Historical Overview

Since the beginning of the twentieth century, attempts have been made to deduce prognostic information from the histological appearance of the individual tumors (Beckwith and Martin 1968; Hughes et al. 1974; Landau 1911; Mäkinen 1972; Wahl 1914). In 1914 Wahl suggested a sequence of maturation of the pNTs (Wahl 1914), and in 1968, Beckwith and Martin proposed a grading system based on the semi-quantitative assessment of neuroblastic cytodifferentia-tion (Beckwith and Martin 1968). In 1974 Hughes and co-workers proposed their grading system,but at this time based on non-quantitative assessment of neuroblastic/ganglionic cytodifferentiation (Hughes et al. 1974). As summarized in a review article by Dehner in 1988 (Dehner 1988), however, those attempts could not successfully satisfy the oncologists dealing with this "enigmatic" disease.

Interestingly, in the first half of the twentieth century, it was believed that older patients had a better prognosis (Landau 1911; Wahl 1914), which was probably due to the inability to distinguish local-regional from stage-4 metastatic disease. In the second half of the twentieth century, however, it was clearly recognized that younger patients (especially diagnosed before 1 year of age) had a significantly better prognosis than older patients (Gross et al. 1959). Furthermore, the majority of tumors in infants with clinically favorable outcome showed no or very limited morphological evidence of cytodifferentiation. Beck-with and Martin concluded that "differences in degree of maturation probably did not account for the more favorable outcome of the neuroblastomas in infancy" (Beckwith and Martin 1968).

In 1984 Shimada and colleagues proposed a classification system based on a unique concept of age-linked evaluation of morphological indicators (Shimada et al. 1984). First they made an age-appropriate framework of the maturational sequence of the pNTs. The maturational sequence was defined by two morphological indicators, grade of neuroblastic differentiation, and degree of Schwannian stromal development. Prior to their study, Schwannian stromal com-ponent,which is one of the major elements in the nor mal ganglionic structure of the sympathetic nervous system, had never been a subject of serious investigation in pNTs. According to this classification system, clinically favorable tumors can be less differentiated when diagnosed in younger patients, and should have morphological features of more advanced maturation in older children (for detailed explanation see Chap. 4). They also found increased numbers of kary-orrhectic cells in highly aggressive tumors, and introduced a concept of mitosis-karyorrhexis index.

In 1992 Joshi and co-workers proposed histological grading by using mitotic rate (MR: low <10/10 high-power fields, high >10/10 high-power fields) and calcification (presence or absence; Joshi et al. 1992). In their report they also proposed a risk grouping by combining the histological grade and age of the patient at diagnosis (low risk: patients in all age groups with tumor having low MR and calcification, and patients < 1 year of age with either low MR or calcification; high risk: patients >1 year of age with either low MR or calcification, and patients in all age group with high MR and no calcification; Joshi et al. 1992). They later published a modified histological grading by replacement of mitotic rate with MKI (Joshi et al. 1996).

In 1994 the International Neuroblastoma Pathology Committee was formed to establish a prognosti-cally significant and biologically relevant classification for international use. The Committee first defined terminology and morphological criteria of pNTs, and then analyzed and tested mainly those two classifications proposed by Shimada et al. (1984) and Joshi et al. (1992,1996). In 1999, after 5 years of collaborative work, the Committee developed the International Classification based on the original Shimada classification with minor modifications (Shimada et al. 1999a,b).

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