PNENs are relatively rare, accounting for less than 5% of all pancreatic tumors. However, their detection frequency has been increasing due to recent advances in diagnostic imaging modalities [1]. While typical PNENs present as homogeneous tumors with well-defined borders and strong contrast enhancement, the disease often exhibits variable imaging findings, including cystic degeneration, intraductal extension, and oligemia.

Cystic PNENs represent a spectrum ranging from predominantly solid tumors with partial cystic degeneration to lesions where the cystic component occupies most of the tumor. These lesions occur in 10–17% of all PNENs [2], with pure cystic variants containing little or no solid component accounting for only approximately one-third of cystic cases [3]. Multiple mechanisms have been proposed for cystic transformation, including central necrosis or infarction associated with tumor growth and fibrous tissue formation, as well as intratumoral hemorrhage secondary to vascular disruption within these highly vascularized tumors [4].

In our case, the absence of necrosis within the tumor lumen and the presence of hematogenous fluid accumulation strongly suggest that intratumoral hemorrhage was the primary mechanism underlying cystic transformation. This finding supports the hemorrhagic etiology proposed in the literature.

Cystic PNENs, previously considered necrotic variants of solid PNENs, are now recognized as a distinct subgroup with significantly lower malignant potential. Singhi et al. analyzed 491 resected PNENs and found that 11% were cystic, demonstrating significantly lower rates of necrosis, invasion, metastasis, and Ki-67 index compared with their solid counterparts [5]. Histologically, these cysts typically present as unilocular lesions with thin fibrous capsules containing clear to pale yellow fluid.

The diagnostic challenge becomes particularly pronounced when cystic PNENs present with minimal or absent solid components, especially when located in the pancreatic tail. In our case, the tumor exhibited a septal-like structure with complete cystic transformation, making preoperative differentiation from MCN extremely difficult. Such cases may be indistinguishable from MCNs, macrocystic variant of SCN, solid pseudopapillary neoplasm (SPN) with cystic degeneration, or epidermoid cyst in intrapancreatic accessory spleen (ECIPAS) based on imaging alone. These imaging findings and clinical characteristics are summarized in Table 2.

MCN typically presents as a unilocular or oligolocular cyst located in the pancreatic body or tail and predominantly affects middle-aged women. Characteristic features include a thick fibrous capsule, peripheral eggshell calcification, and the presence of ovarian-type stroma on histology. On contrast-enhanced imaging, MCN generally demonstrates enhancement of the cyst wall and septations, particularly on delayed-phase images [6, 7].

Macrocystic SCN may also mimic MCN or cystic PNEN, as it can present as an oligolocular cyst without the classic honeycomb appearance. Although uncommon, the presence of a central stellate scar with sun-burst appearance is pathognomonic. On MRI, SCN typically shows high intensity on T2WI with high ADC values, reflecting its serous fluid content [8].

SPN with cystic degeneration represents another important differential diagnosis, particularly because of its predilection for the pancreatic body and tail and its frequent association with intracystic hemorrhage. Although SPN classically occurs in young women, cases in older patients have been reported. Imaging features include a thick capsule, intralesional hemorrhage causing T1WI high intensity, and a gradual enhancement pattern [9].

ECIPAS should also be considered for cystic lesions in the pancreatic tail. This entity is particularly suggested when a solid component demonstrates enhancement identical to that of the spleen across all contrast phases. Identification of surrounding ectopic splenic tissue and confirmation using technetium-99 m–labeled heat-damaged red blood cell scintigraphy or superparamagnetic iron oxide–enhanced MRI are useful to establish the diagnosis and avoid unnecessary surgical intervention [10].

The diagnostic difficulty is reflected in the literature, with Singhi et al. reporting that 43% of cystic PNENs were not accurately diagnosed preoperatively [5]. In our case, the initial MRI revealed a small cystic lesion without solid components, leading to an initial diagnosis of benign or nonneoplastic cystic lesion and a decision for watchful waiting. With interval growth, the lesion was subsequently preoperatively diagnosed as MCN because it presented as a unilocular cyst in the pancreatic tail of a middle-aged woman without a definite mural nodule on EUS, while features suggestive of PNEN (hypervascular solid component), SPN (young age and thick capsule), SCN (honeycomb architecture or central scar), and ECIPAS (splenic-like enhancement) were absent.

While EUS is valuable for differential diagnosis of pancreatic cystic lesions, the absence of characteristic EUS findings specific to PNENs rendered preoperative diagnosis particularly challenging [11].

Fusaroli et al. demonstrated that CE-EUS is useful for identifying neoplastic features of pancreatic cystic lesions, emphasizing that enhancement of the cyst wall or mural structures is suggestive of neoplastic pathology even in the absence of a definite solid mass [12]. Therefore, cyst wall hyperenhancement on CE-EUS may represent an important diagnostic clue for cystic PNENs lacking an apparent solid component.

EUS-guided fine needle aspiration (EUS-FNA) has become increasingly utilized for diagnosing pancreatic cystic lesions, with cytological or molecular analysis, tumor marker measurement, and through-the-needle procedures including probe-based confocal laser endomicroscopy or biopsy [13]. However, EUS-FNA for pancreatic cystic lesions carries inherent risks, including infection and potential tumor seeding [14]. Moreover, the diagnostic yield of EUS-FNA for cystic PNENs remains relatively modest (63.2–71%) [15].

We believe EUS-FNA should only be considered when a solid component can be safely targeted. In our case, the absence of a puncturable solid component precluded cystic sampling due to seeding risk. This conservative approach aligns with current best practices prioritizing patient safety.