Late nodal recurrence after two curative resections for microinvasive intraductal papillary mucinous carcinoma: A case report

Abstract

BACKGROUND

Intraductal papillary mucinous neoplasms (IPMNs) are precursors of pancreatic ductal adenocarcinoma and often harbor KRAS and GNAS mutations. Although disease progression may take a decade or longer, very late recurrence after curative resection is rare. The treatment options for older patients remain limited due to their poor tolerance to standard chemotherapy.

CASE SUMMARY

Herein, we report the case of a 92-year-old woman with multicentric main duct microinvasive intraductal papillary mucinous carcinoma who underwent two curative resections (spleen-preserving distal pancreatectomy in 2005 and pylorus-preserving complete total pancreatectomy in 2007). Thirteen years after the second resection, at age 89, the patient developed an isolated lymph node recurrence with markedly elevated tumor marker levels (carbohydrate antigen 19-9, 1080 U/mL; duodenal pancreatic cancer antigen-2, 820 U/mL). Considering the patient’s advanced age and frailty, alternate-day low-dose S-1 (40 mg/day) therapy was initiated. The treatment was well-tolerated, and complete radiological and serological remission was achieved within 9 months. The patient remained recurrence-free until age 91 and ultimately died of pneumonia and senile decline at age 92 without evidence of cancer.

CONCLUSION

IPMN requires lifelong surveillance; late recurrence can occur, and individualized treatment is crucial in older patients.

Key Words: Intraductal papillary mucinous neoplasm; Microinvasive intraductal papillary mucinous carcinoma; Pancreatic cancer; Long-term recurrence; Older individual; S-1 chemotherapy; Case report

Core Tip: Microinvasive intraductal papillary mucinous carcinoma (IPMC) is generally considered an indolent precursor of pancreatic ductal adenocarcinoma, and curative resection is expected to provide long-term disease control. This case illustrates that microinvasive IPMC can nevertheless exhibit extremely late lymph node recurrence more than a decade after two curative pancreatic resections. The findings highlight the slow but persistent malignant potential of microinvasive IPMC and emphasize the necessity of lifelong postoperative surveillance. In addition, this case underscores the importance of individualized management strategies for recurrence in very elderly patients.

INTRODUCTION

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are precursors of pancreatic ductal adenocarcinoma. Activating somatic mutations in KRAS and GNAS are common founder events in IPMNs, and GNAS alterations have been repeatedly found in cystic fluid and tumor tissue[1,2]. Moreover, synchronous or metachronous lesions arising within the same pancreas can harbor distinct KRAS/GNAS genotypes, supporting multicentric origins rather than simple contiguous intraductal spread[3-5]. Detection of mutant alleles in pancreatic juice provides additional evidence for a ductal “field defect”[6].

The progression from IPMNs to high-grade dysplasia and invasive carcinoma generally involves the acquisition of additional progressor alterations (e.g., TP53, CDKN2A, and SMAD4). Genomic and mathematical modeling studies have estimated that the evolutionary interval from an initiating driver event to clinically detectable carcinoma may span 10-20 years, providing a mechanistic rationale for very late recurrence and long-term surveillance[7-9].

Epidemiological data also indicate an excessive incidence of extrapancreatic malignancies in patients with IPMNs, with colorectal, gastric, and lung cancers being the most commonly reported[10-12]. These findings likely reflect a combination of shared somatic oncogenic pathways, germline predispositions in a subset of patients, and surveillance effects[13].

S-1 (an oral tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate formulation) is widely used in East Asia as a fluoropyrimidine[14]. Because standard continuous schedules can be poorly tolerated in considerably older or frail individuals, alternate-day or other reduced-intensity S-1 schedules have been explored to mitigate toxicity while maintaining efficacy[15-17]; prospective and phase II studies, including pancreatic-cancer-specific trials, have assessed alternate-day dosing[17].

Herein, we report the case of a patient with multicentric main-duct microinvasive intraductal papillary mucinous carcinoma (IPMC) who underwent two curative resections, developed late lymph node recurrence 13 years after the second surgery, and achieved a complete radiologic and serologic response to alternate-day low-dose S-1 therapy.

CASE PRESENTATION

Chief complaints

Incidental dilatation of the main pancreatic duct (MPD) was detected on preoperative imaging before cholecystectomy.

History of present illness

A 73-year-old woman underwent a laparoscopic cholecystectomy for cholelithiasis in 2004. Magnetic resonance cholangiopancreatography performed at that time incidentally revealed MPD dilatation in the pancreatic body. The patient was referred to the Nagoya University Hospital in February 2005 for further evaluation.

History of past illness

The patient had a history of cholelithiasis and underwent cholecystectomy in 2004. The patient had no history of pancreatitis, diabetes mellitus, or malignancy.

Personal and family history

There was no family history of pancreatic cancer or other gastrointestinal malignancies.

Physical examination

Physical examination revealed no remarkable findings.

Laboratory examinations

Serum tumor markers, including carbohydrate antigen 19-9 (CA19-9), duodenal pancreatic cancer antigen-2 (DUPAN-2), and S-pancreas antigen-1 (Span-1), were within normal ranges.

Imaging examinations

Contrast-enhanced computed tomography (CE-CT) performed in March 2005 (Figure 1) revealed marked dilatation of the MPD in the pancreatic body.

Figure 1 Preoperative imaging before the initial surgery. Contrast-enhanced computed tomography image obtained in March 2005, before the initial surgery. The main pancreatic duct in the body and tail of the pancreas is dilated (orange arrowhead), whereas no dilatation is observed in the pancreatic head (orange arrow). These findings led to the diagnosis of main duct-type intraductal papillary mucinous neoplasm in the pancreatic body and tail.

Cytological examination

Cytological examination of pancreatic juice revealed adenomatous cells.

Histopathological examination

Histopathological examination revealed a microinvasive IPMC (Figure 2A and B) and negative surgical margins. Therefore, resection was considered curative, and the patient was followed up on an outpatient basis.

Figure 2 Histopathological findings of microinvasive intraductal papillary mucinous carcinoma (Hematoxylin and eosin staining). A and B: Histopathological images from the first surgery. Atypical columnar epithelium showing dysplasia proliferates in papillary patterns within the dilated pancreatic duct. Slight irregularity of the basal aspect indicating microinvasion is observed in the marginal area (black arrow) (A: × 40; B: × 200); C and D: Histopathological images from the second surgery. Findings similar to those of the first surgery, including microinvasion (black arrow), are observed (C: × 40; D: × 200).

FINAL DIAGNOSIS

Based on these findings, the patient was diagnosed with main-duct IPMN. Surgical resection was performed, and histopathological examination revealed microinvasive IPMC.

TREATMENT

In March 2005, a spleen-preserving distal pancreatectomy was performed at age 74. Histopathological examination confirmed the presence of a microinvasive IPMC, and the surgical margins were negative. Therefore, resection was considered curative, and the patient was followed up on an outpatient basis.

During the follow-up, CE-CT performed in June 2007 demonstrated MPD dilatation in the remnant pancreatic head (Figure 3). Serum tumor marker levels (CA19-9, DUPAN-2, and Span-1) remained within the normal ranges. The lesion was diagnosed as a multicentric recurrence of main duct IPMN, and a pylorus-preserving complete total pancreatectomy was performed in August 2007.

Figure 3 Imaging findings before the second surgery. Contrast-enhanced computed tomography image obtained in June 2007 before the second surgery. The main pancreatic duct in the remnant pancreatic head is dilated (orange arrowhead), leading to the diagnosis of main duct-type intraductal papillary mucinous neoplasm in the remnant pancreatic head.

The histopathological findings confirmed microinvasive IPMC (Figure 2C and D), and curative resection was achieved. Given the increased risk of extrapancreatic malignancies in patients with microinvasive IPMC, annual surveillance using CE-CT and serum tumor marker measurements was continued.

Thirteen years after the second surgery, in January 2020 (at age 89), CE-CT revealed enlargement of the lymph nodes with mixed solid and cystic components adjacent to the right side of the superior mesenteric artery (Figure 4A). Serum tumor marker levels were markedly elevated (CA19-9, 1080 U/mL; DUPAN-2, 820 U/mL).

Figure 4 Radiologic detection and chemotherapy response of lymph node recurrence. A: Contrast-enhanced computed tomography (CE-CT) in January 2020 shows a 27 mm × 22 mm mixed solid-mucinous mass right of the superior mesenteric artery (orange arrowhead), with elevated carbohydrate antigen 19-9 and duodenal pancreatic cancer antigen-2 indicating lymph node recurrence of microinvasive intraductal papillary mucinous carcinoma; B: CE-CT in March 2022 demonstrates complete resolution of the lymph node recurrence (orange arrowhead) and normalization of tumor markers, consistent with a favorable response to S-1 therapy.

Because the patient was advanced in age and frail and because contrast-enhanced CT demonstrated a solitary abdominal lymph node lesion with no other sites suspicious for metastasis, additional functional imaging such as PET-CT or invasive histological confirmation was not performed. Therefore, lymph node recurrence was diagnosed based on a comprehensive clinical assessment, including radiological findings and markedly elevated serum tumor marker levels.

Although the patient was frail and older, she wanted to receive treatment. To minimize toxicity, low-dose S-1 therapy (40 mg/day), administered on alternating days, was initiated in March 2020. The treatment was well tolerated, and no adverse events were observed.

OUTCOME AND FOLLOW-UP

After 9 months of therapy, serum tumor marker levels normalized (CA19-9, 17.1 U/mL, and DUPAN-2, 52 U/mL) in December 2020, and follow-up CE-CT confirmed the complete disappearance of the lymph node lesion. Subsequently, the S-1 therapy was discontinued. Complete remission was maintained on CE-CT performed in March 2022 (Figure 4B) (CA19-9, 23.0 U/mL and DUPAN-2, 51 U/mL).

Thereafter, no recurrence was observed until age 91 (July 2022), when the patient was transferred to another hospital because of age-related physical decline. The patient ultimately died at age 92 in August 2023 because of pneumonia and senescence, without evidence of cancer-related death (Figure 5).

Figure 5 Clinical course and tumor marker trends. The patient’s clinical course is described below. Serum tumor marker levels (carbohydrate antigen 19-9, duodenal pancreatic cancer antigen-2, and S-pancreas antigen-1) are plotted as line graphs. Major clinical events, including surgery and hospitalization for cholangitis, are indicated. Thirteen years after the second surgery, marked elevation of tumor markers was observed at the time of lymph node recurrence adjacent to the superior mesenteric artery. Following 9 months of alternate-day oral administration of S-1, all tumor marker levels returned to within normal ranges. CA19-9: Carbohydrate antigen 19-9; DUPAN-2: Duodenal pancreatic cancer antigen-2; Span-1: S-pancreas antigen-1.

DISCUSSION

This case underscores interconnected biological and clinical lessons for surgeons and clinicians managing IPMN.

Multicentric tumorigenesis and associated extrapancreatic malignancies in IPMN patients

The occurrence of a second main-duct microinvasive IPMC 2 years after the initial distal lesion aligns with molecular evidence that IPMNs frequently harbor early KRAS and/or GNAS mutations and may arise independently within the same gland, supporting a multicentric origin rather than a contiguous intraductal spread[1-5]. Pancreatic juice analyses further suggest that ductal field defects predispose patients to multifocal neoplasia[6]. Although the clonality between the two lesions could not be assessed, their timing and anatomical distribution were compatible with multicentric disease. In this case, considering the patient’s advanced age, staged organ-preserving resections rather than total pancreatectomy were selected to balance oncologic control with the preservation of pancreatic function.

Patients with IPMN also have an increased risk of synchronous and metachronous extrapancreatic malignancies[10-12], likely reflecting shared somatic drivers and, in some cases, germline predisposition, with surveillance intensity contributing as well. Genetic counseling and selective germline testing should be considered when clinical or familial features raise concern.

Biological plausibility of extremely late lymph node recurrence

The extraordinarily late lymph node recurrence observed in this case, occurring 13 years after the second curative resection, suggests that microscopic metastatic deposits or occult tumor clones were likely already present at the time of earlier surgeries, but remained clinically silent for more than a decade. This prolonged latency is biologically plausible in light of genomic and computational modeling studies of pancreatic neoplasia, which indicate that dissemination and subsequent radiologic detectability may occur over an extended evolutionary timescale, often spanning 10-20 years from the initial oncogenic event[7-9]. Such findings support the concept that apparently “late” recurrences do not necessarily reflect newly acquired aggressive behavior, but rather the slow outgrowth of pre-existing micro-metastatic disease that remained below the threshold of detection for many years.

Rarity of ultra-late recurrence and implications for disease behavior

Although several studies have documented postoperative recurrence of IPMNs more than 5 years after resection[18-22], recurrence beyond 10 years is exceedingly rare. To our knowledge, only a limited number of cases have been reported in the literature, including the case described by Marchegiani et al[20], in which recurrence was detected 11 years after surgery. Therefore, the present case, with a 13-year disease-free interval, represents an exceptional example and suggests that a subset of IPMN/IPMC may exhibit indolent biological behavior characterized by prolonged tumor dormancy.

Surveillance strategy: The need for lifelong follow-up

From a clinical perspective, this case highlights the potential for ultra late recurrence long after curative resection and underscores the limitations of time-restricted surveillance strategies. Given the long natural history of pancreatic neoplasia and the possibility of delayed outgrowth of occult disease, lifelong postoperative surveillance may be justified in patients undergoing resection for IPMN, even in the absence of early recurrence or high-risk pathological features[21,22].

Therapeutic implications in considerably older patients: Alternate-day low-dose S-1 therapy

At age 89, the patient achieved complete radiological and serological remission following alternate-day low-dose S-1 therapy, a schedule chosen to maximize tolerability. Alternate-day or reduced-intensity S-1 schedules have been investigated to reduce adverse events[15-17] and pancreatic cancer-specific phase II trials, and randomized studies have examined alternate-day administration[17]. In considerably older patients or those with frailty who desire active therapy, individualized lower-intensity regimens may be a pragmatic option, although conclusions must be made cautiously given the single-case nature.

CONCLUSION

This case demonstrates that microinvasive IPMC can possess slow but persistent malignant potential, leading to extremely late lymph node recurrence more than 10 years after curative resection. These findings highlight the importance of understanding the biological timeline of IPMN, including microinvasive variants, maintaining long-term surveillance strategies, and remaining vigilant even after prolonged disease-free intervals. Furthermore, this case suggests that individualized, lower-intensity chemotherapy may be a feasible option for older patients. However, further studies are needed to establish optimal surveillance and treatment strategies.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to Dr. Shimada S, Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan, for her expert pathological assessment and valuable support.