Bridging Imaging and Pathohistology in Pancreatic Hamartoma: A Systematic Review of the Literature with an Integrated Case Report

TL;DR

This paper reviews pancreatic hamartoma, a rare benign tumor, and highlights how imaging and pathology can help distinguish it from cancer, using a case study and literature review.

Contribution

The study integrates a case report with a systematic review to clarify diagnostic imaging and histopathological features of pancreatic hamartoma.

Findings

PHs typically show low T1 and high T2 MRI signal intensity, distinguishing them from neuroendocrine tumors.

Most PHs are asymptomatic and occur in the pancreatic head, with a male predominance.

Histologically, PHs are solid or solid–cystic with low cellularity and no Langerhans islets.

Abstract

Background: Pancreatic hamartoma (PH) is an exceptionally rare, benign, mass-forming lesion accounting for less than 1% of all pancreatic tumors. Its rarity and non-neoplastic nature contribute to significant diagnostic challenges, often leading to misclassification as malignant disease. This study presents a case of PH and a systematic review of all reported cases, with emphasis on histopathological and imaging characteristics. Methods: A comprehensive electronic search of PubMed, Scopus, and Web of Science was conducted up to 1 April 2025, to identify eligible case reports and series. Results: We describe a 37-year-old woman with a cystic lesion of the pancreatic tail, ultimately confirmed histologically as a cystic pancreatic hamartoma following distal pancreatectomy with splenectomy, with an uneventful postoperative course. Of 687 screened studies, 51 met the inclusion criteria, comprising 77 cases (68 adults, 9 pediatric). PHs occurred most frequently in males (52.9%), with a mean age of 59.5 ± 12.9 years, and were often asymptomatic (57.4%). The pancreatic head was the most common site (52.9%). On MRI, PHs typically exhibited low T1-weighted and high T2-weighted signal intensity, with no FDG uptake (82%) and moderate or no restriction on DWI, distinguishing them from neuroendocrine tumors (NETs). Histologically, most lesions were solid (64.7%) or solid–cystic (35.3%), with low spindle cell cellularity and absent Langerhans islets. Conclusions: Low T1WI signal and moderate DWI signal are the key features distinguishing PHs from NETs. Incorporating these findings with EUS-FNA and immunohistochemistry can support a provisional diagnosis and help avoid unnecessary radical surgery.

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Full text

1. Introduction

Hamartomas are benign neoplasms characterized by the disorganized proliferation of normal cells and tissues native to the site of origin [1]. Although their exact global prevalence remains unknown, this is likely attributable to the rarity of these lesions [2]. Among hamartomas, pancreatic hamartoma represents an exceptionally rare, benign, mass-forming lesion that accounts for less than 1% of all pancreatic neoplasms. Its non-neoplastic nature and infrequency contribute to the considerable challenges associated with accurate preoperative diagnosis [3].

Pancreatic hamartoma was first described by Anthony et al. in 1977 [4]. Subsequently, Pauser et al. and Yamaguchi et al. proposed pathological criteria to define this rare entity, which include: the presence of a well-circumscribed mass, a composition of mature acini and ducts exhibiting disordered architecture and an absence of identifiable islets of Langerhans [5,6,7]. Based on these features, pancreatic hamartomas are further classified into two subtypes: solid or solid and cystic forms [8].

Despite advances in diagnostic imaging technologies, differentiating benign pancreatic tumors, such as hamartomas, from malignant lesions remains a significant clinical challenge. The increasing use of modalities including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic retrograde cholangiopancreatography (ERCP), and particularly endoscopic ultrasound (EUS) has led to more frequent detection of asymptomatic pancreatic lesions [9,10]. However, pancreatic hamartomas lack definitive radiological features, and tissue samples obtained through fine needle aspiration (FNA) are often insufficient for establishing a reliable pathological diagnosis [11]. Consequently, these lesions are frequently misclassified as other pancreatic tumors, leading to surgical resection to achieve a definitive diagnosis [12], which typically relies on histopathological and immunohistochemical evaluation [10]. Although radiological and pathological reports on pancreatic hamartomas have become more numerous in recent years, and imaging features have been increasingly clarified [13,14], a precise correlation between radiological and pathological findings has yet to be established.

Here, we present a case report of pancreatic hamartoma and provide a systematic review of all available reported cases, with a particular focus on differences between histopathological and imaging findings, contributing valuable insights to the existing body of knowledge on this rare entity.

2. Materials and Methods

The systematic review was conducted in compliance with The CARE guidelines (for CAse REports) [15] and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [16]. The review methodologies were predetermined, and no substantial deviations from the established protocol were noted. The review has been formally registered in the Open Science Framework (OSF) (registration DOI: 10.17605/OSF.IO/HM9UN).

2.1. Selection of Studies

The study inclusion screening process for the systematic review was carried out in two phases. At every phase, two reviewers independently evaluated the studies, resolving discrepancies through discussion or consensus. A third reviewer was engaged to address any remaining disagreements. Eligible studies comprised published case reports concerning pancreatic hamartoma. The exclusion criteria included: (1) populations other than those with pancreatic hamartoma, (2) studies not categorized as case reports or case series (reviews), (3) inappropriate population (non-human subjects), and (4) publications not in English.

2.2. Search Strategy

The search strategy was collaboratively designed by two reviewers, one having expertise in abdominal surgery and the other competent in search strategy design. A comprehensive electronic search of PubMed, Scopus, and Web of Science was performed until April 1st, 2025, to identify published studies containing the term “pancreatic hamartoma” OR “pancreas hamartoma”. Detailed search strategies, including the exact search strings used for each database, are available in the Supplementary Materials.

2.3. Data Abstraction

Data extraction was performed independently by two reviewers and encompassed the following variables: study title, author(s), year of publication, country of origin, patient demographics (gender and age), clinical presentation (asymptomatic or symptomatic), duration of symptoms, tumor location and size, reported instances of communication and pancreatitis, imaging techniques utilized, performance of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), provisional diagnoses, treatment modalities, histological characteristics, immunohistochemical results, evidence of recurrence and metastasis, documented postoperative complications, and duration of follow-up. Authors of relevant articles were contacted to obtain missing data. Data synthesis and visual presentation were performed using structured summary tables summarizing key demographic, clinical, imaging, and pathological variables.

2.4. Statistical Analysis

Numerical data were presented as mean or median with corresponding measures of variability (standard deviation, IQR). Categorical variables were summarized by absolute numbers with percentages. Fisher’s exact test was used to assess the differences between radiological characteristics and pathological findings. A p-value of <0.05 was considered to be statistically significant. Analysis was performed using SPSS for Windows (21.0; IBM SPSS, Chicago, IL, USA).

3. Results

3.1. Case Presentation

A 37-year-old female patient underwent treatment for a suspicious lesion on the thigh, highly suggestive of melanoma. Following radical surgical excision of the lesion, additional diagnostic evaluations were performed, including an abdominal ultrasound. This imaging revealed an abnormality abutting the splenic vein in the splenic hilum, initially characterized as a cyst of the pancreatic tail. The patient denied weight loss, nausea, or vomiting but reported intermittent sharp pain beneath the left rib cage, radiating to the back, particularly pronounced after meals. This pain had been present for several years. Physical examination revealed no pathological findings or palpable masses.

The patient’s medical history included endoscopic polypectomy of the uterine cavity in 2017. Hematological testing showed heterozygosity for prothrombin gene mutation (Factor II), for which no specific medical intervention was required. Laboratory analyses showed that tumor markers, including CA 19-9 (33 kU/L), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA 125, and CA 72-4, were within reference ranges. The complete blood count and biochemical profile were also unremarkable.

3.1.1. Imaging Findings

Subsequent imaging included abdominal ultrasound and computed tomography (CT), which identified a mesenteric cyst adjacent to the anterior aspect of the pancreatic tail, initially suggesting it was not arising from the pancreas. Multiple magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) studies, performed over a six-month period, demonstrated a bilocular cystic lesion measuring 20 × 27 × 29 mm, differentiating two compartments with a wall thickness of up to 3 mm. Preoperative imaging noted a subtle internal septum without a clearly visible mural nodule, and mild post-contrast enhancement of both the cyst wall and septum. The lesion exhibited partial extrapancreatic extension and lacked a defined connection with the main pancreatic duct, which remained of normal caliber.

Additionally, an encapsulated multilocular cystic formation measuring 13 × 11 × 30 mm was identified, along the anterior surface of the spleen. A CT scan with a pancreatic protocol suggested a high likelihood of mucinous cystic neoplasm (MCN), with a probable diagnosis of mucinous cystadenoma.

3.1.2. Surgical Findings

The patient underwent surgery via a left subcostal laparotomy. Intraoperative exploration revealed no pathological changes in the liver or peritoneum, and no free fluid was observed in the abdominal cavity. Upon entering the omental bursa, inspection of the pancreas identified a neoplastic lesion measuring 4 × 3 cm in the pancreatic tail, which was adherent to both the splenic flexure of the colon and the splenic hilum. The cystic formation located along the anterior surface of the spleen, as described on imaging, was not confirmed intraoperatively as a distinct pathological entity. The procedure began with mobilization of the inferior margin of the pancreas and dissection of the tumor from the colon. The spleen was then mobilized, and the superior pancreatic margin was freed. The splenic artery was isolated and ligated, followed by clamping of the splenic vein. The pancreas was transected, completing the distal pancreatectomy with splenectomy. The main pancreatic duct, which measured approximately 1 mm in diameter and showed no evidence of dilation, was individually sutured. The pancreatic resection margin was reinforced with fibrin glue.

Following resection, intraoperative hemostasis was evaluated using rotational thromboelastometry (ROTEM). In view of a hypercoagulable profile, the patient received tranexamic acid along with oral antiplatelet and anticoagulant therapy. The postoperative course was uneventful, and the patient was discharged home on postoperative day eight. The patient has been compliant with routine follow-up evaluations and remained alive and well at four years of follow-up.

3.1.3. Gross Pathological Findings

Gross examination of the pathological specimen revealed a well-circumscribed, mixed cystic solid lesion measuring 40 × 30 × 30 mm in the pancreatic tail. The specimen had a smooth external surface that partially extended over the anterior aspect of the gland with interspersed irregular patchy fatty tissue of approximately 7 × 5 mm in size. Sectioning of the specimen demonstrated two distinct cystic locules: one filled with a sero-mucinous fluid and the other containing a gray-yellow mucinous material. These cysts were sharply demarcated from the surrounding pancreatic parenchyma and showed expansile growth without involving the main pancreatic duct. Between the two locules lay a 10 × 10 × 5 mm solid mural nodule, which on the cut section appeared light gray-pink, moderately firm, and finely fibrous (Figure 1, Figure 2 and Figure 3).

3.1.4. Pathohistological Findings

Microscopically, the lesion exhibited heterogeneous proliferation of mesenchymal and epithelial elements. The mesenchymal component predominated and consisted of spindle-shaped cells arranged in subtle swirling and partial fascicles within an edematous, myxoid stroma. Vascular proliferation was prominent, comprising numerous dilated capillaries and occasional venules, alongside irregular nerve bundles. The epithelial component formed cystic structures lined by a single layer of flattened, cuboidal, or, less commonly, columnar cells. Mucin production by these epithelial cells was infrequent, and occasional desquamation was noted. Peripheral pancreatic ductules exhibited areas of low-grade pancreatic intraepithelial neoplasia (PanIN I), with only one microfocus of similar dysplasia within the cystic regions; no evidence of neoplastic epithelial proliferation was present (Figure 4).

Immunohistochemical staining of the epithelial component demonstrated strong positivity for pancytokeratin AE1/AE3, CK7, CK19, CAM5.2, and MUC1, with focal expression of MUC5AC. Desmin and α-SMA highlighted concentric muscle bundles adjacent to the larger cysts, whereas the remaining stromal cells were vimentin positive. The epithelium was negative for CK20, mCEA, and MUC4, and the mesenchymal component did not express CD117, CD34, α-SMA, desmin, or S 100 protein. A focal Ki 67 proliferation index of approximately 3% was observed. These combined histopathological and immunohistochemical findings supported a diagnosis of solid cystic pancreatic hamartoma.

3.2. Systematic Review

A total of 687 potentially eligible case reports were identified from four electronic databases. Following the elimination of duplicates, 487 titles and abstracts were evaluated for relevance. Out of these, 389 reports failed to satisfy the eligibility criteria, resulting in 89 case reports available for further evaluation. Due to the inability to retrieve four reports, 85 reports underwent a comprehensive evaluation. After this screening, 15 studies were excluded due to foreign language, and 19 for not involving pancreatic hamartoma. A total of 51 studies were chosen for review. The process of study selection is illustrated in Figure 5, in accordance with the PRISMA flow diagram.

3.3. Characteristics of Eligible Studies

The characteristics of all 51 publications included in this systematic review are presented in detail in Table 1, Table 2, Table 3 and Table 4. A total of 77 cases were identified in the literature, comprising 68 cases in adults and 9 cases in neonates and children. The included studies were published between 1983 and 2024. Among all reported cases of PH, the highest number was from Japan (n = 15), followed by the United States (n = 10) and the Republic of Korea (n = 7). The geographical distribution of reported cases is shown in Figure 6. More than half of PH cases were males (52.9%), and the mean age was 59.5 ± 12.9 years, ranging from 25 to 78 years in the adult population. More than half of the patients were asymptomatic (57.4%), had pancreatic hamartoma located in the head (52.9%), body (19.1%), and tail (16.2%). The most common provisional diagnoses based on clinical and radiographic findings were neuroendocrine tumor (NET) (32.7%), unspecified pancreatic tumor (9.6%), and pancreatic cancer (9.6%). Regarding treatment modalities, the most frequently employed interventions included pylorus-preserving pancreaticoduodenectomy (PD) (18.5%), standard PD (18.5%), non-specified surgical resection (18.5%), and distal pancreatectomy (14.8%). Notably, the Whipple procedure was performed in 11.1% of all confirmed cases of pancreatic hamartoma. In Table 1 and Table 2, characteristics of studies with the adult and child and newborn population included in the systematic review are presented in detail.

Histological characteristics of pancreatic hamartoma cases of the adult population included in the systematic review are presented in Table 3. The most frequent pattern observed pathologically was solid (64.7%) and solid/cystic (35.3%). Spindle cell cellularity was predominantly low (46.2%). Additionally, Langerhans islets were absent in 91.8% of the reported cases. Immunohistochemical features of pancreatic hamartoma cases included in the systematic review are presented in detail in Table S1.

Median lesion size was 29 mm (IQR: 20–50). Mass effect was seen in 32% and biliary obstruction in 6.5%. Most lesions were well-defined (97%) and commonly showed solid-cystic or heterogeneous appearance. On MRI, they were typically low on T1 (76%) and high on T2 (89%). FDG-PET showed no uptake in 82% of cases. Enhancement patterns and signal intensity varied across imaging modalities (Table 4).

All available data from published case reports were systematically extracted and entered into a database to link radiological characteristics with pathological findings. Cases that were provisionally diagnosed as neuroendocrine tumors (NETs) more often showed low intensity on T1-weighted MRI (p = 0.015) (Table 5). jcm-15-00136-t001_Table 1Table 1Characteristics of studies with adult population included in the systematic review.AuthorYearCountryGender/AgePresentationDuration of Symptoms (Months)SiteSize (cm)Provisional DiagnosisTreatmentPost-Op ComplicationsFollow-Up and OutcomeIzibicki et al. [17]1994GermanyM/25Abdominal pain, nausea/H10.6////Wu et al. [18]1998USAM/39Transient prandial midepigastric pain and a 15 kg weight loss over the past year.10 yearsH8.0 × 8.0 × 6.0/Whipple/Recovered well since surgery without recurrence of pain after 9 moMcFaul et al. [19]2004SwitzerlandM/29Heartburn, vomiting and intermittent right upper quadrant pain associatedwith a 15 kg weight loss13 moH1.0Chronic pancreatitis and a pancreaticneoplasm; calcification also suggested a non-functioningislet cell neoplasm.Pylorus-preserving PD/Alive and well after 2 years

M/62Intermittent abdominal pain associated with vomiting 1–2 h after eating and a 25 kg-weight loss2 yearsH3.5/Kausch-Whipple procedure/Alive and well after 3 moPauser et al. [5]2005GermanyF/36Epigastric pain1.0H7.0PseudotumorWhippleNoRelapse-free after 15 mo

F/55Abdominal pain1 moN2.7PseudotumorDistal pancreatectomy and splenectomyNoRelapse-free after 23 mo Pauser et al. [6]2005GermanyM/51Asymptomatic/T3.0/SurgeryNoRelapse-free after 2 years

M/54Slight abdominal discomfort/B2.0/Left-sided pancreatic resectionNoRelapse-free after 4 yearsNagata et al. [1]2007JapanF/58Asymptomatic/B1.9Pancreatic endocrine tumorDistal pancreatectomyNoRelapse-free after 6 moSamplean et al. [20]2009RomaniaM/46Abdominal pain9 moH8 × 6/Cephalic duodenopancreatectomy//Durczynski et al. [9]2010PolandM/69Asymptomatic/B3.0/Central pancreatic resection with Roux-en-Ypancreaticojejunostomy to the distal pancreatic remnantYesRelapse-free after 55 moKawakami et al. [8]2012JapanF/78Asymptomatic/H1.4Pancreatic cancerPD/Relapse-free after 30 moKim et al. [21]2012KoreaF/52Postprandial abdominal discomfort1 moH2.2 × 1.4SPN or SCNPylorus-preserving PDNoRelapse-free after 10 moKwon et al. [22]2012KoreaF/41Asymptomatic/H2 × 1 NET or SPNPylorus preservingPDNo/Yamaguchi et al. [7]2013JapanF/78Asymptomatic/H1.7Pancreatic cancerSurgical resection/Relapse-free after 32 mo

F/61Abdominal pain/H4.0SPNSurgical resection/Relapse-free after 7 mo

F/71Asymptomatic/B and T5.0Cystic tumorSurgical resection/Relapse-free after 68 mo

F/58Asymptomatic/B2.0NETSurgical resection/Relapse-free after 6 mo

F/59Abdominal pain/T1.0NETSurgical resection/Relapse-free after 10 mo

M/53Abdominal pain/H8.0SPNSurgical resection/Relapse-free after 9 mo

M/53Asymptomatic/H2.5Mass-formatting pancreatitisSurgical resection/Relapse-free after 12 moAddeo et al. [10]2013FranceF/61Asymptomatic/B2.7 × 2.3 × 2.1/A roboticdistal pancreatectomy with a splenectomy//Inoue et al. [23]2014JapanM/65Obstructive jaundice/H4.0/PD/Relapse-free after 3 yearsShahbaz et al. [24] 2015USAF/62Abdominal pain3–4 moH1.4Pancreatic tumorWhipple//Zhang et al. [25]2016ChinaF/53Abdominal pain, anorexia, 2 kg weight loss2 moH2.3 × 1.5 × 1.5/Formal PDNoNo recurrence after 55 moMurakami et al. [26]2016JapanF/62Pancreatitis attacks30 yearsH7.0 × 5.7 × 4.0PancreatitisSubtotalstomach-preserving PDNoPancreatitis has not recurredsince surgeryMatsushita et al. [27]2016JapanM/68Asymptomatic/U4.0 × 4.0 × 2.8Benign tumor such as lipoma, dermoid cyst or the other rare benign tumorPyloric preservingPDNoNo recurrence after 50 moHan et al. [14]2017Republic of KoreaF/35Hypoglycemia/T1NETDistal pancreatectomy//Nahm et al. [13]2017AustraliaF/42Abdominal pain3 moN2.8SPNCentral pancreatectomy/No recurrence after 8 moNagano et al. [28]2017JapanF/72Asymptomatic/H2.0/Subtotal pyloric preservingPD/No recurrence afer 36 moTanaka et al. [29]2018JapanM/54Asymptomatic/T3.6IPMN, SCN, malignant tumorDistal pancreatectomy//

M/74Asymptomatic/H5.0IPMN PD//

M/67Asymptomatic/T6.5LiposarcomaDistal pancreatectomy//Shin et al. [30] 2019Republic of KoreaF/54Asymptomatic/H2.2SPN or NETRobot-assisted pylorus-preserving PDNoNo evidence of local tumor recurrence or distant metastasis after 6 moDasaraju et al. [31]2020USAM/74Asymptomatic/U2.3NETPD//Zhou et al. [32]2020ChinaM/73Abdominal pain/H4 × 3.5Pancreatic liposarcomaPDNoNo sign of local recurrence after 3 moKatayama et al. [12] 2020JapanM/78Asymptomatic/T2.9 × 2.3 NETWhippleNoDisease-free after 34 moCui et al. [33]2020ChinaF/57Asymptomatic/U2.5NETWhipple/Disease-free after 34 mo

M/69Asymptomatic/H1.5/Whipple/Disease-free after 44 moToyama et al. [11]2020JapanM/53Asymptomatic/H3.7Mixed solid and cystic typeSCN, NET with cysticdegeneration,IPMC, SPN, and slow flowvascular malformation (the so-called hemangioma)PD//Yang et al. [34] 2021Republic of KoreaM/68Asymptomatic/H1.8NETPylorus-preserving PD//Jha et al. [35]2021IndiaM/68Progressively enlarging lump7 moB and T19 × 18/Distal pancreatectomy with splenectomy//Noguchi et al. [36] 2021JapanF/70Asymptomatic/B1.9 × 1.6 × 1.4Nonfunctional pancreatic NETSurgical resection//Ahn et al. [37] 2021Republic of KoreaM/68Asymptomatic/H1.8NETPylorus-preserving PD/No recurrence or metastasis after 6 moWoo et al. [38]2022JapanF/49Asymptomatic/B1.3 × 0.9NEN and SPNLaparoscopic distal pancreatectomy//Santana et al. [39]2022SpainM/41Asymptomatic/B1.8Mucinous tumorDistal pancreatectomy/Alive after 5 moTanigawa et al. [40]2022JapanF/78Asymptomatic/H1.7Pancreatic cancer//No recurrence after 98 mo

F/71Asymptomatic/B5.0Cystic tumor///

M/66Asymptomatic/H1.5Pancreatic cancer///

F/58Asymptomatic/B2.0PanNET//No recurrence after 6 mo

M/65Weight loss/H4.0Acinar cell carcinoma//No recurrence after 10 mo

F/67Asymptomatic/B2.5Pancreatic tumor//No recurrence after 6 mo

M/75Asymptomatic/T1.0Pancreatic cancer//No recurrence after 37 mo

F/75Asymptomatic/T0.8PanNET//No recurrence after 3 mo

F/63Asymptomatic/B1.9Paraganglioma//No recurrence after 48 mo

F/59Abdominal pain/T1.0PanNET//No recurrence after 9 mo

M/53Abdominal pain/H8.0SPN//No recurrence after 15 mo

M/53Asymptomatic/H2.5Mass forming pancreatitis//No recurrence after 16 mo

M/68Abdominal pain/H4.0Dermoid cyst//No recurrence after 132 moTee et al. [41] 2022SingaporeM/Middle ageAsymptomatic/B13Pancreatic lipoma and well-differentiatedliposarcomaSurgical resectionYesWell after 3 moKim et al. [2]2023Republic of KoreaF/57Asymptomatic/H3.2Primary hyperaldosteronismPylorus-preserving PDNoNo sign of recurrence after 6 moJeo et al. [42] 2023IndonesiaM/39Jaundice7 daysAll pancreasMultiple cysts ranging ±0.5–5von-Hippel-Lindau diseaseTotal PDYesWell after 6 moShintaku et al. [3]2023JapanF/68Asymptomatic/H1.8NETSubtotal stomach-preserving PDNoRelapse-free after 9 moDas et al. [43]2024USAM/73Abdominal pain/T2.3/Laparoscopicdistal pancreatectomy and splenectomy/Patient alive and well after 5 years

F/68Abdominal pain/H2.7/PD/Patient alive and well after 6 years

M/73Abdominal pain/T0.6/Pancreatectomy/Patient alive and well after 6 yearsLiu et al. [44] 2024ChinaM/63Abdominal distension with abdominal pain15daysH2.1NETPD/No sign of recurrence after 16 moWan et al. [45]2024ChinaM/33Asymptomatic/H6 × 4Clinical benign tumorLaparoscopic enucleationYesRelapse-free after 11 moPresent case2021SerbiaF/37Abdominal painSeveral yearsT3.5 × 3 × 2Mucinous cystic neoplasm, mucinous cystadenomaDistal pancreatectomy with splenectomyNoAlive and well after 4 yearsF, female; M, male; mo, months; head, H; tail, T; PD, pancreaticoduodenectomy; mo, months; w, weeks; y, years. jcm-15-00136-t002_Table 2Table 2Characteristics of studies with population of newborns and children included in the systematic review.AuthorYearCountryGender/AgeSiteSize (cm)PHTreatmentFollow-Up and OutcomeBurt et al. [46]1983USAF/34 wDiffuse11.5Solid and cysticPD and splenectomyAlive at 3 moFlaherthy et al. [47]1992USAF/20 moH9Solid and cysticLocal resectionAlive at 9 moSepulveda et al. [48]2000ChileM/27 wDiffuse12Large multicysticExcision of the tumor andpartial duodenectomySymptom-free at the age of 1 yThrall et al. [49]2007USAM/3 yH3Multicystic adenomatoidPD/Sueyoshi et al. [50]2009JapanM/14 moT14Multicystic adenomatoidLocal resectionAlive at 26 moDelgado et al. [51]2017USAF/33 w/1.2Cysts/Trisomy 18, autopsy case, alive 1 hShah et al. [52]2017USAF/8 mo/14.5 × 11 × 5.5Solid and cysticResection Well after 3 moHosfield et al. [53]2019USAM/4 yearsH9.5Multicystic adenomatoidWhippleWell after 3 moVarlas et al. [54]2022RomaniaF/36 weeksDiffuse11Multicystic adenomatoidLocal resectionAlive at 11 moF, female; M, male; mo, months; head, H; tail, T; PD, pancreaticoduodenectomy; mo, months; w, weeks; y, years. jcm-15-00136-t003_Table 3Table 3Histological characteristics of pancreatic hamartoma cases included in the systematic review.AuthorYearPathologic TypeProvisional DiagnosisSpindle Cells CellularityLangerhansIsletsPeripheral NervesElastic Fibers *Wu et al. [18] 1998/Mucinous cystic tumorSuspicion of malignancy////McFaul et al. [19]2004SChronic pancreatitis, pancreatic neoplasm, islet cell neoplasm////

S ////Pauser et al. [5]2005S/C/HighNo//

S/C/LowNo//Pauser et al. [6]2005S//No//

S//No//Nagata et al. [1]2007SPancreatic endocrine tumorLowNo//Sampelean et al. [20]2009/, myoepithelial/////Durczynski et al. [9]2011S/LowYes//Kawakami et al. [8]2012S/LowNo//Kim et al. [21]2012S/CSPN, SCN

Kwon et al. [22]2012S, myoepithelial/////Yamaguchi et al. [7]2013SPancreatic cancerModerateNoNoNo

SSPNLowNoNoNo

S/CCystic tumorHighNoNoNo

SNETModerateNoNoNo

SNETModerateNoNoNo

S/CSPNModerateNoNoNo

S/CMass-forming pancreatitisLowNoNoNoAddeo et al. [10]2014SSuspicion of malignancy////Inoue et al. [23]2014S/Low///Shasbaz et al. [24]2015SPancreatic carcinoma/Yes//Zhang et al. [25]2016S/////Murakami et al. [26]2016S, myoepithelial/////Matsushita et al. [27]2016S/C, lipomatousSuspicion of malignancy////Han et al. [14]2017S/CNET/Present//Nahm et al. [13]2017S/C, lipomatousSPN/NoNoNoNagano et al. [28]2017SSuspicion of malignancy/No//Tanaka et al. [29]2018S, lipomatousSCN, IPMN, malignant tumor with lipoid degeneration/NoNoNo

S, lipomatousLipoma/NoNoNo

S, lipomatousLiposarcoma/NoNoNoShin et al. [30]2019SSPN, NET////Dasaraju et al. [31]2020SSuspicion of malignancy////Zhou et al. [32]2020S, lipomatousPancreatic liposarcoma/NoNo/Katayama et al. [12]2020S, lipomatousNET, SPN/NoNoNoCui et al. [33]2020S/CNET////

SSuspicion of malignancy////Toyama et al. [11]2020S/CMixed solid and cystic type SCN, NET, IPMN, SPN/NoNo/Yang et al. [34]2021SNET////Ahn et al. [37]2021SNET/NoNoNoNoguchi et al. [36]2021SNET/NoNo/Woo et al. [38]2022SHypovascular NET, SPN/NoNo/Santana et al. [39] 2022S/CNET////Tanigawa et al. [40]2022SPancreatic cancerHighNoNoNo

S/CCystic tumorHighNoNoNo

SPancreatic cancerHighNoNoNo

SNETHighNoNoNo

SAcinar cell carcinomaHighNoNoNo

SPancreatic tumorHighNoNoNo

SPancreatic cancerLowNoNoNo

SNETHighNoNoNo

SParagangliomaLowNoNoNo

SNETHighNoNoNo

S/CSPNLowNoNoNo

S/CMass-forming pancreatitisLowNoNoNo

S/C, lipomatousDermoid cystLowNoNoNoTee at al. [41]2022S, lipomatousPancreatic lipoma, liposarcoma/NoNoNoKim et al. [2]2023S/CNET////Jeo et al. [42] 2023S/CExisting von-Hippel-Lindau disease/Yes//Shintaku et al. [3]2023SNET, MNP, SPN/NoNoNoDas et al. [43]2024S/CIPMN/No//

S/CIPMN/No//

S/CIPMN////Liu et al. [44]2024SNET////Wan et al. [45]2024S/C, lipomatousTeratoma////Present case2025S/C/LowNoYes/Elastic fibers * surrounding pancreatic ducts stained with Elastica von Gieson; S—solid; S/C—solid and cystic; CgA—chromogranin A; NET—neuroendocrine tumor; IPMN—intraductal papillary mucinous neoplasm; SPN—solid pseudopapillary neoplasm; PB—pancreatoblastoma; MNP—mucinous cystic neoplasm, SCN—serous cystic neoplasm; ACC—acinar cell carcinoma. jcm-15-00136-t004_Table 4Table 4Radiologic Features of Pancreatic Hamartoma.Characteristicn/N (%)Size mm 29 (20, 50)Mass Effect11/34 (32%)Biliary Obstruction2/31 (6.5%)NECT   fat density3/18 (17%)  hypodense6/18 (33%)  isodense3/18 (17%)  mixed density6/18 (33%)CT+C A   hyperdense10/24 (42%)  hypodense8/24 (33%)  isodense3/24 (13%)  peripheral hyperdense3/24 (13%)CT+C PVP   hyperdense8/16 (50%)  hypodense2/16 (13%)  isodense2/16 (13%)  peripheral hyperdense4/16 (25%)CT+C DP   hyperdense7/8 (88%)  isodense1/8 (13%)Calcification3/23 (13%)P duct dil.4/28 (14%)Biopsy8/24 (33%)Demarcation   ill1/36 (2.8%)  well35/36 (97%)Inside   cystic5/35 (14%)  heterogenous8/35 (23%)  homogenous1/35 (2.9%)  lipomatous5/35 (14%)  multicystic5/35 (14%)  solid1/35 (2.9%)  solid-cystic10/35 (29%)T1WI   high intensity2/17 (12%)  isointensity2/17 (12%)  low intensity13/17 (76%)T2WI   high intensity17/19 (89%)  isointensity2/19 (11%)T1+C   delayed enhancement2/11 (18%)  enhancement8/11 (73%)  hypoenhancing1/11 (9.1%)DWI   high signal3/12 (25%)  isointense3/12 (25%)  marginal4/12 (33%)  no signal2/12 (17%)Fat2/7 (29%)FDG-PET   high accumulation1/11 (9.1%)  low accumulation1/11 (9.1%)  no accumulation9/11 (82%)Description of size change   enlarged5/6 (83%)  stable1/6 (17%) Median (IQR).

4. Discussion

To the best of our knowledge, this is the first systematic review dedicated to synthesizing all reported cases of pancreatic hamartoma, an exceptionally rare benign pancreatic tumor. Owing to the limited number of published cases, this comprehensive analysis represents an important step toward clarifying its clinical, radiological, and histopathological characteristics. By systematically collating and examining the existing evidence, this review provides a consolidated reference point for clinicians and researchers while identifying recurrent patterns that may facilitate earlier recognition and more accurate distinction from malignant pancreatic neoplasms.

Clinically, pancreatic hamartomas are often silent or manifest with non-specific symptoms, which contributes significantly to their diagnostic complexity. In most instances, these lesions are detected incidentally during imaging performed for unrelated reasons, such as malignancy surveillance or evaluation of vague abdominal discomfort. In our analysis, 57.4% of patients were asymptomatic at the time of diagnosis, and among symptomatic individuals, the most common complaint was vague or intermittent abdominal pain. Symptomatic presentation was more frequent among older adults, who had a significantly higher mean age than asymptomatic patients (63.1 ± 11.3 years vs. 54.9 ± 13.5 years, p = 0.009). These findings are consistent with previous reports, which emphasize the absence of pathognomonic clinical features in pancreatic hamartoma [39,44].

Radiologically, pancreatic hamartomas are frequently misinterpreted as malignant tumors due to their rarity and the lack of well-established imaging criteria. They lack distinctive features on cross-sectional imaging modalities such as CT or MRI, and their appearance often overlaps with that of NETs, mucinous cystic neoplasms, IPMNs, and pancreatic adenocarcinoma. In our review, 32.7% of cases were initially classified as NETs, and approximately 20% were suspected to represent pancreatic cancer or other malignant entities. This considerable overlap often leads to radical surgical interventions, including pancreaticoduodenectomy and distal pancreatectomy, to exclude malignancy and obtain a definitive diagnosis.

Although the number of cases with detailed imaging descriptions remains limited, certain patterns have emerged. Han et al. reported that pancreatic hamartomas may appear solid or solid-cystic on CT or MRI, depending on their composition [14]. Smaller lesions tend to be solid, whereas larger or mixed tumors may exhibit cystic components. A key distinguishing feature described in several cases is progressive, delayed enhancement on post-contrast MRI, likely reflecting the fibrotic stroma characteristic of these lesions. This enhancement pattern may aid in differentiating pancreatic hamartomas from hypervascular tumors such as NETs, which typically show rapid arterial enhancement and less delayed retention. Furthermore, pancreatic hamartomas generally lack diffusion restriction on DWI and show no abnormal FDG uptake on PET, further supporting their benign nature [14].

Our findings are in line with these observations. On MRI, pancreatic hamartomas typically demonstrated low signal intensity on T1-weighted images (76%) and high signal intensity on T2-weighted images (89%), with FDG-PET showing no uptake in 82% of cases. Notably, lesions initially misdiagnosed as NETs were more likely to display low T1 signal intensity. In contrast to NETs, which commonly exhibit high signal on DWI, pancreatic hamartomas showed moderate or no diffusion restriction. This novel observation may provide radiologists with an additional clue during preoperative evaluation that pancreatic hamartoma should be included in the differential when evaluating pancreatic lesions with these characteristic imaging patterns, particularly in cases where malignant tumors are being considered. Han et al. similarly emphasized that a lesion demonstrating progressive enhancement without diffusion restriction should prompt consideration of pancreatic hamartoma [14]. Although not pathognomonic, these imaging features are critical for raising suspicion and potentially avoiding misclassification.

Histopathologically, pancreatic hamartomas are well-circumscribed lesions composed of mature acini and ducts arranged in a distorted architecture, lacking well-formed Langerhans islets and elastic fibers within the ductal walls. The amount of fibrous stroma varies, contributing to their characteristic microscopic appearance. Recognizing this constellation of features is essential, particularly in limited biopsy specimens where diagnostic confusion with other pancreatic entities can arise [3]. In our review, the predominant pathological pattern was solid (64.7%) or solid–cystic (35.3%), with low spindle cell cellularity in 46.2% of cases. Langerhans islets were absent in 91.8% of reported specimens. The benign nature of pancreatic hamartoma is supported by a low Ki-67 proliferative index, consistently reported across both solid and cystic forms of the lesion [5,6,25,29], which was also confirmed in our case. Even in solid variants, the Ki-67 indices remained low compared with malignant pancreatic neoplasms, reinforcing the benign and indolent nature of these tumors. Recognizing this association may assist clinicians in diagnostic interpretation and support a conservative management approach when malignancy has been reasonably excluded.

Fine-needle aspiration or core biopsy often yields scant material composed of normal ductal cells, making definitive preoperative diagnosis challenging [8]. However, advances in endoscopic ultrasound-guided biopsy and the use of new-generation needles combined with immunohistochemistry have significantly improved diagnostic accuracy [55]. As reported by Shintaku et al. [3], even postoperative EUS-FNA evaluation may be challenging, as the small sample size can result in nonspecific findings such as focal pancreatic atrophy and fibrosis. Nevertheless, the presence of mature acinar cells and ductal structures embedded in fibrous stroma, in the absence of islets, may suggest pancreatic hamartoma and should prompt consideration of this entity in the differential diagnosis. In cases where imaging and EUS-FNA findings raise suspicion of a benign lesion, careful radiologic follow-up or repeat sampling may be considered to avoid unnecessary surgery. However, given the rarity of the disease and the limitations of tissue sampling, definitive diagnosis often remains postoperative.

Immunohistochemically, stromal cell expression of CD34 and CD117 is characteristic of but not specific to pancreatic hamartoma and can aid in distinguishing it from other pancreatic lesions [5,6,7,10,12,23]. In cases lacking stromal cell CD34 and CD117 expression, as in our case, the coexistence of ductal and neural elements, absence of cytologic atypia, and a low Ki-67 proliferation index collectively support the diagnosis of pancreatic hamartoma and confirm its benign character. However, CD117 positivity may lead to misinterpretation as gastrointestinal stromal tumor, underscoring the importance of contextual histopathological evaluation. CD34 expression in stromal cells supports the diagnosis, and these markers, when interpreted carefully, can strengthen diagnostic confidence and reduce unnecessary surgery [40].

Careful use of cytological and histological assessment can enable accurate preoperative diagnosis and help avoid radical surgical procedures, which carry significant morbidity. Increased awareness of the subtle but distinctive imaging and histopathological features of pancreatic hamartomas is therefore essential to improve preoperative recognition. As Nahm et al. aptly described, these lesions may mimic the appearance of more aggressive tumors despite their benign nature [13]. While surgical resection is often ultimately required to secure a definitive diagnosis, benign and low-grade malignant lesions must be considered in the preoperative differential. Unlike pancreatic cancer, pancreatic hamartomas are associated with excellent long-term outcomes. When surgery is indicated, minimally invasive, parenchyma-sparing approaches that preserve gastrointestinal and pancreatic function are most appropriate, reflecting the indolent biological behavior of these tumors [29].

Strengths and Limitations

This study represents the most comprehensive synthesis to date of all published cases of pancreatic hamartoma, integrating clinical, radiological, and histopathological findings to identify consistent diagnostic patterns. Additionally, by combining a newly documented case with systematic evidence, it provides novel insights into distinguishing imaging features, particularly the diagnostic value of T1-weighted MRI, and normal DWI patterns, which have direct clinical implications for improving preoperative diagnosis and reducing unnecessary radical surgery. The primary limitation of this study is that EUS-guided fine-needle aspiration (EUS-FNA) was not performed in our case, which could have provided additional preoperative diagnostic information and potentially avoided surgery. Instead, an ex tempore (intraoperative) biopsy was carried out. However, to date, preoperative diagnosis based on EUS-FNA specimens has not been reliably established. The systematic review is based solely on case reports and small case series, which are inherently prone to bias due to their descriptive nature and lack of standardized methodology. Publication bias is also likely, as rare or diagnostically challenging cases are more frequently reported. Additionally, substantial heterogeneity exists across the included studies, reflecting differences in reporting quality, diagnostic workup, imaging techniques, and pathological classification over several decades, resulting in missing or inconsistently reported data. Finally, preoperative diagnostic approaches varied widely, and tissue sampling was often unavailable, limiting conclusions regarding preoperative diagnosis.

5. Conclusions

This systematic review provides the most comprehensive synthesis to date of the clinical, radiological, and histopathological features of pancreatic hamartoma, a rare benign pancreatic tumor. Key findings include low T1-weighted signal intensity, and absence of diffusion restriction with isointense signal on DWI in lesions initially misdiagnosed as NETs. This association is based on a small subset of patients and should be interpreted cautiously. Further studies with larger cohorts are needed to determine whether this feature reliably distinguishes NETs from hamartomas. Clinicians should consider these radiographic characteristics, in conjunction with EUS-guided fine-needle aspiration and immunohistochemistry, when evaluating pancreatic masses. Incorporating these findings into diagnostic algorithms can support a provisional diagnosis of pancreatic hamartoma and help avoid unnecessary radical surgery, promoting more conservative and individualized management strategies.