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Histopathological grading incorporated in the current WHO classification of CNS tumors [2, 3, 11] is mainly directed at prediction of the prognosis typically associated with each type of neoplasm treated with surgery alone, rather than at determination of individual tumor malignancy. It allows prediction of the biological behavior of the lesion and defines the necessity of adjuvant therapy. The main paradigm of this scheme (which has not changed in the updated WHO classification of CNS tumors [11]) is strict matching between the tumor type and grade; WHO grade is automatically assigned upon establishment of the histological diagnosis, which does not allow its variation among gliomas of the same type, regardless of their genetic profiles [4, 11]. Certainly, for each tumor entity, multiple clinical parameters (e.g., age, performance status, extent of surgical resection, etc.) significantly contribute to the overall prognosis, but these factors are not taken into consideration during histopathological diagnosis.

Tumor grading is based on assessment of several benchmarks which make their appearance in a predictable sequence: cytological atypia (referring to a variation of the nuclear shape and/or size with accompanying hyperchromasia [3]) followed by mitotic activity and increased cellularity, and, finally, by microvascular proliferation and/or necrosis [2, 3]. Four discrete WHO grades assigned for gliomas generally correspond to the St. Anne-Mayo system [27], but definition of the most benign lesions differs between these two schemes. WHO grade I is assigned to circumscribed, benign neoplasms with low proliferative potential and the possibility of cure by surgical resection alone, whereas the St. Anne-Mayo system assigns grade l to exceedingly rare DA without cytological atypia [3]. Gliomas with cytological atypia alone are considered to be of WHO grade II. Anaplasia reflects loss of the tissue structural differentiation indicating reversion of the cells to an immature or less differentiated form. Distinct cytological atypia with apparent hypercellularity is considered a sign of anaplasia. Neoplasms showing anaplasia and mitotic activity are considered to be WHO grade III (anaplastic). The presence of mitoses should be unequivocal, but no special recognition is given to their number or morphology. In fact, finding a solitary mitosis in an ample specimen may be insufficient for the diagnosis of anaplastic glioma. Thus, differentiation between WHO grade II and grade III tumors may be better achieved by determining labeling index of Ki-67 [3] or phosphorylated histone H3 (PHH3) [28]. Histone H3 is a core histone protein, the phosphorylation of which reaches a maximum during mitotic chromosome condensation, but which does not undergo phosphorylation during apoptosis. Therefore, anti-PHH3 antibodies may serve as a specific mitotic marker and allow distinction of mitotic figures from apoptotic bodies [28]. Tumors that in addition to anaplasia and mitotic activity demonstrate microvascular proliferation and/or necrosis are assigned WHO grade IV. Microvascular proliferation (previously referred as “endothelial proliferation ,” although pure multilayering of the endothelium is rare) is defined as the presence of a glomeruloid vasculature consisting of smooth muscle cells and pericytes. Necroses may be of any type and perinecrotic palisading need not be present for diagnosis of GBM [2, 3, 11].

As defined by the current WHO classification, gliomas with designated histopathological grades II–IV are infiltrative in nature and considered to be biologically malignant. Survival of patients with WHO grade II neoplasms usually exceeds 5 years, whereas in cases of WHO grade III tumors it is typically limited to 2–3 years [4]. The prognosis in cases of WHO grade IV tumors is variable and largely depends on the availability of an effective treatment regimen; the majority of patients with GBM, particularly the elderly, succumb to disease within 1 year, which is strikingly different from the 5-year survival rate of >60% after standard management of medulloblastoma [2]. In general, the WHO grading scheme has been applied rather successfully to a spectrum of circumscribed and infiltrating astrocytomas, but it is significantly less effective in cases of oligodendroglial and ependymal tumors, and particularly in cases of pediatric gliomas [18].