WHO classification of alveolar echinococcosis: Principles and application

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Abstract

Alveolar echinococcosis is caused by the larval stage of the fox tapeworm (Echinococcus multilocularis) and is frequently diagnosed as a space occupying lesion in the liver. The growth pattern resembles that of a malignant tumor with infiltration throughout the liver, spreading into neighbouring organs and metastases formation in distant organs. Thus, one of the prevailing differential diagnoses is liver cancer. Guided by the Tumor–Node–Metastasis (TNM) system of liver cancer, the European Network for Concerted Surveillance of Alveolar Echinococcosis and the WHO Informal Working Group on Echinococcosis proposed a clinical classification for alveolar echinococcosis. It was designated as PNM system (P = parasitic mass in the liver, N = involvement of neighbouring organs, and M = metastasis). As for TNM in oncology, single PNM categories were combined into four stages, I to IV. The system was developed by a retrospective analysis of 97 patients' records from two treatment centers (Besançon/France and Ulm/Germany). Recently, this WHO classification was applied to 222 patients in 4 clinical centers around the world (Besançon/France, n = 26; Urumqi/China, n = 46; Sapporo/Japan, n = 58; and Ulm/Germany, n = 92). All patients could be classified who had been diagnosed in the period from January 1998 to June 2005. The stage grouping indicated center differences, but appeared to segregate patients according to various treatment regimens. The WHO classification not only serves as a tool for the international standardization of disease manifestation but also aids to evaluate the outcome of a chosen diagnostic and treatment procedure in different treatment centers in Europe and Asia.

Introduction

The larval stage of Echinococcus multilocularis proliferates and expands as a multivesicular (alveolar) tissue in the primarily affected organ, the liver. It takes years, even decades, until first clinical symptoms occur, and the diagnosis of alveolar echinococcosis (AE) can be made [1], [2]. If the disease stays undiscovered, a large, irregular shaped, solid or partly necrotic tumor can be visualized by different imaging methods [3]. The parasitic tumor may involve several liver segments and, most importantly, expand along large liver vessels and biliary tract, particular the hilum. Later, the larva infiltrates neighbouring organs. Cells of the larval tissue frequently detach and disseminate via lymph nodes and blood vessels, thus leading to metastasis in large parenchymatous organs. Therefore, AE is often compared with a slow-growing liver cancer [2], [4]. No curative treatment is yet available, except surgical en-bloc resection at a very early stage of the disease when the infection is still asymptomatic. Left untreated, the disease was usually lethal until late 1970s. The poor prognosis has been reverted, however, during the past 30 years by earlier diagnosis with the improvements of imaging techniques and by a specific anthelminthic chemotherapy of echinococcosis [1], [2], [4]. Nevertheless, relapses and complications occur frequently, even many years after assumed curative surgery or after liver transplantation [5]. Prediction of treatment outcomes remains difficult, in particular since clinical information about this rare disease is rather heterogeneous.

In some cohort studies, attempts have been made to categorize the extent of larval growth in retrospect [6], [7], [8], [9]. Some authors are concentrating either on the size of the parasite or the location of the lesion within the liver as measured on ultrasound, CT or MRI images, others on the pathobiological findings and complications. In addition, the presence or absence of an infiltration of neighbouring organs, and/or distant metastasis is noted. During meetings of the European Network for Concerted Surveillance of Alveolar Echinococcosis and of the WHO Informal Working Group on Echinococcosis a clinical classification was developed [10]. To receive international acceptance for a classification system of a rare disease, a procedure might be preferred with which clinicians are already familiar. The Tumor–Node–Metastasis (TNM) system is one of the most commonly used staging systems. It was developed and is maintained by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) [11], [12]. The TNM staging system was developed as a tool for doctors to stage different types of cancer, and is based on the extent of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M).Thus, describing the anatomical site of the parasitic “tumor” in the liver, its extent into the neighbouring organs or metastatic spreading, was felt to be a widely acceptable approach to the problem.

Section snippets

Principles of PNM staging system for alveolar echinococcosis

Staging for AE is the process of determining how much larval tissue there is in the body and where it is located. In addition, staging describes the extent or severity of an individual's lesion based on the extent of the original (primary) tumor and the extent of spread in the body. Such a staging system should be simply applicable in different settings, in order to facilitate communication among clinicians, to provide guidance for the most appropriate treatment strategy, i.e. surgery,

Development and validation of a classification system for alveolar echinococcosis

The university hospitals in Besançon/France and in Ulm/Germany are located within the classic alveolar echinococcosis-endemic regions of Europe [13]. Both centers served as national clinical referral units, thus special care and scientific attention has been given to this patient group [7], [14]. The diagnosis of AE was based on clinical, imaging and serological findings. In most instances histopathology of resected organ specimens was available, and/or was reviewed by an experienced

Consecutive application in treatment centers

The classification procedure was prospectively applied in Ulm. 92 new cases with AE presented for the first time in Ulm from January 1998 to June 2005, and received standard of care. In some cases further information was obtained from previous hospitalizations, in order to encompass all necessary data for PNM staging. In addition, it was further inquired, whether patients presented first with icterus and/or constitutional symptoms. During the period of 6.5 years, a number of clinicians took

Discussion and prospects

The PNM staging system was used in different clinical settings, and applied prospectively in one treatment center (Ulm), encompassing a total of 92 patients. A further 130 patients were staged retrospectively, and the application of the system was easily feasible in each treatment center. We could show that the PNM staging system for AE provides a common language with which clinicians around the world can communicate about a patient's case (reviewed in Refs. [1], [4], [17]). In comparison, this

Acknowledgments

The initial study was partly supported by the European Commission, Directorate General V DGV, and was presented at the following meetings: 2nd European Congress on Tropical Medicine, Liverpool 1998, presented by P. Kern (abstract no. 339) and the Meeting of European Association for the Study of the Liver (EASL), Naples 1999, presented by S. Bresson-Hadni (abstract no. P/C11/009) and Bresson-Hadni et al. [16]. The development of the staging system was also part of the doctoral thesis of S. Kurz

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