Introduction

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
figure 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)

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Fig. 2
figure 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)

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Fig. 3
figure 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)

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Fig. 4
figure 4

Immunohistochemistry for mismatch repair gene proteins revealed negative PMS2 (A) and positive MLH1 (B), MSH2 (C), and MSH6 staining (D)

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Fig. 5
figure 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

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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 [4,5,6,7], 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, 4,5,6, 9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34] 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
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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. [4,5,6,7] 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.