Diagnostic challenge of intrahepatic splenosis masquerading as hepatocellular carcinoma: A case report and review of literature

Abstract

BACKGROUND

Intrahepatic splenosis (HS) is a rare benign condition characterized by heterotopic autotransplantation of splenic tissue into the liver parenchyma following splenic trauma or splenectomy. Radiological findings on conventional imaging modalities, such as computed tomography and magnetic resonance imaging, are usually inconclusive and nonspecific, making differentiation between splenosis and other hepatic lesions challenging. Therefore, awareness of HS is important to avoid unnecessary surgical procedures or patient anxiety resulting from the misdiagnosis of primary or secondary liver malignancies.

CASE SUMMARY

We present the case of a 61-year-old male patient with a history of chronic alcohol use and childhood splenectomy. He was admitted to the Department of Gastroenterology for focal liver lesions discovered during the diagnostic workup for an ischemic cerebrovascular incident that had occurred 3 months earlier. Notably, the patient had no evidence of cirrhosis and had normal findings for tumor markers. Multislice computed tomography and subsequent magnetic resonance imaging revealed one lesion suggestive of hepatocellular carcinoma (HCC). Although guidelines for indeterminate lesions in non-cirrhotic livers recommend ultrasound-guided biopsy, percutaneous sampling could not be performed due to the lesion’s proximity to major blood vessels. Given the high clinical suspicion for HCC and low suspicion for HS, contrast-enhanced ultrasound (CEUS) and scintigraphy were not performed. Surgery was selected as a combined diagnostic and therapeutic approach, and histopathological analysis confirmed HS. The patient recovered well and was discharged 7 days postoperatively.

CONCLUSION

Suspecting HS allows the use of CEUS or scintigraphy, thereby avoiding unnecessary invasive interventions while ensuring an accurate diagnosis.

Key Words: Splenosis; Splenectomy; Carcinoma; Hepatocellular; Radionuclide imaging; Case report

Core Tip: Intrahepatic splenosis (HS) is a rare benign condition that may mimic malignant liver lesions on conventional imaging. We report the case of a 61-year-old man with a prior splenectomy in whom a hepatic lesion suspicious for hepatocellular carcinoma led to surgical resection. Histopathological examination ultimately confirmed HS. This case emphasizes the diagnostic challenges and common pitfalls associated with this condition and underscores the importance of considering HS in the differential diagnosis of focal liver lesions.

INTRODUCTION

Splenosis is an acquired condition characterized by ectopic autotransplantation of splenic tissue following trauma or splenectomy. While its exact prevalence is unknown, as most patients are asymptomatic and the condition is usually found incidentally during radiological imaging, laparotomy, or autopsy[1,2], it has been reported in up to 67% of patients with a history of splenic trauma[2]. Owing to its nonspecific radiological characteristics, the differential diagnosis is vast[2-4]. Contrast-enhanced ultrasound (CEUS) guides the diagnosis toward splenosis[5-8], whereas the definitive diagnosis is established either by scintigraphy with Technetium-99m-labeled heat-denatured red blood cells (99mTc-DRBC), or by histopathological analysis[1,3].

A comprehensive literature review of reported cases of intrahepatic splenosis (HS) was conducted to synthesize current evidence, delineate diagnostic pitfalls, and summarize reported management strategies. To build on the literature, we present a case of HS that clinically and radiologically resembled hepatocellular carcinoma (HCC), leading to surgical resection of the lesion.

By integrating the present case with a focused literature review, this report underscores the importance of considering HS in the differential diagnosis of focal liver lesions, especially in non-cirrhotic patients, as clinical suspicion may facilitate the use of non-invasive diagnostic methods and help avoid unnecessary interventions.

CASE PRESENTATION

Chief complaints

In August 2024, a 61-year-old man was referred from another center to our Department of Gastroenterology for the evaluation of focal liver lesions.

History of present illness

In May 2024, the patient had attended an evaluation for an ischemic cerebrovascular event at another medical center. The focal liver lesions were incidentally detected at that time on abdominal ultrasound (US). Subsequent contrast-enhanced multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) performed at that same medical center revealed a non-cirrhotic liver and a lesion with imaging features suspicious for HCC. The patient was then referred to our Department of Gastroenterology for the further evaluation.

History of past illness

The patient’s medical history was significant for splenectomy in childhood following trauma, and for an ischemic stroke in May 2024.

Personal and family history

The patient reported chronic alcohol and tobacco use.

Physical examination

At admission, the patient was asymptomatic. Physical examination revealed a postsurgical scar in the midline, a soft and non-tender abdomen, and a palpable left hepatic lobe. Neurological examination demonstrated decreased motor strength in the left arm and left hemianopsia, consistent with sequelae of the prior stroke.

Laboratory examinations

Laboratory tests showed dyslipidemia and normal liver function parameters (aspartate aminotransferase 16 IU/L, alanine aminotransferase 12 IU/L, gamma-glutamyl transferase 23 IU/L, and alkaline phosphatase 46 IU/L). Total bilirubin was 10 μmol/L, the international normalized ratio was 0.9, and albumin was 39.1 g/L. The platelet count was 444 × 10⁹/L. Tumor markers were within the reference range (alpha-fetoprotein 1.5 µg/L and carcinoembryonic antigen 3.5 µg/L), and viral hepatitis serology was negative. Peripheral blood smear demonstrated anisocytosis and poikilocytosis of red blood cells with Howell-Jolly bodies. The patient also underwent esophagogastroduodenoscopy and colonoscopy, which revealed a hiatal hernia and sigmoid diverticula, respectively.

Imaging examinations

The initial evaluation, performed at another medical center, had revealed liver lesions of uncertain etiology. The diagnostic work-up at that institution had included US, contrast-enhanced abdominal MSCT, and MRI. Although US had been performed, its detailed findings were not available at the time of referral. However, the results of the other imaging studies were available and reviewed comprehensively.

We noted the contrast-enhanced abdominal MSCT demonstrated two focal liver lesions in segments III and VIII. The lesion in segment III was consistent with a hemangioma. The lesion in segment VIII measured 43 mm × 30 mm, was located near major vessels, including the inferior vena cava and the portal vein, and had inconclusive radiological features.

Subsequently, the contrast-enhanced abdominal MRI confirmed the hemangioma in segment III, whereas the other lesion exhibited arterial phase hyperenhancement followed by washout during the portal-venous phase, radiological features suggestive of HCC (Figure 1). In addition, the lesion demonstrated significant diffusion restriction on diffusion-weighted imaging (Figure 1), further increasing suspicion of malignancy.

Figure 1 Magnetic resonance imaging findings of the patient. A and B: T2-weighted axial (A) and coronal (B) slices show a slightly hyperintense lobulated lesion measuring 25 mm × 37 mm in segment VIII of the liver (arrow); C: T1-weighted image with fat suppression shows a slightly hypointense lobulated lesion in segment VIII (arrow); D: Diffusion-weighted imaging demonstrates marked hyperintensity of the lesion (arrow); E: Apparent diffusion coefficient map shows low signal intensity (arrow); F: Arterial-phase T1-weighted axial slice shows mild hypervascularity of the lesion compared with the surrounding liver parenchyma (arrow); G-I: A prominent wash-out pattern is demonstrated on the portal-venous (G), 3-minute (H), and 10-minute (I) delayed phase (arrow).

To assess the surrounding liver parenchyma, a US-guided biopsy of non-lesional liver tissue was performed. Histopathological examination revealed healthy liver parenchyma with sparse mononuclear infiltrate and no evidence of fibrosis or cirrhosis.

MULTIDISCIPLINARY EXPERT CONSULTATION

As the etiology of the hepatic lesion remained unclear on the radiological imaging, and given the absence of cirrhosis, a US-guided biopsy of the lesion itself was considered initially. However, due to the lesion’s proximity to the inferior vena cava and portal vein, both US- and CT-guided biopsies were deemed unsafe during the radiology multidisciplinary meeting because of the high risk of bleeding.

In the context of the high suspicion of malignancy and limited feasibility of a percutaneous biopsy, alternative non-invasive diagnostic modalities such as CEUS and scintigraphy were considered; ultimately, however, surgical resection was prioritized instead as a combined diagnostic and therapeutic approach. Subsequently, an exploratory surgery was performed and the lesion from segment VIII was resected without complications.

FINAL DIAGNOSIS

Macroscopically, a subcapsular specimen from segment VIII measured 44 mm × 40 mm × 23 mm and contained a dark red lesion measuring 1.6 cm in diameter, surrounded by a lighter rim. Histologically, the darker area consisted of red pulp composed of splenic cords and sinuses containing macrophages, lymphocytes, plasma cells (CD138+), and hematopoietic cells (myeloperoxidase+, glycophorin A+, and glycophorin C+), as well as white pulp formed by CD3+ lymphocytic mantles surrounding central arterioles and lymphoid nodules predominantly composed of CD20+ cells (Figure 2). These histopathological findings were consistent with splenic tissue, confirming the diagnosis of HS.

Figure 2 Histopathological analysis and immunohistochemical findings of the resected specimen. A: Gross examination of the resected liver segment measuring 44 cm × 4.0 cm × 2.3 cm shows a dark red lesion (blue arrow) 1.6 cm in diameter, surrounded by a lighter rim; B and C: Hematoxylin and eosin staining [magnification × 10 (B) and × 20 (C)] demonstrates splenic tissue (triangle) surrounded by liver parenchyma (orange arrow); D: Immunohistochemical staining shows positivity for glycophorin C in erythroid cells (yellow arrow), magnification × 40.

TREATMENT

Following the histopathological confirmation of a benign condition, no further medical or oncological treatment was required.

OUTCOME AND FOLLOW-UP

The postoperative course was uneventful. The patient made a full recovery and was discharged 7 days postoperatively in good general condition. At the 6-month follow-up, the patient remained asymptomatic, and US showed no evidence of postsurgical complications. Further evaluation was recommended upon clinical indication only. The timeline of diagnoses, laboratory and imaging results, and decision-making leading to the final diagnosis is described in Table 1.

Table 1 Timeline of clinical events.

Year	Clinical events
Childhood	Splenectomy
May 2024	Ischemic stroke. US: Focal liver lesion
June 2024	Contrast-enhanced abdominal MSCT: Focal lesions of unknown etiology
July 2024	MRI: Focal lesion suspicious of HCC
August 2024	Referring to the Department of Gastroenterology
September 2024	Percutaneous biopsy of non-lesional liver tissue: Healthy liver parenchyma; Normal tumor marker values
October 2024	Radiological multidisciplinary meeting: Bleeding risk from biopsy; Surgery chosen as diagnostic and therapeutic modality
November 2024	Surgical resection of the focal liver lesion. Histopathological analysis: Intrahepatic splenosis
November 2024 to April 2025	Regular follow-ups. Further evaluation if clinically indicated

HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; MSCT: Multislice computed tomography; US: Ultrasound.

DISCUSSION

Literature review

A comprehensive literature search of HS cases was conducted using the PubMed database for articles published up to January 2026. The search strategy included a combination of the following terms: “hepatic splenosis”, “intrahepatic splenosis”, “hepatocellular carcinoma”, “focal liver lesion”, and “splenectomy”. No restrictions were imposed regarding language. References cited in the identified articles were also examined as supplementary sources.

Articles reporting human cases of HS were eligible for inclusion. Studies available only as abstracts or images of the month were excluded to reduce the risk of duplication and incomplete data extraction. Animal studies were also excluded. All non-English articles were assessed using translation tools. Studies selection and data extraction were performed by a single reviewer. This work should be interpreted as a narrative review of published case reports, rather than as a systematic review.

The initial search identified 91 articles reporting on 94 cases. After applying the exclusion criteria, 81 cases[4,9-85] published between January 1993 and July 2025, were included in the final analysis. Data were systematically extracted from each for patient sex and age, history of splenectomy (including its indication and the time elapsed since the procedure), pre-existing liver conditions, number of hepatic lesions, presence of extrahepatic lesions, initial diagnosis, and the method used to establish the definitive diagnosis.

A key limitation of this review is the heterogeneity and incomplete reporting of data across the included case reports. Variables of interest, such as patient demographics and initial diagnosis were not consistently available. In addition, the time interval since splenectomy was often reported descriptively (e.g., “in childhood”), limiting precise analysis. Furthermore, the relatively small sample size of confirmed HS cases restricts the statistical strength of the findings.

Male patients accounted for 64 cases (81%). The age of the included patients ranged from 21 years to 73 years, with a median age of 51 years and a mean age of 49.01 ± 10.83 years. The age and sex profiles of the patients are shown in Figure 3A.

Figure 3 Distribution of intrahepatic splenosis. A: Age and sex distribution of intrahepatic splenosis at the time of diagnosis. The majority of cases occurred in male patients, predominantly between 40 years and 60 years of age; B: Distribution of time from splenectomy to presentation of intrahepatic splenosis. Most cases were reported 20-30 years after splenectomy.

Almost all patients had undergone splenectomy, except for 3 cases[38,51,70] in which surgery was not performed, and 1 case[81] in which this information was not provided. The main indication for splenectomy was trauma (86%). The time interval between the splenectomy and HS diagnosis ranged from 1.5 years to 50 years, with a median of 23 years and a mean of 25.48 ± 11.99 years. The time interval between splenectomy and diagnosis is illustrated in Figure 3B.

A total of 30 patients had pre-existing liver conditions, with cirrhosis documented in 7 patients, hepatitis B virus in 9 patients, and hepatitis C virus infection in 17 patients. Relevant epidemiologic and clinical information is summarized in Table 2.

Table 2 Summary of epidemiological and clinical characteristics of reported cases of intrahepatic splenosis[4,9-85].

Epidemiological and clinical characteristics	Cases, n	%
Male sex1	64	81
Age > 40 years1	60	76
Splenectomy
Overall	77	96
Due to trauma2	65	86
Cirrhosis	7	9

¹Not disclosed by Martínez Del Valle Torres et al[24] and Hu et al[84].

²Not disclosed by Lau and Lao[81].

Solitary hepatic lesions were reported in 46 patients, while multiple lesions were reported in 34 cases, of which 14 were associated with additional extrahepatic lesions.

Of the eight papers excluded from the analysis of the initially suspected diagnosis, 2 had insufficient information[4,16]. In 3 cases, diagnoses were made based on radiological findings exclusively[64,71,75]. In 2 cases, HS was an incidental finding during surgery for other indications[55,78], and in 1 case HS was a postmortem diagnosis[11]. The most frequently suspected initial diagnosis was HCC, reported in 36 cases (49%). This was followed by other malignancies and metastatic processes, which together accounted for 16% of cases. HS itself was considered the initial diagnosis in 21% of patients. However, when cases with and without extrahepatic lesions were analyzed separately, HS was the most frequently considered initial diagnosis in patients with extrahepatic lesions (33%), followed by HCC (25%). In contrast, among patients with lesions confined to the liver, HCC was primarily suspected in 54% of cases, whereas HS was considered in only 8%.

The definitive diagnosis was most often established through surgical intervention (56%), whereas other methods, such as biopsy and scintigraphy using 99mTc-DRBC, were less commonly used, accounting for 23% and 21% of cases, respectively. However, in 2 cases[16,20], even though scintigraphy was used, the final diagnoses were confirmed by biopsy. When cases were analyzed separately by lesion localization, scintigraphy was used more frequently (58%) in patients with extrahepatic lesions, whereas surgical intervention was reported in only 33% of these cases. Conversely, among patients with only intrahepatic nodules, surgery was performed in 61% of cases, while scintigraphy was used in 13%. A summary of diagnostic approaches stratified by clinical context is provided in Table 3.

Table 3 Diagnostic methods for intrahepatic splenosis according to initial differential diagnosis and presence of extrahepatic lesions[9,10,12-15,17-54,56-63,65-70,72-74,76,77,79-85].

Extrahepatic lesions	Primary differential diagnosis	Diagnosis	Count
No	HCC	Biopsy	8
		Surgery	22
		Scintigraphy	3
	Other malignancy	Biopsy	2
		Surgery	6
		Scintigraphy	1
	Benign (non-HS)	Biopsy	3
		Surgery	9
		Scintigraphy	2
	HS	Biopsy	3
		Scintigraphy	2
Yes	HCC	Surgery	2
		Scintigraphy	1
	Other malignancy	Surgery	2
		Scintigraphy	1
	Benign (non-HS)	Scintigraphy	2
	HS	Biopsy	1
		Scintigraphy	3

HCC: Hepatocellular carcinoma; HS: Intrahepatic splenosis.

Case analysis

Splenosis is a rare but clinically relevant condition resulting from heterotopic implantation of splenic tissue after splenic injury or splenectomy. Although the exact pathogenesis of splenosis remains incompletely understood, the most widely accepted explanation is the seeding theory. It posits that a portion of the splenic pulp detaches and implants into the adjacent serosa following trauma or rupture of the spleen. Subsequent neovascularization establishes perfusion, enabling the splenic fragment to grow and develop into tissue histologically indistinguishable from the normal spleen[2,28,86]. The most common implantation sites are the left upper quadrant, intestinal serosa, greater omentum, and diaphragm, although engraftment can also occur in extraperitoneal locations, such as the thoracic cavity (through diaphragmatic laceration from thoracoabdominal trauma), pelvis, and, least commonly, subcutaneous tissue[1-3,14,87]. In rare cases, splenic tissue implants within the liver, a condition referred to as HS[2].

An alternative hypothesis proposes that splenic progenitor cells may reach the liver via the portal circulation following splenic injury. Local hepatic hypoxia due to age-related reductions in hepatic perfusion and increases in liver size has been suggested to facilitate the survival and proliferation of ectopic splenic tissue[86]. Furthermore, chronic liver diseases, such as cirrhosis and viral hepatitis, may predispose patients with a history of splenic trauma to the development of HS.

According to the literature, 93% of HS cases occur in patients who have undergone splenectomy[2]. In addition, our review revealed a clear demographic pattern, with a marked male predominance and a mean age of 49 years. Considering the long latency period between splenic trauma and diagnosis, which averages 26 years, this demographic profile closely reflects that of patients undergoing traumatic splenectomy, a procedure that predominantly affects young adult males[88]. These findings highlight the pivotal role of a detailed patient history, particularly regarding abdominal trauma or surgeries.

On rare occasions, depending on the size and localization of splenosis, patients report mild abdominal discomfort, various degrees of gastrointestinal bleeding, or even intestinal obstruction. Furthermore, cases of hydronephrosis secondary to ureteral obstruction have also been reported[2,87]. However, most patients with HS are asymptomatic, and the lesion is typically discovered incidentally during radiologic imaging or at surgery[1,4].

HS remains a diagnostic challenge because of its nonspecific radiologic characteristics that often overlap with those of numerous benign and malignant focal liver lesions. The differential diagnosis is broad and includes HCC, hepatic adenoma, focal nodular hyperplasia, hemangioma, metastatic disease, and, less commonly, lymphoproliferative and peritoneal processes[1-4,80,87,89].

Differentiation from HCC remains crucial, as both lesions typically appear hypoechoic on US and have no specific distinguishing features. Direct comparison of lesion and spleen characteristics on MSCT or MRI may be helpful, but it is usually not feasible since most patients have undergone splenectomy[2,5]. Therefore, diagnosis relies on the combination of imaging features and clinical context.

On contrast-enhanced MSCT, HS usually demonstrates a transient, inhomogeneous, striped-like pattern, known as the zebra pattern, during the arterial phase, and persistent enhancement in the portal venous phase, reflecting differences in perfusion between the red and white pulp[8,80]. However, variability in enhancement patterns has been reported, including portal phase venous washout, which is more commonly associated with HCC and may lead to widespread misclassification[20,23].

In this context, CEUS represents a valuable tool for differentiating malignant from benign lesions, especially in non-cirrhotic patients, by enabling real-time assessment of the lesion vascularity without ionizing radiation. Hepatic malignancies are typically characterized by hypoenhancement in the portal and late phases, regardless of arterial-phase imbibition pattern[6,7,90]. In contrast, benign lesions usually retain contrast for more than 2 minutes[5]. Additionally, splenic tissue has been reported to demonstrate a distinct enhancement pattern on CEUS, with a transient arterial zebra enhancement, followed by progressive homogenization and even longer contrast retention, typically exceeding 5 minutes[5,8]. Therefore, a well-defined, homogeneous liver lesion demonstrating prolonged enhancement in a non-cirrhotic male patient, particularly in the presence of prior splenic trauma or splenectomy, is highly suggestive of splenosis and subsequently narrows the differential diagnosis to benign entities[5,6,8].

MRI characteristics of HS vary[80], although lesions typically appear hypointense on T1-weighted images and hyperintense on T2-weighted images[2]. MRI serves as a complementary modality in indeterminate cases where CEUS findings suggest a benign lesion, but further characterization is required to identify entities with potential clinical implications, such as an inflammatory hepatocellular adenoma, which may warrant monitoring or intervention[5].

The definitive diagnosis of HS can be established using scintigraphy with 99mTc-DRBC. It is a non-invasive method that demonstrates high specificity and sensitivity for detecting heterotopic functional splenic tissue, particularly when combined with CT[3]. Despite its diagnostic value, this modality is underutilized in clinical practice, particularly in patients without extrahepatic lesions when HS is often not considered in the differential diagnosis.

Another way to reach a definitive diagnosis is histopathological analysis[1]. However, it should be noted that invasive approaches, such as biopsies and surgical resections of HS, are frequently overused in clinical practice and should be reserved for cases in which non-invasive methods are inconclusive.

A key limitation in our case was the omission of CEUS or 99mTc-DRBC scintigraphy prior to intervention. This decision was primarily driven by low clinical suspicion, strong radiological concern for malignancy, and the perceived risk of biopsy-related bleeding, ultimately leading to surgical resection as a definitive diagnostic and therapeutic modality. This case, therefore, emphasizes an important learning point, namely the importance of considering HS in non-cirrhotic male patients with a history of splenic trauma and indeterminate liver lesions.

To improve early recognition of HS and reduce unnecessary invasive procedures, we propose a diagnostic algorithm (Figure 4). This stepwise approach integrates key clinical and imaging features to facilitate the appropriate use of non-invasive diagnostic tools when HS is suspected.

Figure 4 Suggested diagnostic algorithm for newly detected focal liver lesion in non-cirrhotic patients with suspicion of intrahepatic splenosis. A stepwise approach is presented based on clinical history, imaging findings, and confirmatory tests. 99mTc-DRBC: Technetium-99m-labeled heat-denatured red blood cells; CEUS: Contrast-enhanced ultrasound; MRI: Magnetic resonance imaging; US: Ultrasound.

CONCLUSION

In conclusion, HS should be considered in the differential diagnosis of focal liver lesions, especially in non-cirrhotic male patients with a history of abdominal trauma or splenectomy. Given the limitations of conventional cross-sectional imaging, increased awareness and appropriate use of CEUS may prompt further evaluation with 99mTc-DRBC scintigraphy, thereby improving patient management and reducing unwarranted invasive procedures.

ACKNOWLEDGEMENTS

The authors would like to thank the Department of Pathology and Cytology, University Hospital Merkur, for preparing the histopathological specimens and the Department of Diagnostic and Interventional Radiology, University Hospital Merkur, for providing the radiological images used in this manuscript.