To this end, we assembled a multi-institutional expert pathology working group as part of a “Symposium on Atypical Neurofibroma: State of the Science.” Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling and recommend molecular profiling for clinically or radiologically worrisome noncutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. The gene discussed is CDKN2A; the disease is malignant peripheral nerve sheath tumor.