**7. Nosograhic position of OA after the "ISN-Haarlem Consensus"**

The "integrated" diagnosis provided for grade II and III adult gliomas covers the diagnostic uncertainties between astrocytoma and oligodendroglioma and, mainly, of OA.

It has been found that OAs more frequently exhibited the molecular signature of either pure oligodendroglioma (IDH1/2, 1p/19q co-deletion, CIC, FUB1, and TERT promoter mutations) or pure astrocytoma (IDH1/2, TP53, and ATRX mutations) with almost total exclusivity [71]. A recent study proved that most low grade gliomas (including 74 OAs) with IDH1/2 muta‐ tions and intact 1p/19q harbored a high frequency of TP53 mutations (94%) and ATRX mutations (86%) [73].

In 31 of 43 OAs (72.1%), the absence of ATRX mutations, associated with IDH1/2 mutations and total 1p/19q co-deletion, reclassified them as oligodendrogliomas; 11 of 43 (25.6%), with concurrent ATRX protein loss and TP53 mutations were reclassified as astrocytomas. The astrocytes within the tumor were, therefore, interpreted as reactive [71]. These results were similar to a previous one [64] and were confirmed in a large collection of cases [38]. The conclusion is that OA should be removed from the WHO classification as a distinct tumor entity, although rare instances of clearly biphasic OAs exhibiting morphologic and molecu‐ lar heterogeneity have been described. Mixed areas of the tumor could show heterogeneous ATRX immunoreactivity with positive reactive astrocytes and negative tumor astrocytes [74, 75]. As ATRX is ubiquitously expressed in normal cells (endothelial cells, reactive astrocytes, microglia cells, and lymphocytes) [38, 71], the real problem in the diagnosis of OA according

to the 2007 WHO classification seems to ascertain the occurrence of ATRX-negative and IDH1R132H -positive astrocytes in the tumor.

The astrocytic and oligodendroglial components have been found to share the same molecu‐ lar signature, but with a sheer cell differentiation [71]. They should be regarded as "morpho‐ logically ambiguous" rather than "mixed" tumors, as conventionally referred. 1p/19q codeletion and TP53 mutations represent distinct mechanisms of oncogenesis but they do not provide evidence for a genetic signature specifically related to OA [76].

The "ISN-Haarlem *Consensus*" suggested considering OA or tumors with ambiguous histolo‐ gy as diffuse astrocytoma when harboring IDH1/2 mutations, intact 1p/19q, and ATRX loss; as oligodendroglioma when harboring IDH1/2 mutations, 1p/19q co-deletion, and intact ATRX and as diffuse astrocytoma when harboring wild type IDH. In the absence of molecular data, the tumor should be diagnosed as oligodendroglioma or diffuse astrocytoma not otherwise specified (NOS). Finally, the denomination of OA would be only maintained when molecu‐ lar testing does not solve tumor diagnosis [27].

Anyway, there is no doubt on the usefulness of the ATRX IHC [72] and of the double ATRX/ IDH1R132H immunostaining [77] in the diagnosis of adult diffuse gliomas. Based on molecular data from the above mentioned markers on 54 OAs, it has been concluded that OA repre‐ sents a morphological grey zone rather than a group of truly "mixed" or "intermediate" gliomas [78]. Importantly, it remains unsolved how to explain IDH mutant diffuse gliomas with ATRX expression and intact 1p/19q (neither merely astrocytic nor oligodendroglial lesions) or, more rarely, cases with loss of ATRX protein expression and total 1p/19q codeletion (both astrocytic and oligodendroglial lesions).
