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Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST.

The cyclin-dependent kinase inhibitor p27Kip1 is a negative cell cycle regulator linking extracellular growth-regulatory signals to the cell cycle machinery in G1. We investigated the pattern and prognostic value of p27Kip1 expression in a population-based group of 203 non-Hodgkin's lymphoma (NHL) patients. The expression of p27Kip1 was identified by immunohistochemistry and correlated with Ki-67 expression and clinical features. Correlation with outcome was determined using uni- and multivariate analysis stratified by clinical grade. Except for very aggressive NHL, there was a negative correlation between p27Kip1 and Ki-67 expression. Low expression of p27Kip1, defined as nuclear p27Kip1 expression in <40% of malignant cells, was predictive of poor survival in indolent and aggressive NHL. However, even in this regard, very aggressive lymphomas behaved differently as those with low p27Kip1 expression tended to do better. Likewise, a high proliferation rate (Ki-67 >40%) was associated with poor survival in indolent and aggressive lymphomas. Multivariate analysis using the proportional hazards model showed that only p27Kip1, and not Ki-67, maintained independent prognostic significance in indolent and aggressive lymphomas (relative risk = 2. 0; P = 0.0095). The low cost and simplicity of this standard immunohistochemistry analysis makes p27Kip1 a promising and suitable prognostic marker in routine diagnostic laboratories in a standard diagnostic panel.

We evaluated the operative outcome in 22 consecutive patients who underwent microvascular decompression (MVD) of the intracranial portion of the cochlear nerve to relieve incapacitating tinnitus and related it to preoperative findings. The patients were selected for operation from the following criteria: severe tinnitus with sensorineural hearing loss and/or changes in brainstem auditory evoked potentials (BAEPs). Fifty percent had unilateral tinnitus. Before operation, 17 patients (77%) had sensorineural hearing loss in their affected ear. BAEPs were abnormal in 21 patients (95%) and acoustic middle ear reflex response was abnormal in six patients (27%). Vascular compression of the cochlear nerve was found in all patients during the operation. After the operation, 33% had relief of their tinnitus (two patients were totally free of tinnitus and five were markedly improved). Eight patients were slightly improved (38%), and the tinnitus did not change in four patients; two patients (10%) became worse. Of the patients with unilateral tinnitus, 63% had relief of their tinnitus. In one patient hearing was noticeably improved after the operation. Five patients (23%) had mild to moderate sensorineural hearing loss due to the operation. No other complications were detected.