Cystic Echinococcosis of the Bone: A European Multicenter Study

INTRODUCTION

Cystic echinococcosis (CE), a zoonosis caused by the larval stage (metacestode) of the tapeworm Echinococcus granulosus sensu lato complex,¹ is a chronic, complex, and neglected parasitic disease, with a worldwide distribution. It is highly endemic in livestock-raising areas.^1,2 The adults of E. granulosus reside in the small bowel of the definitive hosts (dogs and other canids) and releases eggs in their feces. After ingestion by the intermediate hosts (ungulates such as sheep, goats, or swines), the larvae released from the eggs penetrate the intestinal wall and migrate to various organs, especially the liver and lungs, where they develop into cysts.¹ When the definitive host ingests the infected viscera of the intermediate host, the cycle is completed. Humans may become dead-end intermediate hosts by ingesting parasite eggs.¹ Cysts can develop in any part of the body, although the liver and lungs are most frequently involved.³

Osseous CE is very rare; it is reported in the literature that cysts develop in bones in < 1% to 4% of cases reaching medical attention.^4–9 Although uncommon, osseous CE is severely disabling.^6,10 The destructive growth causes a high morbidity, similar to that of locally malignant bone lesions.^{4,5,7,8,11–13} CE of the bone is less noted in the medical community because of its rarity. To increase awareness of this important disease we collected the clinical histories of patients suffering from bone CE seen in several referral centers across Europe.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Previous studies report a varied distribution of cysts within the skeleton: the most common sites are the spine (35–50%), the pelvis (21%), and long bones, including the femur (16%) and tibia (10%).^6,11,13,14 Involvement of the ribs, skull, scapula, humerus, and fibula appears less common (2–6%).^6,13,14 The disease is usually diagnosed between the fifth and the sixth decade^10,13 and is rarely encountered in childhood. Growth of the parasite in the bone tissue is a very slow process. The dynamics of bone involvement in CE are poorly understood. Whether bone is a site of primary parasite implantation or is always secondary to infection in other organs remains unclear. However, not all patients with bone CE also have cysts in other organs.^6,12 While visceral CE cysts expand at a slow pace and grow mostly concentrically, the rigid structure of the bone prevents this pattern from becoming established here as the cyst is not able to induce the development of an adventitial layer as in the case of other organs,^10,13 and the metacestode development leads to the formation of exogenous vesicles containing protoscoleces along bone canals, conferring a branched, polycystic appearance to the lesion.^10,13 Bone destruction is likely the consequence of three factors: compression exerted by the growing parasite on surrounding tissues; ischemic damage due to compression of blood vessels; and demineralization due to osteoclastic proliferation around the compressed bone tissue.¹³ The localization of bone CE in our series is similar to that reported in previous publications.^12,15 In our cohort, the spine was the most frequent site, followed by the pelvis and ribcage, with the humerus and femur being rarer locations. Most of our patients were symptomatic (94%). Symptoms and imaging features of bone CE are nonspecific, making CE an unlikely early consideration. CE is unsuspected clinically due to its low regional prevalence and an overall neglect of CE as a disease.¹⁶ Furthermore, the absence of pathognomonic radiologic findings in bone CE makes it less distinguished from neoplastic and inflammatory processes.¹³ For this reason, patients commonly undergo multiple radiological examinations, and a definitive diagnosis is often reached only postoperatively^5,13 as shown in our cohort. Even in the case of clinical suspicion, serology may be negative, although data on this subject are scant.^17–19 Unfortunately, the clinical records of our cohort regarding serology were also generally unclear or lacking altogether, so we can only provide information on the use of serological tests but not a positivity rate. Furthermore, interpretation of such information would be hampered by the use of different tests across different centers and within centers over time, as one of the problems in CE serology is the lack of standardized tests and diagnostic algorithms.^20,21

Treatment options for bone CE have not been defined in a systematic way and currently include surgery which is used with or without administration of ABZ. In some cases, the use of other drugs such as praziquantel or nitazoxanide in combination with ABZ has also been reported in murine studies and in human case reports,^7,22,23 but their efficacy remains unproven. Currently, no uniform protocol for the use of ABZ has ever been implemented.²⁴

Unfortunately, the retrospective nature of the study, the small number of cases, and the many variables, including different ABZ penetration in bone tissues do not allow us to draw conclusions on the difference in treatment outcome, when ABZ was given continuously or in interrupted cycles.

Some authors are even skeptical about the actual role of medical treatment,^{4,11,12,25,26} supporting the opinion that only radical surgery is able to cure the disease.^13,26 In our cohort, all patients received prolonged courses of ABZ, which was not only longer than the current standard recognized by regulatory agencies (a maximum of three cycles each of 28 days, with a pause of 14 days separating each cycle), but also longer than what is usually done for CE in other organs, where continuous administration of ABZ for 3 to 6 months is generally used.²⁷ Overall, prolonged administration was well tolerated and no patient had to stop the administration of ABZ. Our results suggest that continuous ABZ administrations should be implemented before and after surgery in all patients able to tolerate the treatment, as it is highly plausible that ABZ may halt the progression of the parasitic growth. This is supported by the fairly high survival rate of patients in our study over a long period of time.

With regard to surgery, radical treatment has been advocated as the sole treatment option able to cure the disease, but full removal of the parasitic tissue without harming the patient can be impossible.^6,8,12 Moreover, the persistence of parasitic material because of partial removal has a high potential for future reactivation of parasitic growth.^4,7,8 In our cohort, 97% of the patients were operated on, but a radical intervention was never possible with the exception of one case where the whole upper arm was amputated, and other cases where patients experienced a high number of relapses. If not managed correctly, bone CE has a very poor prognosis in terms of long-term morbidity, comparable with that of cancer.^{4,5,7,8,11–13} In fact, vertebral CE was called le cancer blanc by Devé.^7,10,13 Cystic echinococcosis of the bone is a highly destructive process, capable of spreading from bone segments to the surrounding soft tissues and vice versa^6–8: In our cohort, 27% of patients had more than one localization of bone CE and soft tissue involvement was extremely common.

Overall, our results suggest that radical surgery should only be attempted if there is a high degree of confidence in the possibility of removing all parasitic material, and palliative surgery should be attempted only in cases where a good degree of functionality can be restored. It should also be noted that the use of prosthetics for reconstructive surgery has been discouraged, as the parasite is able to stably attach to the materials used for their construction.^8,10 Bone allograft has also been considered, but it is susceptible to parasite invasion if relapses occur.^7,10 Polymethylmethacrylate has been reported to be effective in the prevention of relapses,^7,10,26 and irrigation of the operational field with hypertonic saline or other scolicidal agents has been shown to reduce the rate of recurrence with a concentration and time-dependent effect.^6,7 Traditional radiotherapy has proven to be completely ineffective,^6,12,24 although other cutting-edge radioterapeutical approaches have not been applied so far.

CONCLUSION

Bone CE is a challenge for clinicians and, given its relative rarity, available data are scarce. International collaboration helps to unveil previously unconsidered cases.

Our study is different from the majority of the current literature on bone CE in that it is not a signle case report but rather a larger cohort analysis that helps provide a spotlight for this neglected disease to the international community. We also show that patients diagnosed with bone CE present serious, sometimes life-threatening and often disabling, complications, in accordance with previous analyses presented by other authors.^7,8 Whereas for liver CE a stage-specific approach has been at least partially agreed on that allows a rational choice among different treatment options,²⁷ no such thing exists for bone CE. As exemplified also in our study, the decision on the general management of patients with bone CE is largely left to the individual physician.

The only possibility of true advancement in the knowledge of this rare yet extremely disabling form of CE will necessarily come only from broad, ideally prospective, multicentric studies, with common protocols for the management of the disease. The increased complexity of bone CE, in comparison to hepatic CE, warrants the organization of a specific international database able to capture its very peculiar clinical features. Such a database would complement the existing ones (such as the European Registry of Cystic Echinococcosis) and provide a basis for further research and thus better diagnosis and treatment.