2025 Volume 11 Issue 1 Article ID: cr.24-0064
INTRODUCTION: Pancreatic neuroendocrine carcinoma (panNEC) is a poorly differentiated, highly malignant neoplasm with an extremely poor prognosis. This tumor often presents as locally advanced or unresectable at the initial diagnosis.
CASE PRESENTATION: A 72-year-old woman presented to our hospital with weight loss. A computed tomography scan showed an enhanced tumor measuring 32 mm in the pancreatic head region, with contact to the common hepatic artery over 180°. The pathological findings from the specimens obtained via endoscopic ultrasonography-guided fine-needle aspiration identified small cell-type NEC with extensive necrosis, leading to a diagnosis of locally advanced unresectable panNEC. Accordingly, she began a course of carboplatin and etoposide therapy. After 7 courses, given the significant shrinkage of the tumor, we performed a pancreatoduodenectomy as a conversion surgery. Pathological examination revealed a localized, residual nodule of NEC, consisting mainly of large neoplastic cells, with carcinoma in situ components scattered within and around the nodule. In addition, the diffuse membrane expression of somatostatin receptor 2 was observed in NEC components. Each component showed the same type of KRAS mutation (p.G12V) and was considered to originate from a single primary tumor in the pancreas. She received 3 courses of the same regimen as adjuvant chemotherapy and has remained recurrence-free for 24 months.
CONCLUSION: This is a rare case of successful conversion surgery for locally advanced, unresectable panNEC after chemotherapy, providing several important histopathological and molecular insights.
common hepatic artery
CIScarcinoma in situ
CTcomputed tomography
EUS-FNAendoscopic ultrasonography-guided fine-needle aspiration
FDG-PET/CT18F-fluorodeoxyglucose positron-emission tomography/CT
H&Ehematoxylin–eosin
NSEneuron-specific enolase
PanINspancreatic intraepithelial neoplasias
panNECpancreatic neuroendocrine carcinoma
PDACpancreatic ductal adenocarcinoma
SpAsplenic artery
SSTR2somatostatin receptor 2
UICCUnion for International Cancer Control
Pancreatic neuroendocrine neoplasms are epithelial tumors with neuroendocrine differentiation, classified into well-differentiated (pancreatic neuroendocrine tumor [panNET] G1, G2, and G3) and poorly differentiated (pancreatic neuroendocrine carcinoma [panNEC]). Both panNET G3 and panNEC are aggressive (Ki-67 index of over 20%) but differ in their differentiation type, genetic variants, and prognosis.1) At the time of initial diagnosis, panNEC is often locally advanced and unresectable. Even when curative resection is achieved, the prognosis after surgery is extremely poor.2,3) The indications for surgery for panNEC are not well established. While some reports suggest that preoperative chemotherapy followed by definitive surgery could be beneficial in select cases,4,5) the use of preoperative therapy for panNEC is still limited.
In this case report, we describe conversion surgery for locally advanced, initially unresectable panNEC that responded favorably to chemotherapy. Furthermore, histopathological and molecular findings from this case provided some insights into the development of panNEC and its response to treatment.
A 72-year-old woman was referred to our hospital with a history of weight loss. She had a history of diabetes, with an elevated hemoglobin A1c level of 7.7%. Her neuron-specific enolase (NSE) level was markedly elevated at 45.9 ng/mL, while CA19-9, DUPAN-2, and Span-1 were within normal limits. An enhanced abdominal computed tomography (CT) scan showed a heterogeneously enhanced tumor measuring 32 mm in the pancreatic head region (Fig. 1A). The tumor exhibited over 180° of contact with the common hepatic artery (CHA) and had also contacted the celiac artery, splenic artery (SpA), left gastric artery, and right hepatic artery. The root of the splenic vein was invaded as well (Fig. 1B). No distant metastases were found in other organs. 18F-fluorodeoxyglucose (FDG) positron-emission tomography/CT (PET/CT) showed increased FDG uptake in the pancreatic head tumor, with a maximum standard uptake value of 11.6 (Fig. 2A).
CHA, common hepatic artery; CT, computed tomography; GDA, gastroduodenal artery; PV, portal vein; RHA, right hepatic artery; SMA, superior mesenteric artery; SpA, splenic artery; SpV, splenic vein; T, tumor
FDG, 18F-fluorodeoxyglucose; PET/CT, positron-emission tomography/computed tomography
Pathological findings of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) identified small cell-type neuroendocrine carcinoma (NEC). Cytological specimens stained with Giemsa and Papanicolaou showed several cell clusters composed of small, round atypical cells with naked nuclei and necrotic cells (Fig. 3A). Histological specimens stained with hematoxylin–eosin showed numerous hypercellular clusters of small, round atypical cells with hyperchromatic naked nuclei (with scant cytoplasm), along with extensive areas of necrosis (Fig. 3B). Immunohistochemically, atypical cells demonstrated diffuse positivity for neuroendocrine markers, including chromogranin A, synaptophysin (Fig. 3C), and Insulinoma-Associated Protein 1 (INSM1), as well as a diffuse loss of RB1 (Fig. 3D). Additionally, the Ki-67 labeling index exceeded 90% (Fig. 3E). Membrane expression of somatostatin receptor 2 (SSTR2) was either mild or obscure (Fig. 3F). The pre-treatment diagnosis was unresectable, locally advanced panNEC, with the clinical stage defined as cT4N0M0 (Union for International Cancer Control [UICC] 8th edition)6). She began a course of chemotherapy with carboplatin (420 mg) and etoposide (80 mg/m2).
EUS-FNA, endoscopic ultrasonography-guided fine-needle aspiration; EUS-FNB, endoscopic ultrasonography-guided fine-needle biopsy; H&E, hematoxylin–eosin stain; Pap, Papanicolaou stain; SSTR2, somatostatin receptor 2; SYP, synaptophysin
After 7 cycles of chemotherapy, an enhanced abdominal CT scan revealed a significant decrease in tumor size, which had reduced to 8 mm (Fig. 1C). The tumor was no longer in contact with the arteries, although some soft tissue density remained around the tumor (Fig. 1D). NSE had remained within normal limits since the second cycle of administration. The PET/CT showed decreased FDG uptake in the tumor, with a maximum standard uptake value of 3.0 (Fig. 2B). A pancreatoduodenectomy was planned as a conversion surgery. The major arteries, including CHA, SpA, and the gastroduodenal artery, could be separated at the layer where the adventitia was exposed, with no evidence of arterial invasion. Notably, compared with general cases of unresectable locally advanced pancreatic ductal adenocarcinoma (PDAC), arterial detachment in this case was relatively easier. Intraoperative rapid pathological diagnosis showed no evidence of malignancy in the peri-SpA plexus, peri-CHA nerve plexus, or periportal tissues, eliminating the need for a combined resection of vessels (Fig. 4). The operating time was 445 min, and the blood loss was 829 mL. Her postoperative course was almost uneventful, and she was discharged on postoperative day 16.
CHA, common hepatic artery; CHD, common hepatic duct; GDA, gastroduodenal artery; IMV, inferior mesenteric vein; LHA, left hepatic artery; Panc, pancreas; PV, portal vein; RHA, right hepatic artery; SMV, superior mesenteric vein; SpA, splenic artery; SpV, splenic vein
Pathological findings of the resected specimen revealed a residual tumor measuring 8 mm in diameter at the pancreatic head–body junction (Fig. 5A and 5B). The tumor was relatively well-defined and localized, with a yellowish-white solid mass on the cut surface. Fibrosis and swollen lymph nodes were observed surrounding the tumor (Fig. 5B). Histologically, the nodule showed a hypercellular tumor (Fig. 5C) composed of large, round to polygonal cells with large nuclei (featuring vesicular chromatin) and abundant cytoplasm, forming nesting and solid structures (Fig. 5D). Mitoses were prominent, but necrosis was very minimal. In the fibrous stroma and swollen lymph nodes surrounding the tumor, fibrosis and granulation tissue, likely representing the site of tumor regression, were widely observed, with proliferation of fibroblasts, infiltration of small lymphocytes, infiltration of macrophages, and myxoid degeneration. Additionally, low-grade pancreatic intraepithelial neoplasias (PanINs) were scattered. Immunohistochemically, tumor cells were diffusely positive for pan-cytokeratin (antibodies AE1 and AE3) and several neuroendocrine markers (chromogranin A [Fig. 6A], synaptophysin, CD56, and INSM1). They were diffusely negative for Bcl10, GATA3, p40, and several hormones (insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, serotonin, and adrenocorticotropic hormone). Additionally, the tumor cells exhibited diffuse overexpression of p53 (Fig. 6B) and a diffuse loss of RB1 expression (Fig. 6C), and the Ki-67 labeling index exceeded 90% (Fig. 6D). Based on the histology and immunohistochemical findings, the tumor was diagnosed as large cell type NEC. Unexpectedly, tumor cells showed a diffuse, prominent membrane expression of SSTR2 (Fig. 6E). Furthermore, a small amount of high-grade PanIN/carcinoma in situ (CIS) was observed around and inside the tumor (Figs. 5A and 6F), displaying a diffuse overexpression of p53 and a diffuse loss of RB1 (Fig. 6B and 6C). The CIS extended to the cut end of the main pancreatic duct, but intraoperative examination of the true pancreatic margin specimen confirmed it to be negative (as noted later, no KRAS mutations were detected either) (Fig. 7). No extrapancreatic invasion or lymph node metastasis was identified (0/39), leading to a pathological stage of ypT1bN0M0 according to the UICC 8th edition staging.6) Surgical margins were negative (R0), and the chemotherapy effect was evaluated as Score 2 (partial response) based on the modified Ryan scheme (College of American Pathologists [CAP] classification).7)
CIS, carcinoma in situ; NEC, neuroendocrine carcinoma
CgA, chromogranin A; CIS, carcinoma in situ; H&E, hematoxylin–eosin stain; NEC, neuroendocrine carcinoma; PanIN, pancreatic intraepithelial neoplasia; SSTR2, somatostatin receptor 2
CIS, carcinoma in situ; EUS-FNA, endoscopic ultrasonography-guided fine-needle aspiration; NEC, neuroendocrine carcinoma
Genetic analysis using Luminex 100/200 technology (Luminex Corporation, Austin, TX, USA) on a formalin-fixed, paraffin-embedded tumor sample from the surgical specimen revealed a KRAS mutation (p.G12V). Furthermore, Sanger sequencing with microdissection confirmed that each component—small cell type NEC from EUS-FNA, as well as large cell type NEC and CIS from the resected specimen—shared the same KRAS mutation (p.G12V) (Fig. 7). This finding supported the final diagnosis of panNEC coexisting with CIS components, rather than indicating a collision nature.
She received adjuvant chemotherapy with 3 courses of carboplatin and etoposide, which was the same regimen as the preoperative treatment, and remained recurrence-free for 24 months after the pancreatectomy.
This is a rare case of locally advanced, unresectable panNEC that was successfully treated with chemotherapy and subsequently underwent conversion surgery with a favorable outcome. The present case allowed us to report in detail the histogenesis and molecular behavior of panNEC and the changes in pathological findings of tumor cells before and after chemotherapy.
This case provides important histopathological and molecular insights. First, high-grade PanIN/CIS was observed around and inside the NEC component. In both components, a diffuse loss of RB1 and overexpression of p53 were observed. This suggests that the CIS components may have preceded or coexisted with the NEC components. Furthermore, the same type of KRAS mutation was detected in all lesions, including the small cell-type NEC from EUS-FNA and the large cell-type NEC and CIS from the resected specimen. These findings indicate that each lesion originated from the same pancreatic tissue, clearly supporting the current consensus that panNEC should be considered a subtype of PDAC, characterized by a high frequency of KRAS mutations.8–10)
Second, the predominant component of the tumor changed before and after chemotherapy. The EUS-FNA before chemotherapy showed predominantly small cell-type NEC with a tendency for extensive necrosis, whereas the residual tumor in the resected specimen after chemotherapy showed only a large cell-type NEC component with minimal necrosis. The contrast pattern of enhanced CT also shifted from a heterogeneously enhanced hypovascular tumor to a hypervascular tumor, reflecting the degree of necrosis. Although speculative, it is possible that the small cell-type NEC components, which originally constituted the majority of the tumor and were characterized by extensive necrosis, disappeared after chemotherapy, leaving only the large cell-type NEC component, which was initially mixed and resistant to chemotherapy. On the other hand, it is not yet clear whether the small cell-type NEC can convert to the large cell-type NEC due to chemotherapy or other factors.
Third, the diffuse membrane expression of SSTR2 was observed in the large cell-type NEC. Membrane expression of SSTR2 is usually seen in NETs, whereas it is absent or localized in NEC. Therefore, SSTR2 serves as an important marker for differential diagnosis and treatment selection between NETs and NEC.11) In the present case, despite the presence of typical NEC, a diffuse and distinct membrane expression was observed, especially in the postoperative NEC component. It remains unclear whether this phenomenon is an exception or whether it occurs in a certain number of cases, and whether diagnosis and treatment (in combination with) targeting somatostatin receptors would be beneficial for NEC with SSTR2 membrane expression requires further case accumulation. Nonetheless, immunostaining for SSTR2 should be considered in NEC.
National Comprehensive Cancer Network (NCCN), European Neuroendocrine Tumor Society (ENETS), and North American Neuroendocrine Tumor Society (NANETS) guidelines4,12,13) recommend platinum-based chemotherapy as adjuvant therapy for panNEC but do not recommend surgical resection or neoadjuvant therapy due to limited evidence. In the present case, platinum-based chemotherapy was administered as recommended for adjuvant therapy, without an intention of resection. There are very few case reports of surgical resection after chemotherapy for panNEC. Table 1 shows the results of a search in PubMed (keywords: “pancreatic neuroendocrine carcinoma,” “pancreas,” “neoadjuvant treatment,” “pancreatectomy”).14,15) All patients had small cell-type NEC and were treated with cisplatin and etoposide for 4–5 months as neoadjuvant therapy. The present case was unique in that the postoperative pathology was converted to large cell type NEC. If significant tumor reduction is achieved and radical resection is deemed feasible, surgical resection could be considered. Although panNEC rarely becomes resectable after chemotherapy, the patient had a favorable survival outcome following surgical resection, suggesting that a promising prognosis may be achievable when chemotherapy proves significantly effective.
| Author, year | Location | Preoperative pathological findings |
Neoadjuvant therapy | Operation | Postoperative pathological findings |
Adjuvant therapy | Survival |
|---|---|---|---|---|---|---|---|
| Li, et al. (2021)14) | Head and neck | Small cell type NEC Ki67 80% |
EP (6c) | DP – CAR | Only necrotic and fibrotic tissues | None | 8 m |
| Elzein, et al. (2021)15) | Head | Small cell type NEC Ki67 80% |
EP (6c) → RT (50.4Gy) |
PD + SMVr | NECKi67 5% | None | 28 m |
| Our case | Head | Small cell type NECKi67 90% | CBDCCA + VP16 (7c) | PD | Large cell type NECKi67 80% | CBDCA + VP16 (3c) | 21 m |
CBDCA+VP16, carboplatin/etoposide; DP, distal pancreatectomy; DP-CAR, DP with celica axis resection; EP, etoposide/cisplatin; NEC, neuroendocrine carcinoma; PD, pancreatoduodenectomy; RT, radiotherapy; SMVr, superior mesenteric vein resection and reconstruction
The present case represents a successful conversion surgery for locally advanced, unresectable panNEC after chemotherapy, revealing some interesting histopathological and molecular findings. Appropriate chemotherapy may enable surgical resection, and the effectiveness of this treatment could be reflected in postoperative survival outcomes. More relevant clinical cases need to be reported in the future to build evidence for the use of conversion surgery in panNEC.
We acknowledge all individuals who were involved in this study.
No grant support or funding from public institutions or private enterprises was received for this case report.
Authors’ contributionsYT drafted the manuscript.
MY supervised the writing of the manuscript.
HK and TS were involved in performing the surgery.
MY, HK, SO, YK, KO, RA, and TS contributed to patient management.
NO, TN, and TS made pathological diagnoses and performed molecular analyses.
All authors read and approved the final manuscript.
Availability of data and materialsAll data analyzed in this study are included in this manuscript.
Ethical approval and consent to participateAll ethical and moral issues have been considered in this study. The present study was approved by the Institutional Review Board of Shizuoka Cancer Center (Approval Number: J2024-153-2024-1).
Consent for publicationWritten informed consent for the publication of this case report and the accompanying images was obtained from the patient.
Competing interestsThe authors declare that they have no competing interests.
