Nonfunctioning Small (≤2 cm) Neuroendocrine Pancreatic Incidentaloma: Clinical and Morphological Findings, and Therapeutic Options (IPANEMA)

With increasing use of high-resolution conventional imaging, pancreatic incidentalomas are being diagnosed more frequently. In two recent surgical series, neuroendocrine tumors (NETs) and carcinomas account for 10-15 % of all pancreatic incidentalomas, the majority ( 75-90 % of cases) well differentiated. The factors affecting the behaviour of pancreatic NETs are differentiation, histological grade, staging, size and intratumoral microvascular density. In updated World Health Organization (WHO) classification, the grading system is based on tumor differentiation, the rate of proliferation and Ki-67 index. The management of pancreatic NETs depends on tumor stage and on presence or not of hormonal syndrome. By definition, the incidentally discovered pancreatic NETs (PNETs) are unassociated with hormonal syndromes (nonfunctioning) and detected in patients who undergo diagnostic evaluations for unrelated conditions.

The therapeutic approach for hormonally functional tumor, or large tumor (> 2 cm) with local, vascular or lymph nodes invasion, highly suggestive of malignancy, or in presence of metastasis, is well admitted: surgery is indicated or should be discussed.

However, the attitude is less consensual for small (≤ 2 cm) non-functioning (NF) and non-metastatic lesions. There is a paucity of literature reporting pancreatic neuroendocrine incidentalomas and their characteristics. However, given their increased incidence, they are an emerging problem and require changes in treatment guidelines. In English, American or French recommendations, systematic surgical resection with lymphadenectomy is currently recommended in all medically fit patients. The follow-up (FU) is possible for tumors <2 cm (T1) located in the pancreatic head and for which enucleation is not feasible. This therapeutic approach has two limitations: 1) the significant incidence of these tumors, because of the widespread use of routine imaging, and the improved technology of multi detector CT scan, the fortuitous discovery of small pancreatic incidentalomas is becoming more common. 2) Pancreatic surgery carries significant postoperative morbidity even in high-volume tertiary centers and even in parenchyma-preserving resection. This may results in many pancreatic resections for tumors with unknown natural history. On the other hand, the follow-up may be a factor of considerable anxiety, and carries the risk, actually difficult to assess, to let the tumor grow between two monitoring controls, with the possible evolution to the irreversible metastatic stage of the disease.

As a result, the investigators are unceasingly facing a dilemma: how to manage asymptomatic patients with small incidentally detected, potentially benign NETs? Several recently published retrospective studies discuss the "non- surgical" management of the small NF incidentally detected pancreatic NETs (IPNETs) and highlight the necessity of developing guidelines for management of these patients. A strict correlation between tumor size and malignancy of these tumors was demonstrated in the single-center retrospective Italian study of Bettini and col. , which included all patients with NF PNETs who underwent curative (R0) resection during 18 years. In the group of 51 patients with small size of T (2 cm or less), incidentally discovered, the majority of lesion was benign, and the authors concluded that follow-up can be proposed in patients with incidentally discovered NF PNETs ≤ 2 cm. However in despite of small size and asymptomatic character of the tumor, the rate of malignancy of NF IPNETs ≤ 2 cm was estimated to be 24 % (in 18% and 6% of cases, uncertain behaviour and carcinoma were present).

Given the inherent morbidities associated with pancreatic surgery, a risk-benefit calculation may favour surveillance rather than surgery in highly selected patients. Thus, a better understanding of NF IPNETs and identification of their prognostic factors can be of help to select a subgroup of patients who could benefit from a long-term surveillance rather than a systematic surgical resection. Clearly, large prospective trials are needed to validate this approach.