy remain unclear. Nevertheless, it is worth the attempt if the tumor is unresectable. The accumulation of additional data from more cases is, therefore, necessary to further elucidate this rare type of carcinoma.

A B

Figure 5 (A) Ultra structural analysis showed that tumor cells contained neurosecretory granules ranging in size from 310 to 435nm, and (B) zymogen granules ranging in size from 400 to 600nm. Mixed acinar-endocrine carcinoma (MAEC) was confirmed by electron microscopy.

A B

C

Figure 6 (A,B) Two hypervascular hepatic nodules, 14mm and 8mm in size in segment 4 of the liver were detected on dynamic CT performed 2 years after the surgery. These tumors were resected by laparoscopic surgery and histologically confirmed as metastatic tumors of MAEC. Another hepatic nodule was detected in segment 3 on MRI examination 1 year later, resected by laparoscopic surgery, and (C) diagnosed as a metastatic MAEC tumor.

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Table 1: Reported cases of mixed acinar-endocrine carcinoma of the pancreas in the literature.

Year Age Gender Size Location Main tumor Treatment Ki-67, MI Metastasis Recurrence Prognosis

1993 50 M 19 x 18 Tail Endocrine NA NA Liver NA Dead (10 M)

1994

81 M 3 Tail Acinar Resection

NA

None NA Alive (3 M) 70 M 4 Multiple Acinar Biopsy (R2) Liver, lung NA Dead (3 M)64 F 10 Head Acinar Biopsy (R2) None NA Dead (18 M)48 F 11 Tail Acinar Resection Liver NA Alive (12 M)79 F 10 Head Acinar Chemo radiation None NA Alive (12 M)

1996 52 F 6 x 6 Head Acinar Whipple + SMV resection (R0) NA None None Alive (12 M)

1997 28 M 3 Tail Endocrine Biopsy (R2) NA Multiple liver NA Dead (10 M)

2000 50 M 3 x 2.5 Head Endocrine PPPD (R0) NA None None Alive (18 M)

2000 72 M 12 x 13 Body-tail Endocrine Biopsy (R2) NA Multiple liver NA Dead (3 M)

2002 33 M 3.5 Head Acinar PPPD (R0) NA None None Alive (15 M)

200458.4(49-65)

M 2F 4 8.2 No preferential

localization Acinar NA >5% (n = 2) NA NA NA

2008 80 M 4 Head Acinar Whipple (R0) NA None NA NA

2009 74 M 12 x 9 x 6 Head Acinar Whipple (R0) 80% None None Alive (3 M)

2010 59 F 8 x 2.5 Tail E = A DP (R0) NA None NA NA

2010 75 M 7 Tail Acinar DP (R0) NA None None Alive (6 M)

2011 52 M1.5 x 1.2 x 1.0

Head EndocrineWhipple (R0), CDDP + Camtothecin (PR) GEM

+ CDDP (PD)

5/1 HPF None Liver, local

(18 M) Alive (30 M)

2013 57 F 2.5 Body Endocrine DP (R1), etoposide + carboplatin + Rtx

40-45% None NA NA

2013

80 M 14 x 9 Head Endocrine

Sandostatin, palliative surgery (R2), FOLFOX

(PD)

53%, 18/10

HPFRt kidney Liver, kidney Alive (36 M)

89 M 3.9 x 3.7 Head Endocrine Whipple

65%, 10/10

HPFNone None Dead (2.5 M)

Complications

60 M 16 x 13 Head Acinar

Colectomy, gastrectomy,

pancreatectomy, GEM + capecitabine

60-70% None Local, liver (3

M) Dead (6 M)

74 M 10 x 5.5 Body Acinar Neoadj (5FU + RTx)

→ DP 10% None Wide metastasis Alive (17 M)

59 M 7.5 x 6.5 Head Endocrine Whipple (R1) 30%,

80% None Local, liver (4 M) Alive (7 M)

2013 66 M 3.1 x 2.8 Head E = A Chemotherapy

50%,18/10

HPFLiver Liver (3 M) Dead (21 M)

Our case 42 M 3 x 8 Body-tail E = A DP (R0), hepatectomy

(X2)

5-10%, 4/1 HPF

None Liver (12 M, 36 M) Alive (48 M)

Abbreviations: E: Endocrine, A: Acinar, PPPD: Pyrolus Preserving Pancreatico duodenectomy, CDDP: Cisplatin, GEM: Gemcitabine, PR: Partial Response, DP: Distal Pancreatectomy, NA: Not Available, M: Months, HPF: High Power Field, R0: Microscopically Cancer Free.

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Kumamoto Y, Kaizu T, Tajima H, Kawamata H, Nishiyama R, et al. (2015) Liver Metastasis from Mixed Acinar-Endocrine Carcinoma of the Pancreas: A Case Report and Review of the Literature. J Liver Clin Res 2(2): 1015.

Cite this article

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