The patient was a 45-year-old woman who received a distal pancreatectomy with splenectomy for a huge mass, encapsulated solid mass with cystic components (measuring 100 × 70 mm) in the body and tail of the pancreas in the local hospital on March 10, 2010. The histologic examination established the presumptive diagnosis of a well differentiated pancreatic neuroendocrine tumor (pNET). Immunohistochemical analysis showed positive staining for synaptophysin (Syn) and negative for cytokeratin (CK), and chromogranin A (CgA). No adjuvant therapy was administered. Metastasectomy of the lesions (maximum size of 50 × 40 cm) in her pancreatic remnant and adjacent peritoneum was performed with lymph node dissection on March 3, 2014. The revised diagnosis was metastases of low-grade pNET accompanied with SPN immunophenotype. The specimen was positive for Syn, CD56, vimentin, progesterone receptor (PR), and β-catenin immunostaining, whereas negative for CgA. The second metastasectomy was performed to remove recurrent nodules of the left adrenal gland (maximum size of 20 × 15 cm) on January 8, 2015 (). During the next 10 months the patient suffered some additional metastatic recurrences (maximum size of 55 × 35 cm) in her left adrenal gland and peritoneum () before her first visit to our hospital on November 17, 2015. The patient participated in a nation-wide clinical study, approved by our hospital’s Ethics Committee, to evaluate the efficacy and safety of sunitinib in the treatment of metastatic pNET in January, 2016. Meanwhile, the pathological features of the tumors from the first three operations were carefully reviewed in the glass slides and paraffin blocks by our own pathologists. All of the tumors were composed of relatively monomorphic polyhedral cells with hyalinized fibrovascular cores. Neoplastic cells were discohesive with round to oval nuclei. Mitotic figures were rare. The growth pattern of the tumor was heterogeneous, with a combination of solid and pseudocystic structures in varying proportions, even in the primary tumor. Sparse vascular invasion was found in the primary tumor with Ki67 index <1%. Immunohistochemical analysis including CD-56, PR, CD10, E-cadherin, and β-catenin was re-performed in the primary and recurrent tumors. All of the tumors were immunopositive for β-catenin (nuclei), CD10, vimentin, PR and Syn and immunonegative for E-cadherin. According to recently published data, a particular dot-like paranuclei expression of CD99 appears to be highly unique for SPN, and this distinctive staining pattern was present in this case. Even in the primary tumor, CD99 expression was punctate and granular positive in the cytoplasm (3+). CD99 accompanied by β-catenin definitely established the diagnosis of SPN in the case (). The patient was finally diagnosed with a metastatic pancreatic SPN with low-grade malignant potential. She rejected the reoperation for fear of harm from multiple surgeries. According to RECIST 1.1 (response evaluation criteria in solid tumors), the patient’s abdominal metastatic tumors were in a stable state, and given that patients did not have any severe comorbidities while taking sunitinib, the patient continued targeted therapy during the following 2 years. In the first quarter of 2018, the patient presented with some new metastatic lesions in the peritoneum, pelvis, and retroperitoneum, and the earlier lesions increased in size significantly (). To obtain the evolutionary features of the tumor immune phenotype, metastasectomy of the biggest peritoneal lesion (maximum size of 75 × 55 cm) was performed on April 18, 2018. The pathological analysis confirmed the metastatic nature of the SPN as capsular with very few capsular and vascular invasions (). Grossly, the cross-section of the peritoneal metastatic tumor revealed a round, well demarcated mass measuring 75 × 50 mm that consisted of a mixed component containing focal hemorrhage. The tumor showed nested-to-diffuse growth of more poorly cohesive monomorphic cells with scattered nuclear atypia and fibrovascular stalks in which mitosis was sparse with the Ki-67 index 5-10%. The cytologic features also included characteristic myxoid clear material surrounding the papillae, the presence of cercariform cells and sparse mitotic figure. Regional cystic degeneration and haemorrhage were observed. Focal solid areas extended towards the surrounding fat tissue with prominent capsular and vascular invasion. No significant nuclear atypia, abundant necrosis, or high mitotic rate was found. The lesion showed typical immunohistochemical features for SPN, such as nuclear expression of β-catenin, paranuclei dot-like expression of CD-99, positive findings for CD10 (focal region, 3+), vimentin and PR. Interestingly, Syn was positive as always from the primary to the recurrent tumors. On the presumption of disseminated peritoneal metastasis, an extended metastasectomy was performed to remove the left kidney, left adrenal gland, partial diaphragm muscle, small liver nodules, several peritoneal nodules, and pelvic nodules in an outside hospital on August 21, 2018. Two months postoperatively, the patient presented with a new metastatic lesion in the right hepatic lobe. She was admitted to our hospital again. Computed tomography (CT) scan revealed a well-defined hepatic encapsulated solid mass with cystic components but no calcification (maximum size of 52 × 36 cm, ). Genomic DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue for next-generation sequencing (NGS) by llumina Genome Analyzer. The patient was positive for CTNNB1 c.98C>G (p.S33C), ATM c.5633C>T (p.S1878L), and PTEN c.379G>A (p.G127R) point mutations with a germline mutation in FANCD2 c.888+1G>T. On December 28, 2018, the patient started treatment with everolimus for targeting PTEN mutations. Assessment of response was performed by means of computed tomography (CT) scan or magnetic resonance imaging (MRI), every 12 weeks of therapy, according to RECIST criteria 1.1. At present, the patient does not seem to have any serious discomfort except for grade 1 cutaneous vasculitis. She is well, and without any signs of disease progression. The serial follow-up magnetic resonance imaging examination on March 2020 () and October 2020 () showed that the patient’s tumor had partially resolved and remained stable for more than 22 months after the targeted treatment of everolimus. It was also noted that the tumor immune phenotype might have a certain degree of evolutionary characteristics over time (). In accordance with the immunohistochemical changes, we subdivided the lesions into early (first to third operations) and late (forth to fifth) lesions. In the early metastatic lesions, the tumors had almost no capsular or vascular invasion with weakly positive immunostaining of β-catenin (nuclei, +). The Ki-67 labeling index was also very low (<1%). In the late lesions, malignant histological features, such as peritumoral infiltration into the fat tissue (from the fourth lesion) and the organ, prominent capsular and vascular invasion were observed (). The specimen was strongly positive for immunostaining of β-catenin (nuclei, +++, ). Furthermore, the average Ki-67 labeling index increased sharply (3%, 5–10%, and 15% in the third, fourth, and fifth metastatic lesions, respectively).