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2015 Annual Meeting
Specialty Conference
Evening Specialty Conference - Neuropathology
(EC13-15) Evening Specialty Conference - Neuropathology - Stemmer-Rachamimov - materials -1
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Clinical History

CASE HISTORY: A 64 year old woman presented with slowly progressive painful mass in left foot. On examination skin fold freckling was present in the right torso (front and back) stopping at midline. The patient’s clinical history includes a previous surgery for resection of a mass from the left ankle diagnosed as schwannoma (2013). In addition, 2 raised dermal lesions were biopsied and diagnosed as dermal nevi. .There is no family history of neurofibromatosis. 

Hybrid Tumors: pathology and clinical significance

Hybrid tumorsshow mixed features of two peripheral nerve sheath tumors (neurofibroma/schwannoma or perineurioma/schwannoma) andare therefor difficult to classify. Review of the literature shows that NF associated hybrid tumorsare of the neurofibroma/schwannoma type. Interestingly, hybrid tumors were found to be more common in NF (all NF forms) than in sporadic patients. The most common forms of hybrid tumors in NF are Schwann cell rich neurofibromas mimicking  schwannomas (as in this case) and a myxoid schwannoma mimicking a neurofibroma. The pathology misdiagnosis of a hybrid tumor may lead to the clinical misdiagnosis of the form of NF.

The most useful panel for the workup of a hybrid tumor includes: S100 and Sox 10 (for Schwann cells), SMA (for myofibroblasts), Glut 1 and Claudine (for perineurial cells) and Neurofilament (for axons).

The use of neurofilament (to highlight axons) is based on the conventional thinking (based mostly on observations on sporadic schwannomasand neurofibromas) that schwannomasare devoid of entrappedaxons, while neurofibromas, which expand from within the nerve, have entrappedaxons within the tumor. However, these findings are not absolute. Intratumoral axonsare present in asignificant number schwannomas associated with NF2 andschwannomatosis, although the number of axons was usually low and in some neurofibromas (as in this case) axons are only seen in the periphery. These observations suggest that one should be cautious in the interpretation of presence/absence of intratumoral axons for the purpose of distinguishing between neurofibromaandschwannoma in the context of adifficult (hybrid) lesion in neurofibromatoses.

Molecular studies:

Sporadic and NF1-associated neurofibromasderive from biallelic inactivation of the NF1 gene (17q11.2) with consequent loss of neurofibromin protein expression, hyperactivation of Ras proteins.NF1 patients have a germline mutation of the NF1 gene.

NF2-associatedschwannomas have biallelic inactivation of the NF2 gene (22q12.2) leading to loss of the Merlin protein activity. The most frequent mechanism for loss of the second allele in NF2-associatedschwannomas is LOH due to monosomy of the entire chromosome 22 (35% of tumors in some series). NF2 patients have a germline mutation of the NF2 gene.

In schwannomatosis, loss of NF2 gene is observed in tumors, but in contrast with NF2, there is no NF2 germline mutation.  SMARCB1 germline mutations have been found in some of schwannomatosis cases (30% of familial; 8% of sporadic). Recently another gene has been implicated in a subset of familial and sporadic schawnnomatosis is LZTR1 (40% of familial; 30% of sporadic).

The most difficult cases to classify clinically are mosaic patients with segmental manifestation of NF. This condition is caused by post-zygotic mutation which results in segmented patterns of affected tissues. Molecular testing for germline mutation in blood is difficult as only a subset of cells carry the mutation, Testing for NF1, NF2 and SMARCB1 can be performed in difficult cases and when possible, analysis of two or more tumors is recommended.

Immunohistochemical staining for NF1 (neurofibromin), NF2 (merlin) are not performed because there are no good antibodies for tissue staining. Staining for SMARCB1 encoded protein (INI1) may be useful in some cases. A mosaic pattern of expression (mixed positive and negative cells) is strongly associated with syndromic schwannomas (familial schwannomatosis and NF2) while most sporadic schwannomas have a diffuse pattern of staining.  

Recent studies have reported BRAF mutations in a subset of schwannomas (10%). Unfortunately there is poor correlation between BRAF immuno and BRAF mutations, as non specific staining is seen in many schwannomas. It is unclear if there is any clinical correlates to BRAF mutant schwannomas. 


MacCollin M et al. Diagnostic criteria for schwannomatosis. Neurology, 64(11):1838-45, 2005.

Harder A et al. Hybrid Neurofibroma/Schwannoma is overrepresented among schwannomtosis and neurofibromatosis patients. American Journal of Surgical Pathology, 36(5):702-709, 2012

MacCollin M et al. Familial schwannomatosis: exclusion of the NF2 locus as a germline event. Neurology, 60 (12):1968-74, 2003

Smith MJ et al. Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics. 2012 ;13(2):141-5.

Patil S et al. Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannoma. Brain Pathol; 18(4):517-9, 2008

Carroll SL: Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms, Acta Neuropathol, 123:321-348, 2012

Paganini I et al. Expanding the mutational spectrum of LZTR1 in schwannomatosis 2014

Serrano C et al. BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours. Histopathology. 2013;62(3):499-504.

Nonaka D et al.Sox10: a pan-schwannian and melanocytic marker. ,2008 ;32(9):1291-8.