Abstract
OBJECTIVE:
To evaluate the contrast enhanced ultrasound (CEUS) and contrast enhanced magnetic resonance imaging (CEMRI) features of intrahepatic splenosis (IHS).
METHODS & MATERIALS:
Five patients (three males and two females, median age, 44 years; range,32–73 years) with seven IHSs were retrieved from the database of our hospital from March 2012 to October 2021. All IHSs were confirmed histologically by surgery. The CEUS and CEMRI characteristics of individual lesion were fully analyzed.
RESULTS:
All IHS patients were asymptomatic and four out of five patients had history of splenectomy. On CEUS, all IHSs were hyperenhancement in arterial phase. 71.4% (5/7) of IHSs manifested overall filling within few seconds, the other two lesions showed centripetal filling. Subcapsular vascular hyperenhancement and feeding artery was seen in 28.6% (2/7) and 42.9% (3/7) of IHSs, respectively. During portal venous phase, IHSs presented hyperenhancement (2/7) or isoenhancement (5/7). Moreover, rim-like hypoenhanced area was uniquely observed surrounding 85.7% (6/7) of IHSs. In late phase, seven IHSs remained continuous hyper- or isoenhancement. On CEMRI, five IHSs showed mosaic hyperintense in early arterial phase, the other two lesions showed homogeneous hyperintense. In portal venous phase, all IHSs revealed continuous hyper- (71.4%, 5/7) or iso-intense (28.6%, 2/7). During late phase, one IHS (14.3%, 1/7) became hypointense, the other lesions remained hyper- or isointense.
CONCLUSION:
Diagnosis of IHS can be based on typical CEUS and CEMRI features in patients with history of splenectomy.
Introduction
Intrahepatic splenosis (IHS) is a kind of rare benign focal hepatic lesions (FLL) inferred to be bound up with history of splenectomy or trauma [1]. As benign neoplasm, IHS is relatively stable in size over time, thus no further treatment is needed unless intolerable abdominal pain. Although documented, data regarding imaging features of IHS remains scarce [2–6]. Once detected, it can be easily mistaken for hepatocellular carcinoma (HCC), focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA) or metastasis, eventually resulting in unnecessary invasive treatment [4]. Herein, evaluation of IHS by non-invasive imaging method is crucial for appropriate decision-making in clinical management.
The characteristics of IHS has been summarized as a triad: past history of splenectomy, lack of risk factors for hepatic malignancy, typical imaging features on Technetium-99m red blood cell (RBC) scintigraphy or contrast-enhanced computerized tomography/magnetic resonance imaging (CECT/MRI) [2]. RBC scintigraphy has been proposed as the first choice for diagnosis of IHS, but it is not recommended as first line method for FLL yet [7, 8]. CECT/MRI is promising technique in the preoperative diagnosis of FLL, whereas about 27 –34% of IHS shows washout during late phase mimicking HCC [2, 9]. Besides, the increase incidence of non-alcoholic fatty liver disease (NAFLD) associated HCC as well as AFP-negative HCC makes it more difficult to differentiate IHS from HCC [10].
CEUS has been widely applied to FLL for its strict intravascular contrast media, radiation-free nature, and harmless to chronic kidney disease patients [11]. Compared with CECT, remarkable improvement in sensitivity and specificity has been made by CEUS particularly for small hepatic lesions [12]. What’s more, CEUS has been proven to be invaluable in diagnosis of indeterminate FLL on CEMRI because of real-time dynamic enhancement pattern in the arterial phase [13]. Additionally, the low cost of CEUS also makes it attractive. Up till now, the CEUS findings of IHS have not been fully analyzed.
The aim of this study was to evaluate further information about CEUS and CEMRI characteristics of IHS. To the best of our knowledge, this was the largest case series of contrast enhanced imaging features of IHS so far.
Patients and methods
Patients
This work was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (B2021-051). Informed consent was obtained from each patient. A systematic research was retrospectively performed in database of our hospital between March 2012 and October 2021. Totally, three males and two females with median age of 44 years (range:32–73years) were included.
The inclusion criteria were as follows:(1) Histochemical examination confirmed as IHS after surgery, (2) CEUS and CEMRI performed within four weeks before surgery. The patients with the following criteria were excluded: (1) preoperative biopsy or locoregional therapy (radiotherapy, TACE, targeted therapy, etc.), (2) target lesion invisible on B-mode ultrasound (BMUS), (3) incomplete clinic-pathological data or contrast enhanced images.
CEUS image acquisition
Ultrasound examinations were performed by sonographers with over 10 years of CEUS experience. All examinations were performed using one of the following premium ultrasound equipment: LOGIQ E9 (GE Healthcare, C1-5convex array probe, 1.0–5.0 MHz); Philips EPIQ7 (Philips, C2–9 convex array probe, 2.5–5.0MHz); Acuson Sequoia (Siemens Healthineers, 5C1 convex array probe, 3.5–5.0 MHz).
SonoVue® (Bracco, Milan, Italy) was injected intravenously as quick bolus via 20-gauge catheter placed in the cubital vein with dose of 1.5–2.5 mL, and then 5 mL of 0.9% normal saline solution was followed. All images were recorded for up to 5 min after injection of Sonvue®. Repeated injection was performed at least 15 min later when necessary.
CEUS imaging analysis
Two experienced sonographers who were blinded to the clinicopathologic data of patients reviewed the images independently. Firstly, the BMUS features were recorded as follows: maximum diameter of lesions, echogenicity (hypoechoic, isoechoic or hyperechoic), homogeneity (heterogeneous or homogeneous), margin (ill- or well-defined), shape (regular or irregular), and color Doppler flow signals. The CEUS features were analyzed according to the 2020 World Medical Biology Ultrasound Federation Congress (WFUMB) guidelines [11]. The contrast enhancement degree (hyperenhancement, isoenhancement, or hypoenhancement), enhancement pattern (overall, centripetal, or centrifugal filling), homogeneity (heterogeneous or homogeneous) in the arterial phase (10 –45 s), portal venous phase (30 –120 s) and late phase (120 –300 s). The additional features during the whole enhancement phases were noted as well, e. g., feeding artery (Fig. 1b), subcapsular vascular hyperenhancement (Fig. 2c), and rim-like hypoenhanced area (Fig. 2d).
Contrast enhanced images of intrahepatic splenosis (IHS). (a) A homogeneous hypoechoic lesion with well-defended margin is detected under the capsule of left lobe of liver. (b) On CEUS, the IHS lesion shows homogeneous hyperenhancement in few seconds in early arterial phase, the feeding artery could also be observed (▵). (c) During late phase, it remains continuous hyperenhancement compared to the surrounding liver parenchyma. (d) On CEMRI, the hepatic lesion presents mosaic enhancement in early arterial phase. (e) During portal venous phase, it presents homogeneous hyperintense. (f) During equilibrium phase, the lesion becomes isointense, suggesting benign tumor. (g) After surgery, the gross specimen of IHS is enveloped by a thin fibrous capsule (⇑). (h) The H&E staining of IHS reveals features of typical spleen tissue(100X). Microscopically The plentiful lymphocytes surround the central artery, forming a lymphocyte sheath, and lymph node nodules can be seen nearby, blood sinusoids are under the capsule, lined with endothelial cells, and there are cord-like separations formed by lymphoid tissue rich in blood cells between the blood sinusoids.
Contrast enhanced images of IHS. (a) On B-mode ultrasound, a slight hypoechoic lesion with thin enveloped capsule is detected under hepatic subcapsular (▵). (b) Short rod-like blood flow signal is seen around IHS on color Doppler flow imaging. (c) In arterial phase, the hepatic lesion displays overall hyperenhancement homogeneously, the subcapsular vascular enhancement is also displayed (▵). (d, e) During portal venous and late phase, IHS presents continuous hyperenhancement, and rim-like hypoenhancement area can be seen surrounding the lesion (▵). (f) The hepatic lesion is hypointense on T1WI with a thin hypointense rim (▵). (g) On T2WI, IHS is homogeneous hyperintense lesion lying under the liver capsule with slight hepatic capsule impression (▵). (h) On contrast enhanced scan, the hepatic lesion shows homogeneous hyperintense in early arterial phase. (i) During portal venous phase, the IHS lesion presents isointense. (j) In equilibrium phase, the IHS becomes hypointense, capsule-like enhancement is detected, mimicing HCC (▵). (k) H&E staining of IHS (100X) reveals features of spleen tissue.
All patients were examined with 3.0 Tesla MR scanner (Magnetom Aera, Siemens, Erlangen, Germany). The pro-enhanced T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion weighted imaging (DWI) were performed at first. Then, the contrast agent gadoxetic acid (Primovist; Bayer HealthCare, Berlin, Germany) was administered via a power injector (Spectris; Medrad, Pittsburgh, PA, USA) intravenously at dose of 0.025 mmol/ kg with the rate of 2 mL/s, followed by 20 mL saline flush. The dynamic contrast enhancement performance during the arterial, portal venous, and equilibrium phase were acquired.
CEMRI imaging analysis
MR images were evaluated by two abdominal radiologists (with 6 and 10 years of experience in liver MRI, respectively) in a blinded manner independently. The reviewers were unaware of that the patients’ medical history, laboratory tests, and pathologic findings. The consensus review was regarded as reference standard when disagreement occurred. Major morphological features were as follows: the maximum diameter, number (single or multiple), signals on unenhanced TIWI, T2WI and DWI, a thin enveloped capsule (yes or no), as well as slight hepatic capsule impression (yes or no). The contrast enhanced features were evaluated as: enhancement pattern (mosaic or overall) in early arterial phase, enhancement homogeneity (homogenous or heterogeneous), signals (hyperintense, isointense or hypointense) in the arterial, portal venous, and equilibrium phase.
Histopathological diagnosis
All IHS patients underwent segmental hepatectomy. Haematoxylin-eosin (H&E) staining was performed in seven lesions. Two experienced pathologists reviewed all tissues.
Results
Clinical characteristics
The final study group comprised five IHS patients with seven lesions. All IHS patients were asymptomatic and the hepatic lesions were detected incidentally in health examination. Four out of five IHS patients had history of splenectomy, but they didn’t recall any correlation between the hepatic lesion and splenectomy. Two patients infected with hepatitis B virus (HBV), nevertheless none of liver cirrhosis was detected. The serum tumor markers of all patients were in normal range. The clinical characteristics of patients were listed in Table 1.
Clinical characteristics of IHS patients included in the present study
Clinical characteristics of IHS patients included in the present study
Among five IHS cases, four patients presented with single nodule, the other one with multiple nodules. The dimension of IHSs ranged from 18 to 52 mm (median 25 mm). On BMUS, the IHSs were well-defined, homogeneous, hypoechoic lesions lying just under the liver capsular, thus slight hepatic capsule impression was detected in 57.1% (4/7) of lesions (Fig. 1a). 71.4% (5/7) of IHSs were encapsulated by a thin capsule (Fig. 2a). As for the liver parenchyma, IHSs occurred on normal (71.4%, 5/7) or fatty liver (28.6%, 2/7). Color Doppler flow imaging showed short rod-like or rim-like vessels in most IHSs.
On CEUS, all IHSs were hyperenhancement in arterial phase. 71.4% (5/7) of IHSs manifested overall filling in few seconds, others showed overall hyperenhancement. Subcapsular vascular hyperenhancement and feeding artery was seen in 28.6% and 42.9% of IHSs, respectively. During portal venous phase, IHSs presented hyperenhancement (28.6%, 2/7) or isoenhancement (71.4%, 5/7). Moreover, rim-like hypo-enhanced area was uniquely observed surrounding 85.7% (6/7) of IHSs. In late phase, all IHSs remained continuous hyper- or isoenhancement. The CEUS findings of IHSs were summarized in Table 2.
CEUS and CEMRI features of intrahepatic splenosis (n = 7)
CEUS and CEMRI features of intrahepatic splenosis (n = 7)
Hyperenhancement, Iso = Isoenhancement, Hypo = Hypoenahncement; T1WI/T2WI: Hyper = hyperintense, Iso = Isointense, Hypo = Hypointense; CEMRI, contrast-enhanced magnetic resonance imaging; CEUS, contrast-enhanced ultrasound.
For the signal features, IHSs were mainly hypointense (71.4%, 5/7) on pre-enhanced T1WI with a thin enveloped capsule (Fig. 2f) and hyperintense (85.7%, 6/7) on T2WI. On DWI, all IHS were hyperintense. What’s more, hepatic capsule impression (Fig. 2g) was seen around each IHS lesion. After injection of contrast agent, five IHSs showed mosaic hyperintense (Fig. 1d) in early arterial phase, the rest two lesions were overall hyperenhanced. During portal venous phase, all IHSs revealed continuous hyper- or isointense. During late phase, 85.7% (6/7) of IHSs were hyper- or isointense, the other one showed hypointense. The CEMRI findings of IHSs were displayed in Table 2.
Final diagnosis and management of IHS
All IHSs enrolled in this study were confirmed by histologic examination after surgery. Microscopically, the histopathological examinations with H&E staining revealed typical spleen-like mass consisting of plentiful lymphocytes surrounding the central artery, which formed a lymphocyte sheath. Lymph node nodules can be seen nearby, blood sinusoids were under the capsule, lined with endothelial cells, and there were cord-like separations formed by lymphoid tissue between the blood sinusoids (Fig. 1h).
The IHS patients were followed up by clinic visits regularly (four patients) or telephone interview (one patient) for 0.5 to 4 years, no recurrence was observed.
Discussion
Splenosis is an under diagnosed entity that occurs almost exclusively in patients suffered from splenectomy or trauma, but liver is an unusual site for splenosis to arise [2]. Previously, IHS has been speculated to closely resemble HCC, FNH, or metastatic tumor [4]. Since invasive treatment is needed for those FLL, accurate preoperative diagnosis of IHS can provide reference for clinical treatment.
As was displayed by our results, IHS patients were symptomless and the tumor markers were all negative, which coincided with previous researches [14, 15]. The history of splenectomy or splenic injury strongly suggested IHS, but patients usually couldn’t remember that when they first came to clinic [16].
On gray-scale ultrasound, IHSs were hypoechoic lesions lying just under liver capsular with well-defined margin, regular shape, and a thin hyperechoic capsule. Although BMUS is precise in location and size of the lesion, it is insensitive in detecting blood flow signals [11]. The contrast agent SonVue® is an excellent blood pool tracer to reflect the microflow [17]. On CEUS, the majority of IHSs showed homogeneous hyperenhancement in the arterial phase, and continuous hyper- or iso-enhancement till late phase, indicating benign tumor. There was abundant venous sinus in the splenic tissue, so the microbubbles persisted longer in IHSs than the normal hepatic parenchyma during late phase [5]. Up to date, only two pieces of case report described CEUS performance of IHS, and our results were in line with the published cases [3, 5]. What’s notable was that rim-like hypoenhanced area during portal venous phase was uniquely seen surrounding the IHSs. For malignancy, the hepatic artery blood volume is more than the liver parenchyma, which leads to washout in the portal or late phase [12]. Similarly, the splenosis implants on the surface of the liver and then grows into the intrahepatic space, thus enveloped by a thin fibrous capsule [2]. The fibrous capsule is supplied by branches of hepatic artery but lacks portal venous blood, so rim-like hypoenhanced area can be observed since portal venous phase.
Due to its highly sensitive and accurate modality, MRI currently represents the preferred technique for examination of patients with suspected hepatic tumor [12]. In the cases of our center, IHSs were mainly hypointense on T1WI with thin enveloped capsule, which represented the fibrous capsule and was detected surrounding each HIS lesion. The fibrous capsule was also observed by Tsitouridis et al. [18]. On T2WI, IHSs were homogeneous hyperintense lesion lying under the liver capsule with slight hepatic capsule impression. The location, thin fibrous capsule, and slight hepatic capsule impression were valuable factors suggesting splenosis implanting on the liver surface rather than intrahepatic lesion. On contrast enhanced scan, mosaic hyperintense was observed in five larger lesions (with maximum diameter of 23 mm, 25 mm, 29 mm, 30 mm, 52 mm) in early arterial phase just like normal splenic tissue [4], whereas overall hyperenhancement was seen in the other two smaller lesions (with maximum diameter of 18 mm, 22 mm). During portal venous and equilibrium phase, one IHS lesion became hypointense, which was misdiagnosed as HCC. The enhancement pattern of washin without washout, negative serum AFP, lack of HBV infection as well as hepatic cirrhosis might contribute to accurate diagnosis of IHS preoperatively [17]. Recently, the prevalence of NAFLD associated HCC makes it more difficult to distinguish HCC from HIS [10]. Furthermore, IHS has been reported to arise in hepatic cirrhosis in a case study [19]. On that condition, biopsy is needed when necessary.
Because of rarity, IHS has been misdiagnosed as FNH in our center. The enhancement pattern in the arterial phase was important to identify FNH from IHS, conversely it is hard to tell atypical FNH from HIS [17]. Both FNH and IHS can be treated with conservative method, so regular follow up can be suggested.
HCA is another kind of rare benign FLL to be distinguished with HIS [20]. Although benign lesion, HCA has potential to be HCC and even life-threatening bleeding, so that surgery is needed in due time. HCA manifests as rapid hyperenhancement homogeneously in arterial phase and slight washout in late phase. The subcapsular vascular hyperenhancement formed by the feeding artery of the lesion is a defining characteristic of HCA [21]. Nevertheless, the subcapsular vascular of IHS is made up by the fibrous capsule.
Peliosis hepatis also needs to be differentiated from IHS. Peliosis hepatis is always detected secondary to autoimmune disease or anti-tumor treatment. On BMUS, it is characteristically hypoechoic nodule without mass effect. On CEUS, it presents heterogeneous hyperenhancement mildly in the arterial phase, and slight washout in the portal venous and late phase [22].
Hepatic metastasis should also be excluded [8, 9]. As shown in the present study, IHS is mostly single lesion, while metastasis represent as multiple lesions in the liver with rim-like hyperenhancement in arterial phase and marked washout in 60 seconds on CEUS/CEMRI [12]. In addition, the history of primary tumor should also be taken into consideration.
What’s worth noting was that the enhancement performance of IHS on CEMRI was not all agree with CEUS. The reasons are as follows: Firstly, CEMRI is superior in revealing the position relationship of lesion and the liver capsule than CEUS; Secondly, the contrast agent of CEUS is pure endovascular contrast agent that vividly reflects the microvascular distribution of FLL, conversely the contrast media of CEMRI can permeate the intercellular space of lesions. Despite of this, CEUS findings coupled with CEMRI aid the diagnosis of IHS noninvasively.
In addition, both 99 mTc RBC single photon emission computed tomography has been reported to differentiate IHS from malignancy to avoid unnecessary surgical intervention [2]. Though SPECT is specific for diagnosis of IHS, it is no longer used as first line examination nowadays in many medical center [8, 9].
Limitations
As retrospective study, selection bias may exist inevitably. Besides, the sample size of IHS is so tiny, it will be continuously focused on in our following study.
Conclusion
In conclusion, IHS is rare benign, well-defined hypoechoic hepatic lesion lying just under the liver capsular. The CEUS features of IHS include homogeneous hyperenhancement in atrial phase, rim-like hypoenhanced area in portal venous phase and continuous hyer- or isoenhancement in late phase. The CEMRI images reveal that IHS is characterized by slight hepatic capsule impression, thin enveloped capsule and mosaic hyperintense in early arterial phase. Diagnosis of IHS can be based on typical contrast enhanced image features in patients with history of splenectomy.
Grant support
Supported by Shanghai Municipal Natural Science Foundation (Grant No. 20ZR1452800); Shanghai Shenkang Center major clinical research project (Grant No. SHDC2020CR1031B); Shanghai Municipal Key Clinical Specialty (Grant No. shslczdzk03501).