==== Front Surg Case Rep Surg Case Rep Surgical Case Reports 2198-7793 Springer Berlin Heidelberg Berlin/Heidelberg 37386324 1709 10.1186/s40792-023-01709-5 Case Report Mixed acinar-neuroendocrine carcinoma of the pancreas with positive for microsatellite instability: a case report and review of the literature http://orcid.org/0000-0003-2863-4702 Yoshino Kenji kenji.yoshino1980@gmail.com 12 Kasai Yosuke yokasai@kuhp.kyoto-u.ac.jp 13 Kurosawa Manabu manakurojp@yahoo.co.jp 4 Itami Atsushi atsushi_itami@kcho.jp 2 Takaori Kyoichi takaori@iasgo.org 1 1 grid.416372.5 0000 0004 1772 6481 Department of Surgery, Nagahama City Hospital, 313, Oinui-cho, Shiga 526-8580 Nagahama, Japan 2 grid.416289.0 0000 0004 1772 3264 Department of Surgery, Nishi-Kobe Medical Center, 5-7-1 Koji-dai, Nishi-ku, Hyogo 651-2273 Kobe, Japan 3 grid.258799.8 0000 0004 0372 2033 Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507 Kyoto Japan 4 grid.416372.5 0000 0004 1772 6481 Department of Pathology, Nagahama City Hospital, Nagahama, Japan 30 6 2023 30 6 2023 12 2023 9 12225 4 2023 27 6 2023 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Background Mixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas is a rare tumor. We report a case of successful surgical resection of expansively growing MANEC of the pancreas with microsatellite instability (MSI)-high. Case presentation The patient was an asymptomatic 65-year-old male. A computed tomography (CT) scan for a follow-up after treatment of pneumonia incidentally revealed a hypoenhancing 12-cm expansively growing tumor in the pancreatic body. An endoscopic ultrasound-guided fine-needle aspiration of the tumor suggested the diagnosis of MANEC. We performed distal pancreatectomy with combined resection of the spleen, left adrenal gland, transverse colon, small bowel, and stomach. The intraoperative findings showed that the tumor was capsular and was in contact with the SMA, SMV, and CA; however, obvious infiltration of these vessels was not observed..Pathological findings indicated MANEC with MSI-high. Among mismatch repair (MMR) gene proteins, PMS2 was lost and MLH1, MSH2, and MSH6 were retained. The tumor recurred 5 months after surgery. The patient was treated with gemcitabine plus nab-paclitaxel followed by pembrolizumab, which did not show objective response. Discussion This is the first report investigating MSI and MMR in MANEC. Standard chemotherapy has not been established for MANEC. Detection of MSI-high is essential since PD-1 monoclonal antibodies for MSI-high cases might be one of the good treatment options. Herein, we discuss the various cytomorphologic and clinical features of MANEC and present a brief review of the literatures. Conclusions The accumulation of data from additional cases is necessary to further evaluate this type of carcinoma and provide a standardized optimal therapy for MANEC. Keywords Mixed acinar-neuroendocrine carcinoma Microsatellite instability-high tumors Programmed cell death-1 monoclonal antibody issue-copyright-statement© Japan Surgical Society 2023 ==== Body pmcIntroduction A mixed acinar-neuroendocrine carcinoma (MANEC) is a rare pancreatic neoplasm, with less than fifty reported cases [1]. MANEC is a variant of acinar cell carcinoma (ACC) exhibiting neuroendocrine differentiation only immunohistochemically, and is distinguished from mixed-neuroendocrine-nonendocrine neoplasm (MiNEN) which is a mixture of acinar and neuroendocrine tumors confirmed by solely morphological features. The key diagnostic feature of MANEC is that MANEC expresses both neuroendocrine antigens (eg, synaptophysin and chromogranin) and pancreatic exocrine antigens (eg, trypsin and lipase). The behavior of MANEC may be similar to that of acinar cell carcinoma (ACC) [2], and surgical resection is the first choice, if the tumor is localized and resectable [1, 3]. However, with the limited number of reported cases of MANEC, its appropriate treatment modalities and overall prognosis remain unclear. Recently, pembrolizumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has been used in malignant solid tumors with microsatellite instability (MSI)-high. However, there have been no reports investigating MSI in MANEC. Herein, we present a case who underwent a successful surgical resection of an expansively growing MANEC of the pancreas with MSI-high and brief literature review. Case presentation The patient was an asymptomatic 65-year-old man with a recent history of pneumonia. A follow-up computed tomography (CT) scan incidentally revealed a large tumor on his left upper abdomen. The patient did not have a reported family history of pancreatic cancer. Laboratory examinations showed elevated serum C-reactive protein (CRP) levels (2.76 mg/dl). His serum albumin and hemoglobin levels slightly decreased to 3.9 g/dl (normal range 4.1–5.1 g/dl) and 13.5 g/dl (normal range 13.7–16.8), respectively. His serum transaminase, pancreatic enzymes (amylase and lipase), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total bilirubin, blood glucose, and HbA1c levels were within normal limits. His serum elastase-1 level elevated to 3250 (normal range 0–300), while his carcinoembryonic antigen (CEA), cancer antigen 19–9 (CA19-9), duke pancreatic monoclonal antigen type 2 (DUPAN-2), and s-pancreas antigen-1 (Span-1) levels were within their normal ranges. A contrast-enhanced CT revealed a hypoenhancing 12-cm tumor in the pancreas body and tail, suggesting a primary pancreatic cancer. The tumor was close to the celiac artery (CA), superior mesenteric artery (SMA) and vein (SMV), and common hepatic artery (CHA, Fig. 1A–D). Notably, the splenic artery was patent despite circumferential involvement by the tumor (Fig. 1 A–C), which indicated the expansive-growth pattern of the tumor. The magnetic resonance imaging (MRI) showed that the tumor had a low intensity on the T1-weighted imaging, a high intensity on the T2-weighted imaging, and a marked restricted diffusion on the diffusion-weighted imaging. Neither CT nor MRI scans indicated any distant metastases. The patient underwent an endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the mass. This revealed the presence of tumor cells with round nuclei and eosinophilic to amphophilic granular cytoplasm. An immunohistochemical examinations showed that the tumor was positive for BCL-10, trypsin, chymotrypsin, chromogranin A (80% positive), and synaptophysin (20% positive). We diagnosed the tumor as a pancreatic ACC or MANEC. The patient underwent a complete surgical resection by distal pancreatectomy with combined resection of the spleen, left adrenal gland, transverse colon, small bowel, and stomach (Fig. 2). The intraoperative findings showed that the tumor was capsular and was in contact with the SMA, SMV, and CA; however, obvious infiltration of these vessels was not observed. The pathological examination indicated an MANEC with positivity for BCL-10, trypsin, chymotrypsin, and chromogranin A (Fig. 3A–E). The MIB-1 as per the Ki-67 expression was 80% positive in the immunochemical staining (UICC TNM classification 8th edition: pT3, pN2, pMX StageIII) (Fig. 3F). The tumor tissue DNA was analyzed for genomic abnormalities, and the resected specimen indicated that the tumor was MSI-high and negative for RAS/BRAF mutation. Immunohistochemically, The mismatch repair (MMR) gene protein PMS2 was lost and MLH1, MSH2, and MSH6 were retained (Fig. 4). The patient did not receive any adjuvant therapy because of fatigue and loss of appetite. The progress after the surgery is shown in Fig. 5. Three months after the surgery, there was no recurrence of the tumor. However, five months after surgery, a CT scan revealed multiple liver, lung, and lymph node metastases and peritoneal dissemination. Chemotherapy with gemcitabine plus nab-paclitaxel was administered as the first-line treatment. Due to the side effects (leukopenia and severe malaise) and poor efficacy (tumors enlarged < 20%), the patient stopped receiving the treatment after two courses. Considering MSI-high of the tumor, pembrolizumab was administered as the second-line treatment. Although the patient tolerated this regimen, a CT scan revealed the tumor´s progression. The patient's general condition gradually deteriorated, and he died 8 months following the surgery.Fig. 1 Preoperative contrast-enhanced computed tomography. The tumor was close to the celiac artery (CA), superior mesenteric artery (SMA) and vein (SMV), and common hepatic artery (CHA, A–D) The splenic artery was patent despite circumferential involvement by the tumor (A–C) Fig. 2 Macroscopic view of the resected specimen. Distal pancreatectomy with combined resection of the spleen, left adrenal gland, transverse colon, small bowel, and stomach (A). The tumor was encapsulated (B) Fig. 3 Histopathological findings. Hematoxylin and eosin staining at a magnification of A × 40 and B × 400; C BCL-10 staining, magnification, × 400; D trypsin staining, magnification, × 400; E chromogranin A staining, magnification, × 400; F MIB-1 staining, magnification, × 400). A, B Hematoxylin and eosin staining revealed an acinar growth of tumor cells with round nuclei and eosinophilic vesicles. Immunohistochemistry revealed positive BCL-10 (C), trypsin (D), and chromogranin A staining (E). The MIB-1 as Ki-67 expression was 80% positive (F) Fig. 4 Immunohistochemistry for mismatch repair gene proteins revealed negative PMS2 (A) and positive MLH1 (B), MSH2 (C), and MSH6 staining (D) Fig. 5 Summary of the treatments. Five months after surgery, a CT scan revealed the presence of multiple liver, lung, and lymph node metastases and peritoneal dissemination. Chemotherapy with gemcitabine (GEM) plus nab-paclitaxel (nabPTX) was administered. Subsequently, pembrolizumab was administered as the second-line treatment, however, did not show a good response Discussion MANEC of the pancreas is extremely rare, and very little is known about its clinical and radiological features and pathogenesis. Therefore, it is difficult to differentiate MANEC from ACC or endocrine neoplasms on clinical and radiological evaluations. EUS-FNA is the most common technique used for the diagnosis of pancreatic neoplasms, including MANEC, and it also plays a crucial role in determining the treatment and triage. However, there are only a few reports on the effectiveness of perioperative chemotherapy for MANEC [4–7], and a standardized management protocol for a pancreatic MANEC has not yet been established. Hence, it has been agreed that generally surgery is the sole curative therapy for resectable MANEC [8, 9]. The list of reports describing cases of MANEC is shown in Table 1. [1, 2, 4–6, 9–34] MANEC is common in males, and the susceptible age is 50–70 years old. Despite the presence of endocrine components, most patients do not have specific hormonal symptoms. Moreover, there are no useful tumor markers related to MANEC. Hence, MANEC is usually diagnosed at advanced stages [median size of 7.9 cm with synchronous distant metastases being present in 40.5% (17/42) of the cases]. These findings are based only on small case series or case reports with very short follow-up periods (median 12 months), and they do not thoroughly discuss the treatment strategies and their effects.Table 1 Literature review of the reported cases diagnosed with mixed acinar-neuroendocrine carcinoma Author Publication date Age Symptom Sex Size (cm) Metastasis Treatment Regimen of chemotherapy Follow-up Recurrence Ulich et al Nov, 1982 30 Epigastric pain F 9.3 × 8.6 × 5.8 None PD Alive (4 months) – Ichijima et al Jan, 1985 6 – F 8 × 5 × 4 None Resection Alive (13 years) – Hassan et al Sep-Oct, 1993 50 Weight loss, constipation, abdominal pain M 19 × 18 Liver, multiple DP + splenectomy + colectomy Deceased (10 months) Klimstra et al Aug, 1994 81 Nausea, abdominal pain M 3 None Resection Alive (3 months) – 70 Back pain M 4 × 10 Liver, lungs, lymph nodes Resection Deceased (3 months) 64 Hematemesis F 10 None Bypass (inoperable) Deceased (18 months) – 48 – F 11 Liver Resection Alive (12 months) 79 Abdominal pain F 10 None Bypass chemoradiation N/A Alive (12 months) – Cho et al Apr, 1996 52 Jaundice F 6 × 6 None PD + SMV resection Alive (12 months) – Shimoike et al Dec, 1997 28 - M 3 Liver, multiple; vertebral bone TAE, chemotherapy STZ, 5-FU Deceased (10 months) Frank et al Aug, 1998 61 Uncharacteristic abdominal complaints M 4.9 × 3.6 × 2.8 Liver, later peritoneal carcinomatosis, skin PD+ left hemihepatectomy + chemotherapy Octreotide, a-interferon Deceased (3.5 years) Muramatsu et al Sep, 2000 72 Appetite loss, weight loss M 12 × 13 Liver, multiple N/A Deceased (3 months) Ogawa et al Jun, 2000 50 - M 3 × 2.5 None PD Alive (18 months) – Skacel et al Sep, 2000 69 N/A M 10 None Resection Deceased (20 months)  +  75 N/A M 5.5 None Resection Alive (10 months) – Mizuno et al May, 2001 67 - F N/A Liver, multiple; at autopsy: spleen, stomach, left ovary, para-aortic lymph nodes Chemotherapy Octreotide, diazoxide, 5-FU, doxorubicin Deceased (7 years) Ohike et al (6 cases) Jul, 2004 Mean 58.4 (49–65) N/A M:F (2:4) 8.2 (n = 2) N/A N/A N/A – Imaoka et al Oct, 2008 80 N/A M 4 None PD N/A – Kyriazi et al Apr, 2009 74 - M 12 × 9 × 6 None PD Alive (3 months) – Chung et al Nov, 2010 59 Watery diarrhea F 8 × 2.5 None DP + splenectomy N/A – Kobayashi et al Apr, 2010 75 - M 7 None DP Alive (6 months) – Soubra et al Mar, 2013 52 Epigastric pain, fatigue, jaundice M 1.5 × 1.2 × 1.0 Liver, soft tissue PD + chemotherapy 1st: cisplatin, camtothecin 2nd: gemcitabine, cisplatin Alive (30 months) Lee et al Feb, 2013 66 Mid-epigastric discomfort M 3.1 × 2.8 Liver Chemotherapy Irinotecan, capecitabine, erlotinib, docetaxel Deceased (21 months) Sullivan et al April, 2013 75 Acute pancreatitis M 0.6 Liver Chemotherapy N/A N/A 51 - M 1.6 None DP N/A – Kanemasa et al Sep, 2013 63 Left flank pain M 6 Liver Chemotherapy 1st: S-1 2nd: gemcitabine Deceased (18 months) Ogbonna et al Nov, 2013 57 Epigastric pain radiating to the back F 2.5 None DP + splenectomy + chemoradiation etoposide,carboplatin N/A – Yu et al Apr, 2013 80 Epigastric pain associated with dyspepsia and early satiety M 14 × 9 Liver, kidney Chemotherapy, palliative surgery 1st: carboplatin, etoposide 2nd: FOLFOX Alive (36 months) 89 Poor appetite and weight loss M 3.9 × 3.7 None PD Deceased (2.5 months) – 60 Abdominal pain, diarrhea M 16 × 13 None Colectomy, gastrectomy, pancreatectomy, chemotherapy Cetuximab, irinotecan Deceased (6 months) 74 Epigastric pain, weight loss M 10 × 5.5 None Chemoradiation + DP neoadjuvant: 5-FU Alive (17 months) – 59 Fatigue, poor appetite, intermittent jaundice M 7.5 × 6.5 None Whipple Alive (7 months) Local recurrence and liver (4 months) Kumamoto et al Apr, 2015 42 Back pain M 3.1 × 8.0 × 2.9 Liver, multiple DP + hepatectomy Alive (48 months) 4 months Liu et al Aug, 2015 65 Jaundice, nagging epigastric pain, intermittent diarrhea F 8 × 6 Liver, multiple PD + partial hepatectomy Alive (12 months) Sugimoto et al Apr, 2017 48 Abdominal pain M 7.7 × 5.9 None Chemotherapy + PD Neoadjuvant: FOLFIRINOX Alive (21 months) – Takano et al Oct, 2017 50 Epigastralgia and back pain M 3 None DP Alive (1 year) – Hara et al Dec, 2017 45 Severe anaemia F 11 Liver, multiple; later, stomach TACE followed by DP + splenectomy; later gastrectomy Alive (7 years) Strait et al Nov, 2018 33 Abdominal discomfort, back pain, early satiety, weight loss M 3.6 × 2.9 Liver, multiple Chemotherapy + PD Neoadjuvant: FOLFIRINOX Alive (10 months) 66 Abdominal pain M 10 None Chemotherapy FOLFIRINOX, panitumumab Alive (4 months) – Tang et al Jun, 2019 52 Tenderness in the right upper quadrant M 10.6 Liver, multiple Chemoradiation Etoposide, cisplatin Deceased (5 months) Niiya et al Oct, 2020 72 Upper abdominal pain M 2.9 None DP N/A – Akki et al Jul, 2021 60 s Abdominal pain M 2.2 None PD Alive (31 months) liver 60 s - M 4 None DP Alive (6 months) - our case 65 – M 12 None DP + splenectomy + left adrenal, transverse colon, small bowel resection, partial gastrectomy, chemotherapy 1st: gemcitabine, nab-paclitaxel 2nd: pembrolizumab Deceased (8 months) liver, lung, lymph node, peritoneal dissemination (5 months) Concerning neoadjuvant therapy, the usefulness of FOLFIRINOX has only been described in two case reports [6, 35]. Yu et al. performed chemoradiation therapy with 5-fluorouracil; however, the effectiveness of the treatment was not evaluated [5]. The malignant potential of MANEC is considered to be less than that of pancreatic ductal adenocarcinoma. MANEC has the characteristics of expansive growth, a well-defined margin with a capsule, and a lack of or relatively mild vascular and bile duct encasement [36]. In our case, even though the tumor appeared to be in contact with major vessels such as CA and SMA on CT imaging, it did not actually infiltrate the vessels, and margin-negative curative resection was achieved through aggressive surgical procedure. Meanwhile, tumor recurrence was observed in approximately 50% of patients who underwent curative resection, indicating that micrometastases were already present, even in a clinically resectable MANEC. Therefore, adjuvant therapy may be considered to reduce recurrence risk and improve outcomes, even after a curative resection. However, there have been no reports with respect to adjuvant chemotherapy following surgery for MANEC. For unresectable or recurrent MANEC, there are only a few case reports of treatment with FOLFIRINOX, FOLFOX, and S-1 and their effectiveness is not clear. [4–7] Currently, the efficacy of anti-PD-1 monoclonal antibodies for MSI-high solid tumors has attracted considerable attentions. This is the first report investigating MSI in MANEC. In MiNEN, several reports have examined the presence of MSI. Sahnane et al. reported a MSI-high rate of 12.4% in gastroenteropancreatic neuroendocrine carcinoma and MiNEN tumors [37]. Additionally, Ishida et al. studied MiNEN tumors of the stomach and reported MSI- high rate of 7.7% [38]. The tumor was MSI-high and out of the four mismatch repair genes, only PMS2 was inactivated. In a previous report, PMS2 was required for the cisplatin-induced activation of p53, which is a member of the p53 family of transcription factors with proapoptotic activity in ovarian cancer [39]. Furthermore, Jia et al. reported that PMS2 expression was regulated post-translationally by Akt and was essential for the platinum-induced apoptosis in ovarian cancer [40]. Thus, the efficacy of chemotherapy may differ depending on the type of MMR deficiency. A PMS2 deficiency may be associated with the efficacy of chemotherapy. Although the recurrent tumors in our case did not show a good response to pembrolizumab despite the MSI-high status, pembrolizumab may be one of the good treatment options for MSI-high MANEC, given the lack of robust evidence of chemotherapies for MANEC. In our case, a mutation in the RAS/BRAF gene mutation was not identified. In previous reports, only two reports have investigated genetic mutation in MANEC [30, 34]. Therefore, further investigations are needed to expand our understanding of genetic mutations in MANEC. Conclusion While surgical resection remains the first choice for the treatment of MANEC without distant metastasis, new modalities such as anti-PD-1 monoclonal antibodies may be considered for advanced MANEC with MSI-high. The accumulation of more data from additional cases is necessary to further evaluate this type of carcinoma and provide a standardized optimal therapy for MANEC. Abbreviations ACC Acinar cell carcinoma ALP Alkaline phosphatase CA Celiac artery CA19-9 Cancer antigen 19–9 CEA Carcinoembryonic antigen CHA Common hepatic artery CRP C-reactive protein CT Computed tomography DUPAN-2 Duke pancreatic monoclonal antigen type 2 EUS-FNA Endoscopic ultrasound-guided fine-needle aspiration LDH Lactate dehydrogenase MANEC Mixed acinar-neuroendocrine carcinoma MiNEN Mixed-neuroendocrine-nonendocrine neoplasm MMR Mismatch repair MRI Magnetic resonance imaging MSI Microsatellite instability PD-1 Anti-programmed cell death-1 SMA Superior mesenteric artery SMV Superior mesenteric vein Span-1 S-pancreas antigen-1 Acknowledgements Not applicable. Author contributions KY, YK, AI, and KT analyzed and interpreted the data. KY collected and assembled the data. KY and MK drafted the article. All authors participated in critical revision of article for important intellectual content. Funding Nothing. Availability of data and materials The data that support the findings of this manuscript are available from the corresponding author, Kenji Yoshino, upon reasonable request. Declarations Ethics approval and consent to participate Not applicable. Consent for publication The consent for publication was obtained from the patient. Competing interests All authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ==== Refs References 1. Liu Z Dong C Wang C Liu Q Sun D Wang L Mixed acinar-endocrine carcinoma of pancreas: a case report and brief review of the literature Onco Targets Ther. 2015 8 1633 42 10.2147/OTT.S87406 26170699 2. Klimstra DS Rosai J Heffess CS Mixed acinar-endocrine carcinomas of the pancreas Am J Surg Pathol 1994 18 8 765 778 10.1097/00000478-199408000-00002 8037290 3. 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