Remnant pancreatic carcinoma: The current status

Abstract

Pancreatic carcinoma is one of the most lethal malignancies and has a dismal prognosis. However, advances in diagnostic modalities and better multidisciplinary management have contributed to improved survival in these patients. Of late, various recurrence patterns have been observed; the most common of them being distant metastasis followed by the pancreatic bed and lymph node recurrence. Recurrence in the remnant pancreas is on the rise due to improved survival in patients who previously underwent surgery for pancreatic cancer. Total remnant pancreatectomy is an appealing option in resectable remnant pancreatic carcinoma without distant metastasis. It is an entity showing an increasing incidence and demanding further in-depth studies to elucidate the exact pathological mechanism and to establish appropriate management protocols.

Key Words: Pancreatic cancer; Remnant pancreatic carcinoma; Pancreatic stump carcinoma; Recurrence; Total pancreatectomy; Completion pancreatectomy

Core Tip: The incidence of remnant pancreatic cancer is increasing as advances in diagnostic modalities and better multidisciplinary management have contributed to improved survival in patients with pancreatic cancer. Recognition of various genetic factors may help in the early detection of remnant pancreatic carcinoma and provide better management. Recent trends show a shift towards surgical management of remnant pancreatic cancer. However, managing remnant pancreatic carcinoma needs further detailed introspection and research to optimize outcomes.

INTRODUCTION

Pancreatic malignancy has been a significant health problem for many decades, mainly due to its asymptomatic initial clinical presentation that delays early diagnosis and hampers timely management. It is one of the most lethal malignancies of the gastrointestinal tract, having a dismal prognosis with a 5-year relative survival of around 9%[1]. Even after the curative-intent resection, pancreatic cancer recurs in most patients, usually within 2 years after the index surgery[2]. Various recurrence patterns have been observed; the most common is liver metastasis followed by peritoneal carcinomatosis and local recurrence. However, knowledge of the exact pattern and mechanism of recurrence is still immature.

With advances in perioperative systemic therapy and improved surgical management, there has been a recent trend towards improving long-term outcomes after resection of pancreatic carcinoma. Consequently, the detection of remnant pancreatic carcinoma has also been gradually increasing. While patients with systemic metastasis are generally offered palliative therapy, patients with remnant pancreatic carcinoma may be eligible for operative intervention. However, due to a lack of a standardized definition and evidence-based management protocol, there is still no consensus on the appropriate evaluation and treatment of remnant pancreatic carcinoma. The present minireview highlighted the areas for future research on this emerging health problem.

EPIDEMIOLOGY

Current survival statistics reflect that survival is highest in malignancies like thyroid, prostate, testis, and melanoma, whereas it is lowest in pancreatic (12%), liver, and esophagus malignancies. Pancreatic malignancy is the fourth leading cause of cancer-related mortality in the United States. Mortality rates in males went from 12.1% in 2000 to 12.7% in 2020 and 9.3% to 9.6% in females over the same time[1]. In 2023, an estimated 64050 new cases were diagnosed, and 50550 deaths were reported[1].

Poor survival in patients with pancreatic cancer is due to a high incidence of local and systemic recurrence, which can be as high as 80%. However, recent advances in neoadjuvant and adjuvant therapy combined with improvements in surgical techniques contributed to improvement in overall survival[3,4]. Improved survival after surgical resection has increased the number of long-term survivors, which in turn increases the risk of recurrence.

In the last few years, many case reports of remnant pancreatic carcinoma have been published, and recent cohort studies focusing on the mechanism of recurrence and management strategies have been published. Recently, the Japanese Clinical Practice Guidelines for Pancreatic Cancer 2022 recommended continued long-term surveillance even in patients surviving for more than 5 years after initial resection to detect remnant pancreatic carcinoma[5].

Early diagnosis of pancreatic carcinoma is of the utmost importance for successful treatment, and surgical resection with negative margins is the cornerstone of the management. However, due to late identification and aggressive biological behavior of the disease, many patients have locally advanced or metastatic disease at the time of diagnosis, making surgical resection possible only in 20% of cases[6]. The overall 5-year survival rates are less than 5% in pancreatic carcinoma; however, patients with successful surgical resection have noted improvement in 5-year survival rates up to 15%-40%[7,8]. In Japan, pancreatic cancer is the fifth leading cause of cancer-related mortality, and the 5-year survival rate after surgical resection ranges from 15%-20%[9].

The incidence of remnant pancreatic carcinoma is 4.6%, and the cumulative 3-year and 5-year incidence rates are 3.1% and 17.7%, respectively[10]. The incidence of remnant pancreatic carcinoma is similar to the incidence rate seen with remnant gastric carcinoma, which is 1.9%-5.5%[11,12]. However, the cumulative 5-year incidence is higher in remnant pancreatic carcinoma[10]. In one of the studies, it was reported that median survival was only 7 months in remnant pancreatic carcinoma when surgery was not performed[13]. Numerous names have been suggested in the literature for this entity, including remnant pancreatic cancer, pancreatic cancer in the remnant pancreas, carcinoma developing in the remnant pancreas, metachronous pancreatic cancer, second primary pancreatic ductal carcinoma, and isolated local recurrence[10,14-20].

Clinically remnant pancreatic carcinoma presents with significant weight loss, exocrine insufficiency, abdominal pain, or back pain. In a few patients tumor markers, including carbohydrate antigen 19-9 or carcinoembryonic antigen, may be elevated. Hence, serial measurements in the follow-up period are essential for early diagnosis of recurrence. Contrast-enhanced CT and positron emission tomography with CT are crucial in evaluating recurrence and its extent. A representative image of contrast-enhanced CT showed a heterogeneously hypodense mass lesion measuring approximately 3.8 cm × 2.8 cm in the body and tail region involving the splenic vein (Figure 1). Endoscopic ultrasound with or without fine needle aspiration or endoscopic retrograde cholangiography cytology has also been used to confirm the diagnosis[21]. Moreover, previous surgical pathology, staging, and the time interval between index surgery and recurrence are important factors for planning further management. Usually, the interval between the index surgery and recurrence ranges from 6 months to 4 years. However, it can be seen even after 5 years.

Figure 1 Contrast-enhanced computed tomography scan results. A: Remnant pancreatic carcinoma axial view; B: Remnant pancreatic carcinoma coronal view.

Remnant pancreatic carcinoma has been defined as a tumor located in the remnant pancreas after R0 resection and meeting at least one of the following: Time gap of more than 3 years after index surgery; and new lesion not in contact with the pancreatic stump[10,22]. However, there is no consensus on this definition.

RECURRENCE PATTERNS

Various patterns and timings of the recurrence have recently been seen, depicting a broad spectrum of biological behavior. The unfavorable outcome in pancreatic cancer following surgery is mainly due to preexisting systemic disease at the time of surgery, leading to liver metastasis in half the patients or peritoneal metastasis in one-fourth of patients[23,24]. Moreover, in patients undergoing R0 resection, tumor cells may still exist on the remnant stump leading to recurrence in the remnant pancreas[23]. In the recent reports one-fourth of patients were seen to have remnant pancreas as the primary site of recurrence[25].

Possible mechanisms in the pathogenesis of remnant pancreatic carcinoma are local recurrence of the initial tumor of the remnant pancreas or a metachronous new tumor in the remaining pancreas[15,19,26]. When the positive resection margin is the cause of remnant pancreatic carcinoma, the secondary lesion tends to be close to the pancreatic stump. In contrast, metachronous new tumors may have hematological or lymphatic spread[26]. An alternative mechanism is the intraductal dissemination of the tumor cells, which is likely seen in intraductal papillary mucinous neoplasm[27]. Previous studies have found synchronous multifocal lesions in 20%-32% of histopathological specimens of total pancreatectomy performed for pancreatic carcinoma, suggesting the possibility of preexisting lesions[28,29]. Genetic alterations in these tumors give a window to assess the mechanism of recurrence.

ROLE OF GENETICS

Based on the genetic alterations in Kristen rat sarcoma viral oncogene homolog (KRAS), MUC1, and MUC2 immunohistochemical analysis in the index lesion and the remnant pancreatic lesion, attempts have been made to classify remnant pancreatic carcinoma into recurrent lesion or new primary/metachronous lesions[15]. Some researchers have used KRAS mutations and TP53, CDKN2A, and SMAD4 immunohistochemical analysis for this differentiation[19]. Some authors have used next-generation sequencing for mutational and histopathological analysis to distinguish recurrence from new primary/metachronous lesions[26]. Recognition of such factors may help in the early detection of remnant pancreatic carcinoma and provide better planning and management.

One retrospective study reported that out of 379 patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma 14 patients had remnant pancreatic carcinoma. On multivariate analysis the link with intraductal papillary mucinous neoplasm was found to be an independent predictive factor for remnant pancreatic carcinoma[30]. Researchers have postulated that genetic testing has shown similar mutation patterns in different lesions in intraductal mucinous papillary neoplasm and suggested that tumor cells propagate via the pancreatic duct[31-33]. One study postulated that not all intraductal papillary mucinous neoplasms spread via the duct, and some are independent of their primary[32]. Similarly, another author found that coexisting pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm are genetically apparent in around one-fifth of patients[34].

Moreover, some investigators have noticed that precursor lesions are found more frequently in patients with familial pancreatic ductal adenocarcinoma[35]. Limited tumor heterogeneity observed by a few authors may help in the success of targeted therapies[36]. On the contrary, some researchers have found multiple forms of KRAS mutations and intratumoral heterogeneity in pancreatic ductal adenocarcinoma[37]. The genomics of pancreatic cancer need further introspection to delineate the genetic mechanisms involved in pancreatic cancer.

TREATMENT

Chemotherapy or chemoradiotherapy has been commonly applied after surgery in the adjuvant setting to reduce recurrence and improve survival (Table 1)[38-44]. The role of neoadjuvant therapy in resectable pancreatic cancer is still evolving. Neoadjuvant therapy in locally advanced pancreatic cancer has established its role, and evidence shows a benefit in borderline resectable pancreatic malignancy. Chemotherapy has been commonly applied for managing patients with remnant pancreatic carcinoma.

Table 1 Chemotherapy in pancreatic cancer.

Trial	Year	Drug regimen	DFS (months)	OS (months)
ESPAC-1[38]	2001	5FU vs observation	15.3 vs 9.4 (P = 0.02)	20.1 vs 15.5
CONKO-001[39]	2007	Gemcitabine vs observation	13.4 vs 6.9 (P < 0.001)	22.8 vs 20.2
ESPAC-3[40]	2010	5FU vs gemcitabine	14.1 vs 14.3 (P = 0.53)	23.0 vs 23.6
CONKO-005[41]	2017	Gemcitabine vs erlotinib	11.4 vs 11.4 (P = 0.26)	26.5 vs 24.5
ESPAC-4[42]	2017	Gemcitabine vs capecitabine	13.1 vs 13.9 (P = 0.082)	25.5 vs 28.0
PRODIGE 24[43]	2018	Gemcitabine vs FOLFIRINOX	12.8 vs 21.6 (P < 0.001)	35.0 vs 54.4
APACT[44]	2019	Gemcitabine vs gemcitabine + nab	13.7 vs 16.6	36.2 vs 40.5

5FU: 5-fluorouracil; DFS: Disease free survival; OS: Overall survival.

However, recent trends show a shift towards surgical resection for better median and overall survival, especially in tumors limited to the remnant pancreas[45]. Surgical resection encompasses the need for total remnant pancreatectomy, which is a procedure with high morbidity. Also, previous adjuvant treatment in the form of chemoradiation may have morphological changes in the form of fibrosis, making surgical resection difficult[46]. Moreover, during redo surgery, anatomical changes like adhesions, invasion of main vessels, and loss of tissue planes can be challenging. However, beneficial results have been seen after resection[3,30,47]. A Japanese multicenter study of 90 patients with remnant pancreatic carcinoma reported post resection morbidity of 8.9% and 30-day and 90-day mortality of 0% and 1.1%, respectively[48]. Another pooled analysis showed no perioperative mortality and an overall 3-year and 5-year survival of 49.2% and 40.6%, respectively[49].

The most frequently performed operation is total remnant pancreatectomy or completion pancreatectomy, which can also be safely accomplished using minimally invasive techniques[50-52]. Total remnant pancreatectomy would be best suited in a patient with small-sized tumors located at least 10 mm away from the pancreatic stump[48]. It has also been shown that completion pancreatectomy following initial distal pancreatectomy has more blood loss and increased operative time. Similar to gastric stump carcinoma, with numerous unsettled queries regarding the definition, classification, staging, and surgical management, remnant pancreatic carcinoma also needs further detailed introspection and research[53].

CONCLUSION

The incidence of remnant pancreatic carcinoma is steadily increasing, with a cumulative 5-year incidence higher than gastric stump carcinoma. Postoperative surveillance is of the utmost importance in pancreatic cancers even beyond 5 years for early detection and timely management of recurrent remnant carcinoma. However, more studies are still needed to define the entity and plan better management of these patients.