Abstract
INTRODUCTION: While para-aortic lymph node recurrence may occur after curative resection for pancreatic ductal adenocarcinoma (PDAC), it is rarely seen as a late recurrence and is usually treated with systemic chemotherapy. In contrast, recurrence of pancreatic neuroendocrine neoplasms (Pan-NENs) can occur more than a decade after surgery and may be amenable to surgical resection. Although immunohistochemical techniques have significantly enhanced the diagnostic distinction between PDAC and Pan-NEN, challenges remain, particularly in older cases.
CASE PRESENTATION: A 77-year-old man underwent distal pancreatectomy for pancreatic body cancer 11 years prior, initially diagnosed as PDAC based on glandular morphology, and received adjuvant S-1 chemotherapy. Surveillance ended after 5 years without recurrence. Eleven years after surgery, imaging performed during evaluation for elevated prostate-specific antigen revealed a 16-mm para-aortic lymph node enlargement. CT-guided biopsy showed neuroendocrine morphology with chromogranin A and synaptophysin positivity, consistent with neuroendocrine tumor (NET). Retrospective histological review of the original surgical specimen revealed previously unrecognized NET-G2 components (Ki-67, 5.0%). Surgical resection of the para-aortic and mesenteric lymph nodes was performed, and pathology confirmed NET-G2 metastases (Ki-67, 6.7%). The patient recovered uneventfully and remains recurrence-free at 7 months postoperatively under active surveillance.
CONCLUSIONS: This case highlights the importance of tissue diagnosis when late-onset recurrence is observed in patients with a prior diagnosis of PDAC. It also underscores the potential for extremely delayed recurrence in Pan-NENs and the importance of long-term surveillance. For patients presenting with isolated distant recurrence long after initial treatment for PDAC, biopsy and pathological re-evaluation should be considered to ensure appropriate therapeutic decision-making.
Abbreviations
EUS-TA
endoscopic ultrasound-guided tissue acquisition
FDG
fluorodeoxyglucose
NET
neuroendocrine tumor
PALN
para-aortic lymph node
Pan-NEN
pancreatic neuroendocrine neoplasm
PDAC
pancreatic ductal adenocarcinoma
INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies; thus, we often experience a recurrence after curative resection. Typical recurrence occurs within 5 years, and the common recurrent sites are liver, peritoneal, lung, and local recurrence.1) Although para-aortic lymph node (PALN) recurrence is not as common as the aforementioned metastatic sites, Hishinuma et al. reported approximately 20% of PALN metastasis in patients with PDAC recurrence based on autopsy analysis.2) In such cases, systemic chemotherapy is generally the mainstay of treatment.
In contrast, pancreatic neuroendocrine neoplasms (Pan-NENs) generally carry a more favorable prognosis than PDAC. Nevertheless, recurrence after curative resection occurs in approximately 20%–30% of cases.3) The most frequent recurrent site is the liver, accounting for nearly 80% of metastases. Although PALN metastasis has also been reported in Pan-NENs,4,5) it remains relatively uncommon. Unlike PDAC, treatment options for distant recurrence of Pan-NEN include surgical resection, depending on factors such as tumor burden, recurrent tumor location, and biological behavior.
Although immunohistochemistry of neuroendocrine markers has greatly improved the ability to distinguish PDAC from Pan-NEN, it sometimes remains challenging. Notably, in the early 2010s, the classification of neuroendocrine tumors (NETs) was still evolving, and tumors with ambiguous histological features may have had their neuroendocrine components underrecognized or misclassified.
Here, we report a case of PALN recurrence 11 years after curative resection for a tumor initially diagnosed as PDAC. The lesion’s atypical clinical behavior prompted re-biopsy and pathological re-evaluation, which revealed previously unrecognized neuroendocrine differentiation. This case highlights the importance of histological reassessment in patients with unusual recurrence patterns, particularly in those diagnosed prior to the establishment of current diagnostic standards.
CASE PRESENTATION
A 77-year-old man was diagnosed with a tumor in the pancreatic body and underwent distal pancreatectomy with splenectomy 11 years ago. Histopathological examination of the surgical specimen at the time of the initial surgery revealed glandular structures. Periodic acid Schiff–Alcian blue staining confirmed the presence of mucin-containing cells (Fig. 1), leading to a diagnosis of invasive PDAC. Based on the pathological findings, the tumor was diagnosed as pT3pN1pM0, fStage IIB according to the Union for International Cancer Control 7th edition. Postoperative adjuvant chemotherapy with S-1 was completed successfully.
Routine surveillance for PDAC was discontinued after 5 years with no evidence of recurrence. Eleven years after the initial surgery, during an evaluation for elevated prostate-specific antigen levels at another facility, MRI revealed a 16-mm PALN enlargement adjacent to the left renal artery (Fig. 2). Contrast-enhanced CT verified the enlarged PALN seen on MRI and confirmed no other evidence of tumor. Fluorodeoxyglucose PET/CT (FDG-PET/CT) demonstrated no significant abnormal uptake, including in the enlarged lymph node. Serological examinations, including tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9, and neuron-specific enolase, revealed no remarkable abnormalities. Given the unusually late onset and isolated nature of the recurrence, which was atypical for PDAC, a CT-guided biopsy of the PALN was performed. Initial histological examination revealed tumor cells positive for chromogranin A and synaptophysin, with a Ki-67 labeling index of 30.9%, initially suggestive of NET-G3 according to the World Health Organization (WHO) 2019 classification. However, closer inspection revealed that background lymphocytes also exhibited nuclear Ki-67 positivity, and the true proliferative index within the tumor cells was estimated to be approximately 5% (Fig. 3). Following these findings, somatostatin receptor scintigraphy was undertaken but demonstrated no significant uptake.
Given these unexpected findings, a retrospective histopathological review of the archival surgical specimen from the initial surgery was performed. Detailed examination revealed scattered cord-like structures suggestive of neuroendocrine differentiation in a small part of the PDAC tumor. Because morphological evaluation alone was insufficient for a definitive diagnosis, additional immunohistochemical staining was performed, revealing focal positivity (< 30%) for chromogranin A and synaptophysin, with a Ki-67 labeling index of 5.0%, consistent with NET-G2 (Fig. 4). As the neuroendocrine component accounted for less than 30% of the total tumor volume, the diagnosis of mixed neuroendocrine–non-neuroendocrine neoplasm was excluded in accordance with the WHO 2019 classification, which requires both components to exceed 30%. Based on this re-evaluation, the initial tumor was retrospectively diagnosed as PDAC with a neuroendocrine component.
Based on these findings, we concluded that the PALN lesion was a metastasis originating from the NET component of the pancreatic tumor. Given the lesion’s indolent progression and solitary presentation, open surgical resection of the PALN was undertaken. Two additional enlarged mesenteric lymph nodes were also identified intraoperatively and subsequently resected. Histopathological examination of the 3 lymph nodes confirmed metastases of NET-G2 with a Ki-67 index of 6.7% (Fig. 5).
The postoperative course was uneventful, and monthly lanreotide treatment was administered as adjuvant therapy for 6 months based on the clinical judgment of the attending physician. At the 7-month follow-up, the patient remained disease-free under active surveillance.
DISCUSSION
This case represents an unusual instance of PALN recurrence occurring 11 years after resection of a tumor initially diagnosed as PDAC. The lesion exhibited an atypical clinical course for PDAC recurrence, including the extremely late onset, lack of FDG uptake, and absence of other metastatic disease. These atypical features prompted a tissue biopsy to achieve a definitive diagnosis before initiating systemic therapy. CT-guided biopsy was chosen due to the lesion’s location beyond the reach of endoscopic ultrasound-guided tissue acquisition (EUS-TA), although, when feasible, EUS-TA offers comparably high sensitivity and accuracy.6)
PDAC is known for early recurrence, typically within 2 years following resection.7) On the other hand, Pan-NENs exhibit variable recurrence patterns. While most recurrences occur within 5 years after surgery, multiple studies have documented recurrence even after a decade. For example, Yao et al. reported that delayed recurrence beyond 10 years is possible in Pan-NENs, highlighting their potential for prolonged dormancy.8) In our institutional cohort of 145 patients who underwent curative resection for localized Pan-NETs between January 2014 and September 2023, postoperative recurrence occurred in 9 cases (6.2%), with 2 of these cases presenting recurrence more than 5 years after surgery (Table 1).
Table 1 Cases with postoperative recurrence
|
Age |
Sex |
RFS
(months) |
OS
(months) |
Recurrence
site |
Ki-67 index
(%) |
WHO grade |
Status |
| 1 |
49 |
Female |
14.4 |
114.7 |
Liver |
1.4 |
G1 |
Alive |
| 2 |
45 |
Male |
17.7 |
81.1 |
Lymph node |
12.7 |
G2 |
Alive |
| 3 |
46 |
Female |
21.3 |
73.5 |
Liver |
1.5 |
G1 |
Alive |
| 4 |
59 |
Male |
26.2 |
76.9 |
Liver |
27.5 |
G3 |
Alive |
| 5 |
81 |
Female |
28.4 |
58.3 |
Liver |
9.4 |
G2 |
Alive |
| 6 |
62 |
Male |
33.6 |
91.7 |
Liver |
2.6 |
G1 |
Alive |
| 7 |
64 |
Male |
42.6 |
93.7 |
Liver |
3.6 |
G2 |
Alive |
| 8 |
65 |
Male |
86.4 |
116.1 |
Liver |
1.0 |
G1 |
Alive |
| 9 |
71 |
Male |
91.1 |
92.5 |
Liver |
7.5 |
G2 |
Alive |
Age indicates the patient’s age at the time of surgery. WHO grade was assigned based on the WHO 2019 classification of neuroendocrine tumors.
OS, overall survival; RFS, recurrence-free survival; WHO, World Health Organization
Management of distant recurrence in Pan-NENs, including liver and lymph node metastases, is often debated. However, several reports have shown that in cases with isolated metastases, surgical resection can offer durable disease control. Mayo et al. demonstrated improved survival in patients undergoing resection of hepatic metastases.9) In the context of lymph node recurrence, Hane et al.4) and Kishimoto et al.5) reported long-term survival exceeding 7–10 years after resection of PALN metastases. Although the observation period is limited, our case also demonstrates a disease-free course following surgery, with no evidence of recurrence at 7 months postoperatively. According to the National Comprehensive Cancer Network guidelines, follow-up includes assessment, markers, and imaging at 12 weeks to 12 months after resection, then every 6–12 months for 10 years. Given the high risk of recurrence associated with distant lymph node metastasis, we consider a follow-up schedule of imaging every 3 months in the 1st year, every 6 months from the 2nd through the 5th year, and annually thereafter up to 10 years, with extension as clinically indicated.
This case also underscores the diagnostic complexity of differentiating PDAC from Pan-NENs with atypical morphology. The pancreatic tumor was diagnosed as adenocarcinoma based on glandular architecture and mucin production, and the lesional lymph node metastasis was predominantly composed of adenocarcinoma elements at the initial pathological diagnosis. In addition, imaging showed a hypovascular mass with ill-defined margins and an associated pancreatic duct stricture, which contrasts with the typical NET appearance of a well-circumscribed, hypervascular lesion. Therefore, NET was not considered in the differential diagnosis at the time, and immunohistochemical staining for neuroendocrine markers was not performed. However, on retrospective review, additional immunohistochemical staining revealed focal positivity for chromogranin A and synaptophysin, with a Ki-67 labeling index of 5.0%, consistent with NET-G2. This likely reflects both the limited use of immunohistochemical staining and the relatively low clinical recognition of NETs in the early 2010s,10) which made accurate histopathological differentiation more difficult. We now explicitly note that older cases—diagnosed years earlier—may warrant immunohistochemical re-evaluation using modern techniques, as this can reveal previously unrecognized tumor components and impact management.
Upon retrospective review, a portion of the tumor exhibited features consistent with NET-G2. Taking the above observations into consideration, it is likely that the adenocarcinoma component was completely eradicated by surgical resection followed by adjuvant S-1 chemotherapy, whereas the residual NET component persisted, causing delayed recurrence. Another possibility is that the lesion represented a de novo NET in the lymph node; however, this is considered extremely unlikely, as comprehensive imaging studies revealed no evidence of another primary site. Recognition of the NET component at the outset would not have altered the adjuvant treatment, as S-1 remains standard for PDAC and no proven adjuvant therapy exists for NETs.
Another important consideration in this case is the discrepancy between Ki-67 indices obtained from the biopsy specimen (30.9%) and the resected surgical specimens (6.7%). One possible explanation is that reactive lymphoid proliferation in the biopsy may have led to an overestimation of the Ki-67 index. In daily practice, such discrepancies are not uncommon, particularly in small biopsy samples, because it can be difficult to determine whether Ki-67-positive nuclei belong to tumor cells or inflammatory cells.11) In the present case, surgical resection was undertaken due to the lesion’s indolent progression. However, if the lesion had been definitively classified as NET-G3, a more conservative approach to surgical intervention may have been considered.12) This highlights the importance of meticulous tumor grading to optimize treatment planning.
CONCLUSIONS
We report a rare case of PALN recurrence of Pan-NEN occurring 11 years after initial resection, which had originally been diagnosed as PDAC. This case highlights an important clinical consideration: in patients with a prior diagnosis of PDAC who present with atypical patterns of recurrence, tissue biopsy and histopathological reassessment should be strongly considered before initiating systemic therapy. Such diagnostic vigilance may reveal previously unrecognized neuroendocrine components, enabling potentially curative surgical intervention. Ultimately, this case underscores the importance of individualized management, long-term surveillance, and critical re-evaluation in the setting of unexpected recurrence.
DECLARATIONS
Funding
No funding was involved in this case report.
Authors’ contributions
YT: Performed the surgical procedures and prepared the manuscript.
HT: Conceptualization, data collection, and contributed to the discussion.
DA: Critical revision of the manuscript and contributed to the discussion.
SM and YI: Contributed to the discussion.
HU: Performed the surgical procedures and contributed to the discussion.
KA and EK: Critical revision of the manuscript and contributed to the discussion.
YKa and YKi: Data collection, critical revision of the manuscript, and contributed to the discussion.
DB: Final approval of the manuscript.
All authors have read and approved the manuscript.
Availability of data and materials
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
All study procedures were approved by our institutional review board (Human Research Ethics Committee, Institute of Science Tokyo; approval ID: 1080).
Consent for publication
Written informed consent was obtained from the patient for publication of this case report.
Competing interests
The authors of this manuscript have no conflicts of interest to disclose.
REFERENCES
- 1) Tanaka M, Mihaljevic AL, Probst P, et al. Meta-analysis of recurrence pattern after resection for pancreatic cancer. Br J Surg 2019; 106: 1590–601.
- 2) Hishinuma S, Ogata Y, Tomikawa M, et al. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings. J Gastrointest Surg 2006; 10: 511–8.
- 3) Bader A, Landau S, Hwang J, et al. Recurrence and treatment trends of pancreatic neuroendocrine tumors. Surgery 2025; 177: 108835.
- 4) Hane Y, Tsuchikawa T, Takeuchi S, et al. Long-term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms: a report of two cases. J Surg Case Rep 2021; 2021: rjab446.
- 5) Kishimoto Y, Ogura T, Takahashi A, et al. A case of pancreatic neuroendocrine neoplasm with para-aortic lymph node metastases without recurrence for 7 years after resection. J Jpn Surg Assoc 2021; 82: 174–9. (in Japanese)
- 6) Hara H, Hijioka S, Yamashige D, et al. Clinical significance and efficacy of endoscopic ultrasound-guided tissue acquisition for para-aortic lymph node metastasis. Dig Endosc 2025; 37: 775–86.
- 7) van Oosten AF, Daamen LA, Groot VP, et al. Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: a bi-institutional validated risk classification. Eur J Surg Oncol 2023; 49: 106910.
- 8) Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26: 3063–72.
- 9) Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010; 17: 3129–36.
- 10) Fitzgibbons PL, Goldsmith JD, Souers RJ, et al. Analytic validation of immunohistochemical assays: a comparison of laboratory practices before and after introduction of an evidence-based guideline. Arch Pathol Lab Med 2017; 141: 1247–54.
- 11) Ahn S, Lee J, Cho MS, et al. Evaluation of Ki-67 index in core needle biopsies and matched breast cancer surgical specimens. Arch Pathol Lab Med 2018; 142: 364–8.
- 12) Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 2016; 103: 153–71.
