Ultrasound Diagnostics in Alveolar Echinococcosis: An Update Open Access

Alveolar echinococcosis (AE) is a rare, potentially fatal zoonosis [1]. The diagnosis of AE remains a difficult diagnosis, especially in non-endemic areas [2, 3]. With a long asymptomatic latency period of 5–20 years, AE in human intermediate hosts usually manifests as a liver tumor with variable B-scan sonographic appearances and a high potential for differential diagnostic confusion [4‒6]. The risk factor of dog ownership as a vector appears to be becoming increasingly important for transmission to humans [7]. If left untreated, the disease leads to severe hepatopathy. In most cases, the diagnosis is only discovered when resection is no option any more. In over 98% of cases, only the liver is affected [2]. If diagnosed early, surgical resection of the liver lesions is the method of choice. In advanced, inoperable stages, treatment is recommended with benzimidazoles [1]. In recent years, imaging diagnostics have become increasingly important compared to serologic diagnostics in AE [5, 8]. In 2003, Kodama et al. [9] introduced a five-part classification for assessing hepatic AE with magnetic resonance imaging (MRI). In 2015, our working group presented the first classification for ultrasound imaging, also consisting of 5 typical presentation patterns (Fig. 1) [4]. In the following, we will provide an overview of the importance of ultrasound diagnostics in AE in the detection of the disease and its significance in follow-up, as well as the typical sonographic presentation patterns and pitfalls (shown in Fig. 1a–e).

Just as with MRI classification, sonographic classification of AE (fox tapeworm disease) can distinguish among five forms of presentation. The so-called storm and hail pattern (54.1%) is the most common in Germany. The other patterns occur with a frequency of (13.5%) for the pseudocystic pattern, ossification pattern (13.0%), hemangioma-like pattern (8.1%), and metastatic pattern (6.5%). A total of 4.8% of the ultrasound findings could not be assigned to any of the patterns described above [5].

The storm and hail pattern is the most common found in Germany, accounting for over 50% of cases, and is pathognomonic for the disease (shown in Fig. 1a). The typical hailstorm appearance is characterized by indistinct, irregular boundaries, nonhomogeneous pattern and hyperechoic formations, with or without dorsal acoustic shadow. There are only few other differential diagnoses in B-scan sonography, so that a sonomorphological diagnosis is possible with typical presentation. Most commonly, this manifestation form is mistaken for cholangiocellular carcinoma [10].

Pseudocystic AE lesions are primarily characterized by a hyperechoic, irregular and nonhomogeneous rim that is non-vascularized at power Doppler and color-coded duplex ultrasonography. It may appear to be >10 mm in thickness. There is a hypo- or anechoic, often nonhomogeneous central zone that may contain hyperechoic material. At most, a differential diagnosis can be differentiated from a large liver abscess. By including these clinical symptoms, this form of presentation of the AE B scan is easy to diagnose using sonography because a liver abscess could largely be ruled out due to the persistent absence of fever in the patient’s history (shown in Fig. 1b). The pseudocystic pattern usually presents as a significantly larger mass in the liver than the other typical patterns [4].

The so-called ossification pattern could be detected in approximately 13% of the cases recorded in the German National Fox Tapeworm Register (shown in Fig. 1c) [11]. The ossification pattern presents with solitary or grouped, mostly sharply delineated lesions with dorsal acoustic shadow. In terms of their differential diagnosis, these AE lesions are often difficult to distinguish from inflammatory or hyperechoic metastases of various carcinomas. Very large ossification-type AE lesions represent a rarity. Both uni- and multifocal involvement is possible. It can be assumed that the ossification pattern is an encapsulated and no longer infectious calcification structure. The previous results of the few available PET-CT studies failed to demonstrate activity with this form of presentation [12]. Differential diagnosis includes hepatolithiasis or hyperechoic metastasis of rectal cancer.

A hemangioma-like pattern represents the most difficult form with respect to differential diagnosis (shown in Fig. 1d). Sonomorphologically, the lesions present as a relatively clearly demarcated nonhomogeneous tumor that appears hyperechoic in comparison with the surrounding hepatic parenchyma. Echogenicity ranges from slightly and nonhomogeneously hyperechoic to strongly and homogeneous hyperechoic. With a frequency of approx. 8.1%, it is one of the rarer patterns. Again, the distinction between a true hemangioma and a hemangioma-like pattern in AE can only be made using contrast-enhanced ultrasound [13]. The hemangioma-like pattern in AE may demonstrate early arterial rim enhancement. The typical contrast behavior of hemangiomas includes arterial peripheral nodular contrast enhancement and centripetal contrast flooding with complete or incomplete iris diaphragm phenomenon, as well as hyperechogenic visualization in the late phase compared with the liver parenchyma, which is less echoic [13]. These phenomena, detectable in “true hemangiomas,” are not found in the hemangioma-like pattern of AE [14].

The metastasis-like pattern represents the greatest differential diagnostic challenge next to the hemangioma-like pattern. The lesions are mostly hypoechoic, these lesions exhibit as a typical characteristic – compared to typical hepatic metastases (e.g., of colorectal cancer) – the absence of the halo phenomenon. Instead, there is a central, hyperechoic, nonhomogeneous scar. The metastatic pattern can also not be diagnosed without contrast-enhanced sonography. At 4.8%, it is the rarest pattern in Germany [15]. The metastatic pattern is often seen as an incidental finding. During a routine clinical examination or as part of the workup for other medical conditions, the diagnostic differentiation from “true metastases” is difficult (shown in Fig. 1e). In a recent prospective study, all patients with a metastatic pattern showed annular rim enhancement in the arterial and portal venous phases in contrast-enhanced ultrasound (CEUS) [15]. Throughout the entire 4-min study period, none of the reference lesions showed central contrast enhancement – i.e., all exhibited a complete “black hole sign.” A small central scar was seen in 81.8% of cases. In clinically unremarkable patients with incidentally detected metastasis-like lesions of the liver, contrast-enhanced ultrasound detection of rim enhancement without central contrast uptake (black hole sign) should be considered evidence supporting a diagnosis of hepatic AE with a rare metastasis-like pattern [15]. Without the use of contrast-enhanced sonography, both the hemangioma-like and the metastasis-like pattern in AE cannot be reliably differentiated. For the metastatic pattern, histological confirmation of the mass should be sought at an early stage if necessary [3]. In the hemangioma-like pattern, a true hemangioma should be excluded by MRI before a possible puncture [16, 17]. Approximately 5% of the liver lesions identified as AE foci cannot be assigned to any of the patterns described above. Figure 2 shows such a previously unclassifiable histologically confirmed AE lesion (shown in Fig. 2).

In recent years, contrast-enhanced ultrasound (CEUS) has become increasingly important in the diagnosis of HAE [14, 15, 17‒21]. Importantly, misdiagnosis of HAE in unclear liver lesions can lead to inappropriate treatment strategies and significantly delayed diagnosis [3]. In a prospective study on the hemangioma-like pattern of AE, it was shown that the behavior of hemangioma-like AE lesions and typical liver hemangiomas differ significantly. Especially in the late phase, hemangioma-like AE lesions almost always show a complete or almost complete black hole sign, while typical hemangiomas almost always present with a hyperenhancement in the late phase (shown in Fig. 3a–d, 4a–d) [14]. It is important to note that before a possible puncture to histologically confirm a hemangioma-like pattern if AE is suspected and inconclusive findings in the contrast-enhanced ultrasound, a liver-specific magnetic resonance tomography may have to be carried out to reliably rule out a true hemangioma, which should not be punctured [22].

A CEUS study in a rat model allowed imaging in the early stages of AE infection, and revealed that 28 of 30 lesions exhibited annular rim enhancement in the arterial phase, which corresponded to histological findings of inflammatory rim reaction and no filling effect in either the portal or the delayed phase [18]. The retrospective study by Cai et al. [21] on the metastasis-like pattern in hepatic AE was able to confirm the results of the animal model study and also describes a rim enhancement and an echo point as well as a “black hole sign” for the first time. The results of the retrospective study by Cai et al. [21] were confirmed in a prospective study by Schweizer et al. [15]. On contrast-enhanced ultrasound, all 11 reference lesions with a histologically confirmed metastatic pattern showed a ring-shaped enhancement in the arterial and portal venous phase. During the entire 4-min examination period, none of the reference lesions showed central contrast enhancement, i.e., all showed a complete “black hole sign.” A small central scar was seen in 81.8% of cases [15, 21]. Figure 5a–d shows a typical contrast agent behavior of a histologically confirmed liver metastasis in breast carcinoma with typical chaotic early arterial contrast agent uptake (Fig. 5a–d). In contrast, the image series (Fig. 6a–d) shows the typical contrast agent behavior of a histologically confirmed metastatic pattern in AE, with arterial ring enhancement and a so-called black hole sign in the portal venous and late phase (shown in Fig. 6b–d).

The exact differentiation between hepatic AE and bile duct carcinoma was also demonstrated using CEUS [23]. In countries where both Echinococcus multilocularis and Echinococcus granulosus are endemic, CEUS has become an indispensable part of diagnostics. CEUS is a more effective technique than US for differentiating the type of HE between CE and AE technique for diagnosing AE than US [24].

As shown by Azizi et al. [12] in an MRI/PET study, the different manifestation patterns in the Kodama classification are differently metabolically active or non-metabolically active. As shown in cystic echinococcosis, different morphologies represent different stages of activity, which also lead to different treatment approaches [5]. This has not yet been clearly demonstrated for AE in ultrasound imaging. In a retrospective study, we were able to show the pattern change in AE, with the change from hemangioma-like to pseudocystic and storm and hail patterns, as well as the change from pseudocystic to storm and hail patterns being the most striking findings. The preliminary study included 59 patients. At the time of initial ultrasonography, a hailstorm pattern was present in 42.4% (25/59) of cases, a hemangioma-like pattern in 16.9% (10/59), a pseudocystic pattern in 15.3% (9/59), and a metastasis-like pattern in 25.4% (15/59). The sonomorphologic pattern remained unchanged in 84.7% (50/59) of the AE reference lesions, 15.3% (9/59) showed a change over time. A change in pattern was seen exclusively for AE lesions initially classified as hemangioma-like or pseudocystic. A total of 70% (7/10) of AE lesions initially classified as hemangioma-like showed a relevant change in pattern over time, and 85.7% (6/7) of these were secondarily classified as having a hailstorm pattern, with the remainder (1/7; 14.3%) classified as having a pseudocystic pattern. A total of 22.2% (2/9) of AE lesions initially classified as pseudocystic showed a relevant change in pattern over time and were classified as having a hailstorm pattern. For AE lesions initially classified as having a hailstorm or metastatic pattern, no pattern change was evident. All patients with pattern change were on continuous drug therapy with albendazole (shown in Fig. 7) [25]. The extent to which the sonographic presentation patterns correspond to different developmental stages of AE and whether therapeutic conclusions can be drawn from this must be shown in future prospective long-term studies. Comparative studies of different methods can also be helpful here, but these should be based on known classification schemes, e.g., the Kodama classification, as there are already corresponding comparative studies with PET [12]. The value of PET-MRI comparative studies could potentially lead to more rapid insights into the metabolic activity of different ultrasound morphologies [26].

Despite the progress made in ultrasound diagnostics, method-related limitations of the procedure must still be taken into account. In addition to the individual sonographic conditions of the patient, such as obesity and/or meteorism, the experience of the examining physician or sonographer plays a decisive role in the quality of the findings. In addition, a high-quality high-end ultrasound system also contributes significantly to better diagnostics.

Our experience in a specialized center shows that the definitive diagnosis of an AE could only be made after more than 2 years on average [3]. Early contrast-enhanced ultrasonography of the liver and a possible puncture can clarify unclear liver masses much more quickly and better, while avoiding radiation-intensive diagnostics. Patients also benefit from referral to a specialized center for echinococcosis diseases. In the case of a biopsy of the unclear lesion, the risk of bleeding and the risk of an implantation metastasis or further seeding are negligible; however, special features must be taken into account when clarifying a hemangioma-like pattern that is suspicious for AE.

Developments in recent years show that ultrasound diagnostics using CEUS and high-end ultrasound systems in the hands of experienced examiners can provide an early diagnosis of AE and also help minimize more radiation-intensive procedures during follow-up. The significance of different presentation patterns in relation to disease activity remains the subject of current research.

The author would like to thank the members of the Echinococcus Multilocularis Study Group who are not listed as authors: Thomas Barth, Ambros J. Beer, Meinrad Beer, Andreas Binzberger, Beate Gruener, Mark Hänle, Benedikt Haggenmueller, Nele Hergesell, Lynn Peters, Patrycja Schlingeloff, Julian Schmidberger, and Dennis Skotnik.

The author has no conflict of interest to declare.

There was no funding.

W. Kratzer wrote the manuscript.