Contrast-Enhanced Ultrasound Pattern of Splenic Metastases a Retrospective Study in 32 Patients

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1 264 Original Article Contrast-Enhanced Ultrasound Pattern of Splenic Metastases a Retrospective Study in 32 Patients Kontrastunterstützte sonografische Befunde bei Milzmetastasen eine restrospektive Studie an 32 Patienten Authors A. Neesse 1, J. Huth 1, S. Kunsch 1, P. Michl 1, T. Bert 2, J. J. Tebbe 3, T. M. Gress 1, C. Görg 4 Affiliations 1 Gastroenterology, Endocrinology and Metabolism, University of Marburg 2 Department of Internal Medicine, Gastroenterology, Oncology and Endocrinology, Zentralklinikum Bad Berka 3 Department of Internal Medicine and Gastroenterology, Klinikum Lippe 4 Hematology, Oncology and Immunology, University of Marburg Key words spleen contrast-enhanced ultrasonography splenic metastases focal splenic lesions received accepted Bibliography DOI /s Published online November 6, 2009 Ultraschall in Med 2010; 31: Georg Thieme Verlag KG Stuttgart New York ISSN Correspondence Dr. Albrecht Neesse Gastroenterology, Endocrinology and Metabolism, University of Marburg Baldingerstr Marburg Germany Tel.: ++ 49/64 21/ Fax: ++ 49/64 21/ neesse@med.uni-marburg.de Zusammenfassung Ziel: Ziel ist die Charakterisierung von Milzmetastasen in der kontrastmittelunterstützten Sonografie (CEUS) und die Evaluation der diagnostischen Wertigkeit im Vergleich zur konventionellen B-Bild-Sonografie. Material und Methoden: Von Januar 2004 März 2009 wurde bei ca abdominellen B-Bild- Sonografien n = 279 Fällen (< 0,6%) eine fokale Milzläsion detektiert. Bei n = 32 (11,5%) bestand der hochgradige Verdacht auf Milzmetastasierung von unterschiedlichen soliden Tumoren. Die Läsionen wurden im B-Bild hinsichtlich Anzahl, Größe, Echogenität, Häufigkeiten von Halozeichen und Nekrosebildung untersucht. In der CEUS wurde das Ausmaß der Kontrastmittelanreicherung im Vergleich zum umgebenden Milzgewebe während der arteriellen (5 30 s) und parenchymatösen Phase (3 5 min) bestimmt. Alle Daten wurden retrospektiv ausgewertet. Ergebnisse: Im B-Bild waren die Läsionen solitär n = 18 (56%), multiple n = 14 (44%), < 2 cm n = 11 (34%), 2 cm n = 21 (66%), echoarm n = 14 (44%), isoechogen n = 12 (38%), echoreich n = 6 (19%), glatt begrenzt n = 27 (84%) irregulär begrenzt n = 5 (16%). In der arteriellen Phase der CEUS waren die Läsionen hypoechogen n = 21 (66%), isoechogen n = 3 (6%), hyperechogen n = 1(3%) und komplex n = 8 (25%). In der parenchymatösen Phase waren die Läsionen hypoechogen n = 24 (75%) und komplex n = 8 (25%). In n = 12 (38%) Fällen konnte mittels CEUS eine bessere Darstellung der Milzmetastasen erzielt werden. Schlussfolgerung: Milzmetastasen zeigen sowohl in der arteriellen als auch parenchymalen Phase der CEUS eine verminderte Kontrastmittelanreicherung. CEUS kann bei ca. 40% der Patienten die Darstellung der Milzmetastasen im Vergleich zur B-Bild-Sonografie verbessern. Abstract Purpose: To characterize the pattern of contrastenhanced ultrasonography (CEUS) in splenic metastases compared to standard B-mode ultrasonography. Materials and Methods: Between January 2004 and March 2009, about 50,000 abdominal ultrasound examinations were performed, and n = 279 (< 0.6%) of focal splenic lesions were detected of which n = 32 (11.5%) were highly suggestive for splenic metastases of various solid tumors. The number of lesions, size, echogenicity, rim appearance, presence of halo sign and necrosis were recorded via B-mode sonography. Contrast enhancement was determined in the arterial phase (5 30 sec) and parenchymal phase (3 5 min). B-mode sonography and CEUS were compared in terms of the visibility of splenic metastases. All data was evaluated retrospectively. Results: On B-mode sonography lesions were solitary n = 18 (56%), multiple n = 14 (44%), < 2 cm n = 11 (34%), 2 cm n = 21 (66%), hypoechoic n = 14 (44%), isoechoic n = 12 (38%) and hyperechoic n = 6 (19%), with regular rim appearance n = 27 (84%), and with irregular rim appearance n = 5 (16%). During the arterial phase CEUS lesions were hypoechoic n = 21 (66%), isoechoic n = 2 (6%), hyperechoic n = 1 (3%) and complex n = 8 (25%). During the parenchymal phase lesions were hypoechoic n = 24 (75%) and complex n = 8 (25%). CEUS provided improved visualization of splenic metastases in n = 12 (38%) cases. Conclusion: CEUS of splenic metastases is characterized by reduced contrast enhancement in both the arterial and the parenchymal phase in most cases. Moreover, CEUS improved the visualization of splenic metastases in about 40% of cases in comparison to standard B-mode sonography. Neesse A et al. Contrast-Enhanced Ultrasound Pattern Ultraschall in Med 2010; 31:

2 Original Article 265 Introduction Splenic metastases are a rare clinical and sonographic phenomenon. In autopsy studies the frequency of splenic metastases deriving from solid tumors varies between 0.3% and 16%, of which about 25% are exclusively detected on microscopy [1, 2]. Accordingly, imaging studies have revealed a frequency of splenic metastases of approximately 0.3% [3, 4]. Interestingly, ultrasonography has determined the prevalence of splenic metastases originating from solid tumors to be less than 0.1% [5]. The knowledge of metastatic disease is crucial for further therapeutic decision-making in tumor patients. The majority of patients with splenic metastases suffer from advanced tumor disease. However, isolated splenic metastases have been reported in a variety of solid tumors such as colorectal cancer, endometrial carcinoma and adenocarcinoma of the lung [6 9]. Among a variety of imaging modalities, abdominal ultrasound often represents the first option for a noninvasive diagnostic work-up and staging of patients with suspected malignancies. However, differential diagnosis of splenic lesions is challenging and B-mode sonography is not sufficient to accurately determine the malignancy of splenic lesions due to the lack of a characteristic sonographic appearance. Moreover, cytological and histological diagnosis is rarely accomplished due to the relatively poor sensitivity and the associated risk of severe hemorrhage [10 13]. Therefore, clinical and sonographic followup examinations and alternative imaging techniques such as computed tomography (CT) are currently used for the clinical assessment of suspected splenic metastases [14, 15]. With the advent of second-generation contrast agents, CEUS has become the most important imaging method for the detection and evaluation of focal liver lesions and the monitoring of local or systemic treatment of liver tumors [16 31]. Moreover, CEUS provides major advantages for the characterization of focal renal lesions and prostate cancer [17, 32, 33]. Notably, second-generation contrast agents have revealed spleen-specific uptake of the microbubble contrast agent, and previous data suggests an additional diagnostic value of CEUS in the diagnosis of accessory spleens, functional asplenia, high vascular splenic hemangioma, and vascular splenic pathology such as splenic infarction, splenic abscess, and trauma of the spleen [34 38]. However, comprehensive data regarding the CEUS pattern of splenic metastases is currently not available. Here, we characterize for the first time the pattern of contrast-enhanced ultrasonography in a consecutive series of 32 patients with splenic metastases and compare the results to standard B-mode ultrasonography. Patients and methods Between January 2004 and March 2009, about 50,000 abdominal ultrasound examinations were performed in the interdisciplinary ultrasound unit of our university hospital. During this time, n = 279 patients ( 0.6%) with focal splenic lesions were diagnosed with B-mode sonography as follows: splenic infarction n = 72 (25.8%), Non-Hodgkin s Lymphoma n = 57 (20%), splenic incidentaloma (incidentally detected focal splenic lesion, no history of tumor, infection or trauma, stable on follow-up examination) n = 51 (18.4%), splenic rupture in n = 35 (12.6%), splenic abscess n = 7 (2.5%), miscellaneous splenic lesions (i. e., hemangioma, hamartoma) n = 25 (9,1%). In n = 32 cases (11.5%) detection of focal splenic lesions on B- mode ultrasonography was highly suggestive for splenic metastases of solid tumors owing to the fact that all of these patients suffered from advanced metastatic tumor disease with distant metastases to at least one other organ. Further evidence of suspected splenic metastases was provided by the detection of either a novel focal splenic lesion or increase in the size of a pre-existing focal splenic lesion. Inclusion criteria for the retrospective study were: 1. Histological confirmation of an advanced metastatic tumor disease; 2. B-mode sonographic detection of a novel focal splenic lesion or increase in the size of a pre-existing focal splenic lesion (> 10% in diameter) after 1 2 months; 3. CEUS investigation performed Data from 32 patients met the inclusion criteria and was retrospectively collected and evaluated after having gained a positive ethical vote for the retrospective study. The following demographical data was collected: sex, age, diagnosis of the underlying tumor disease, and mode of diagnostic confirmation of splenic metastases (histology vs. follow-up). For B-mode sonography, the number, size, and echotexture of the metastases were evaluated. A differentiation was made between single and multiple metastases, and the size was classified according to the maximum diameter into < 2 cm and 2 cm. In the case of multiple metastases, the largest one was measured. The echotexture was interpreted as anechoic, hypoechoic, isoechoic and hyperechoic in comparison to the surrounding splenic tissue as an in vivo reference. The lesion borders were classified into regular or irregular. The sonomorphological pattern of a focal lesion with a hypoechoic rim was documented as a halo sign. A sonographically distinctive reflection with a following sound shadow was interpreted as calcification. Anechoic areas within a metastasis were evaluated as necrosis. For all examinations, Acuson Sequoia 512 (Siemens) with a linear and convex scanner with frequencies of 3, 5, and 5 MHz was used as the ultrasound unit. Contrast-enhanced sonographic studies were performed with a contrast-devoted unit that had contrast-specific, continuous-mode software. A low mechanical index was applied. A sulfur hexafluoride-based microbubble contrast medium (Sonovue, Bracco SpA, Milan, Italy) was injected intravenously in 2 sec via a 20-gauge canula. A volume of 2.4 ml was administered, followed by a 5 ml saline flush immediately after contrast medium injection. The left upper quadrant was continuously scanned sonographically for 3 5 min until the enhancement effect began to decrease. Evidence of contrast agent uptake in the spleen was monitored over 5 min using uptake of the left kidney as an in vivo reference [39]. CEUS studies were analyzed on the basis of the review of clips stored in the sonographic unit. Between January 2004 and October 2005, n = 11 patients were investigated with CCI (Coherent Contrast Imaging) software. Between November 2005 to March 2009, n = 21 patients were investigated with CPS (Contrast Pulse Sequencing)-software. The use of ultrasound contrast agent followed the guidelines of the EFSUMB [40]. The following CEUS patterns of focal lesions using the surrounding splenic tissue enhancement as an in vivo reference were considered: extent of enhancement during the arterial phase between 5 30 sec after injection and during the parenchymal phase between 3 5 min after injection (anechoic vs. hypoechoic vs. isoechoic vs. complex). A complex pattern was diagnosed in the case of inhomogeneous hypoechoic en- Neesse A et al. Contrast-Enhanced Ultrasound Pattern Ultraschall in Med 2010; 31:

3 266 Original Article hancement with intralesional areas of reduced enhancement, non-enhancement, or ring enhancement. The value of CEUS examinations for the visualization of splenic metastases was compared to standard B-mode US and classified as better (improvement in number and/or quality of splenic metastasis imaging) or equal (no improvement in number and/or quality of splenic metastasis imaging). The CEUS parameters were determined by two observers (C. G., T. B.) who reached consensus. In cases of dissent a third observer (J.T.) was consulted. CEUS was performed in all patients immediately after baseline sonography. Results B-mode ultrasound 15 female and 17 male patients were enrolled in the study. Their ages ranged from years (mean age 59.7 years). The underlying tumor diagnosis was colorectal cancer (n = 6), lung cancer (n = 6), malignant melanoma (n = 3), pancreatic cancer (n = 3), esophageal cancer (n = 2), gastric cancer (n = 2), ovarian cancer (n = 2), breast cancer (n = 1), renal cell cancer (n = 1), urothel cancer (n = 1), medullar thyroid cancer (n = 1), head and neck cancer (n = 1), hemangiosarcoma (n = 1), endometrial cancer and cancer of unknown primary (n = 1). There were no histological confirmations of the diagnosis in 31 cases. In one case the diagnosis of hemangiosarcoma metastasis was confirmed by splenectomy. The confirmation of splenic metastasis was carried out by sonographic follow-up in all patients with evidence of tumor progression. N = 18 (56%) patients showed solitary metastases, and n = 14 (44%) had multiple focal lesions. The size of metastases varied from < 2 cm in n = 11 cases (34%) and 2 cm in n = 21 cases (66%). The echotexture of the splenic metastases was divided into hypoechoic lesions in n = 14 (44%) patients, isoechoic lesions in n = 12 patients (38%) and hyperechoic lesions in n = 6 (18%) patients ( Fig. 1). The lesion border was regular in n = 27 (84%), and irregular in n = 5 (16%). In n = 6 patients (18%) metastases were surrounded by a hypoechogenic rim. Sign of a central anechoic area as an indicator for necrosis could be detected in n = 6 patients (19%). Calcification could not be found in any patient. Apart from splenic metastases, all patients revealed at least one other metastasis in a different organ system. Contrast-enhanced ultrasound In all patients marked enhancement of normal splenic tissue in comparison to the left kidney was observed and recorded up to 5 min. During the arterial phase, focal lesions were hypoechoic in n = 21 (66%), isoechoic in n = 2 (6%), hyperechoic in n = 1 (3%), or displayed complex enhancement in n = 8 (25%) ( Fig. 1). During the parenchymal phase, focal lesions were hypoechoic in n = 24 (75%), or had complex enhancement in n = 8 (25%) ( Fig. 1). N = 7 of these patients had necrosis, n = 3 had rim enhancement, and two had both rim enhancement and necrosis. Visualization of focal splenic metastases with CEUS compared to B-mode ultrasonography was classified as equal in n = 20 patients (62%) and better in n = 12 patients (38%). In n = 5 of these cases, even more lesions were seen by CEUS in comparison to B-mode US. The distribution of characteristic echotextures of splenic metastases in B-mode sonography and CEUS is schematically depicted in Fig. 1. Fig. 1 Schematic distribution of characteristic echotextures of splenic metastases in B-mode US and contrast-enhanced ultrasound (CEUS). Abb. 1 Schematische Verteilung charakteristischer Echomuster von Milzmetastasen im B-Mode-Ultraschall und der kontrastunterstützten Sonografie (KUS). Characteristic findings of splenic metastases in B-mode sonography and CEUS are depicted in Fig Discussion The advent of new microbubble-specific methods with secondgeneration contrast agents has given the ultrasonography community much to celebrate. The sensitivity and specificity of diagnostic ultrasonography have dramatically increased, allowing real-time evaluation of the vascular and parenchymal phase for the detailed characterization of the most frequent focal liver lesions with high accuracy similar to that of CT or magnetic resonance imaging (MRI) [16 31]. In contrast, the available data on CEUS for the differential diagnosis of focal splenic lesions is scarce owing to the low frequency of occurrence. However, first reports revealed that CEUS is superior to B-mode sonography for detecting spleen infarcts and traumatic splenic lesions [35, 36]. Therefore, CEUS of the spleen is currently predominantly used in traumatology [34, 35]. Previous data demonstrated that the appearance of splenic metastases on B-mode sonography is rather variable and nonspecific [41]. This data was confirmed by the present study showing a heterogeneous distribution of echotextures in splenic metastases (hypoechoic [44%], isoechoic [38%], hyperechoic [18%]). In contrast, CEUS was able to demarcate the majority of splenic metastases either as hypoechoic (66%) or complex (25%) in the early arterial phase. Notably, a complex pattern has a very similar appearance compared to a hypoechoic pattern and is characterized by inhomogeneous hypoechoic enhancement with intralesional areas of reduced enhancement or non-enhancement. In the parenchymal phase hypoechoic appearance further increased up to 75% of lesions. Furthermore, no calcifications were observed in all patients with sple- Neesse A et al. Contrast-Enhanced Ultrasound Pattern Ultraschall in Med 2010; 31:

4 Original Article 267 Fig. 2 a Patient with ovarian cancer. On B-mode US a solitary focal hyperechoic lesion is seen. b Contrast-enhanced ultrasound (CEUS) demonstrates hyperechoic enhancement. c After 1 min the lesion shows hypoechoic enhancement. d After 2 min the lesion shows nearly complete anechoic enhancement. Abb. 2 a Patient mit Ovarialkarzinom. Im B-Mode- US zeigt sich eine solitäre echoreiche Läsion. b Die kontrastunterstützte Sonografie (KUS) zeigt ein hyperechogenes Enhancement der Läsion. c Nach 1 min zeigt die Läsion ein hypoechogenes Enhancement. d Nach 2 min zeigt die Läsion ein nahezu fehlendes Enhancement. Fig. 3 a Patient with endometrial cancer. On B-mode US sonography multiple inhomogeneous predominantly hyperechoic lesions are seen. b Contrast-enhanced ultrasound (CEUS) demonstrates complex enhancement. The arrow indicates an area with hypoechoic enhancement within the unenhanced necrotic lesion. c After 2 min the lesion appears cystic with an irregular border. Abb. 3 a Patient mit Endometriumskarzinom. Im B-Mode-US zeigen sich multiple inhomogene vorwiegend echoreiche Läsionen. b Die kontrastunterstützte Sonografie (KUS) zeigt ein komplexes Enhancement der Läsion. Der Pfeil zeigt ein Areal mit einem echoarmen Enhancement innerhalb einer nicht kontrastaufnehmenden nekrotischen Läsion. c Nach 2 min stellt sich die Läsion zystisch dar mit einer irregulären Begrenzung. Fig. 4 a Patient with pancreatic cancer. On B-mode US a solitary focal hypoechoic lesion with a central anechoic area is seen. b Contrast-enhanced ultrasound (CEUS) demonstrates complex enhancement. The arrow indicates rim enhancement. A central unenhanced, necrotic area is additionally seen within the lesion. c After 1 min a wash-out phenomenon of the rim enhancement is seen. Abb. 4 a Patient mit Pankreaskarzinom. Im B-Mode-US zeigt sich eine solitäre echoarme Läsion mit einem zentral echofreien Areal. b Die kontrastunterstützte Sonografie (KUS) zeigt ein komplexes Enhancement der Läsion. Der Pfeil zeigt ein ringförmiges Enhancement und ein zentral nekrotisches, nicht kontrastaufnehmendes Areal. c Nach 1 min zeigt sich ein rasches Auswaschen des ringförmigen Kontrastmittelenhancements. nic metastases. These results may be helpful for the differential diagnosis of incidentally discovered splenic lesions in asymptomatic patients with an unknown history of neoplasia. Previous studies have demonstrated that incidental hypoechoic splenic lesions on B-mode US and pronounced early arterial enhancement on CEUS are highly suggestive of a benign splenic lesion such as hemangioma/hamartoma [37, 42]. Our data confirms this observation and only 1 out of 32 patients with Neesse A et al. Contrast-Enhanced Ultrasound Pattern Ultraschall in Med 2010; 31:

5 268 Original Article Fig. 5 a Patient with colorectal carcinoma. On B-mode US a solitary focal hypoechoic lesion is seen. b Contrast-enhanced ultrasound (CEUS) demonstrates hypoechoic enhancement of the lesion during the arterial phase. The lesions are better seen by CEUS than by B-mode US. c Contrast-enhanced ultrasound (CEUS) demonstrates hypoechoic enhancement of the lesion during the parenchymal phase. The lesions are better seen by CEUS than by B-mode US. Abb. 5 a Patient mit kolorektalem Karzinom. Im B-Mode-US zeigt sich eine solitäre echoarme Läsion. b Die kontrastunterstützte Sonografie (KUS) zeigt ein hypoechogenes Enhancement der Läsion während der arteriellen Phase. Die Läsion demarkiert sich in der KUS besser als in der B-Mode-Sonografie. c Die kontrastunterstützte Sonografie (KUS) zeigt ein hypoechogenes Enhancement der Läsion während der parenchymatösen Phase. Die Läsion demarkiert sich in der KUS besser als in der B-Mode-Sonografie. splenic metastases showed a hyperechoic appearance exclusively in the early arterial phase. Therefore, incidental detection of uncharacteristic splenic lesions on B-mode sonography that reveal a rather homogeneous (hypoechoic or complex) CEUS pattern in both the arterial and parenchymal phase suggests a potentially malignant underlying disease with an isolated splenic metastasis. In our series, the underlying malignant disease was always known and histologically confirmed. However, isolated splenic metastases have been reported in a variety of solid tumors such as colorectal cancer, endometrial carcinoma and adenocarcinoma of the lung [6 9]. In these cases, CEUS of the spleen can be of diagnostic value and invasive diagnostic procedures might thus be omitted. Our study is limited by the fact that histological diagnosis of splenic metastases is only provided in a single case. In all other cases detection of a novel splenic lesion or increase in the size of a pre-existing focal splenic lesion in histologically confirmed and advanced solid tumor diseases were regarded as criteria for splenic metastases. However, although unlikely, it cannot be fully excluded that benign splenic lesions can occur and increase in size in advanced stage tumor patients. Furthermore, the extent of the vascularization of the primary tumor was not accounted for in our study. However, in contrast to B-mode ultrasonography, CEUS revealed a rather homogeneous appearance. Therefore, it remains to be elucidated whether the vascularization of the primary tumor affects the CEUS pattern of splenic metastases. Conclusion To the best of our knowledge, we are providing the first comprehensive data on the pattern of contrast-enhanced ultrasonography in a large number of patients with splenic metastases. 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