Peripheral nerve sheath tumors are common neoplasms, with classic identifiable features, but on occasion, they are diagnostically challenging. Although well-defined subtypes of peripheral nerve sheath tumors were described early in the history of surgical pathology, controversies regarding the classification and grading of these tumors persist. Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches. In this review, we discuss current concepts and problematic areas in the pathology of peripheral nerve sheath tumors. Diagnostic criteria and differential diagnosis for the major categories of nerve sheath tumors are proposed, including neurofibroma, schwannoma, and perineurioma. Diagnostically challenging variants, including plexiform, cellular and melanotic schwannomas are highlighted. A subset of these affects the childhood population, and has historically been interpreted as malignant, although current evidence and outcome data suggest they represent benign entities. The growing current literature and the author's experience with difficult to classify borderline or “hybrid tumors” are discussed and illustrated. Some of these classification gray zones occur with frequency in the gastrointestinal tract, an anatomical compartment that must always be entertained when examining these neoplasms. Other growing recent areas of interest include the heterogeneous group of pseudoneoplastic lesions involving peripheral nerve composed of mature adipose tissue and/or skeletal muscle, such as the enigmatic neuromuscular choristoma. Malignant peripheral nerve sheath tumors (MPNST) represent a diagnostically controversial group; difficulties in grading and guidelines to separate “atypical neurofibroma” from MPNST are provided. There is an increasing literature of MPNST mimics which neuropathologists must be aware of, including synovial sarcoma and ossifying fibromyxoid tumor. Finally, we discuss entities that are lacking from the section on cranial and paraspinal nerves in the current WHO classification, and that may warrant inclusion in future classifications. In summary, although the diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer, yet borderline and difficult-to-classify neoplasms continue to be problematic. In the current review, we attempt to provide some useful guidelines for the surgical neuropathologist to help navigate these persistent, challenging problems.

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Pathology of Peripheral Nerve Sheath Tumors: Diagnostic Overview and Update on Selected Diagnostic Problems

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported that PRKAR1A, which codes for the type 1A regulatory subunit of protein kinase A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in some CNC families. To evaluate the spectrum of PRKAR1A mutations, we identified its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were informative for linkage analysis: four of four families that mapped to 17q had PRKAR1A mutations, whereas there were no mutations found in seven families exhibiting at least one recombination with 17q. In six of the latter, CNC mapped to 2p16. PRKAR1A mutations were also found in 12 of 20 non-informative families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mutations were identified in 22 of 54 kindreds (40.7%). In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. We conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. CNC is the first human disease recognized to be caused by mutations of the PKA holoenzyme, a critical component of cellular signaling.

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Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex

The present WHO classification of meningiomas has served us well. In keeping with the adage, “if it ain't broke, don't fix it,” alterations should be made with due caution. These proposed modifications of the WHO classification are prompted by advances in our understanding of the pathobiology of meningeal neoplasms, as well as a need for an orderly scheme based upon factors of clinical importance. The author is well aware, that given the vastly differing technologies available to those utilizing the “blue book,” its application must have a basis in routine histology rather than in “high-tech” procedures. No classification is ideal, but the modifications suggested represent a compromise between the pathologist's need for a complete morphologic exposition and the clinician's desire for a concise classification of therapeutic and prognostic significance.

Tumors of the meninges: proposed modifications of the World Health Organization classification.

Aim

To clarify the prognosis of melanotic schwannoma. This is a rare tumour which is generally considered as a benign lesion, reported in many cases with a short follow-up only.



Methods and results

Five cases of spinal melanotic schwannoma were retrospectively studied. The tumours were examined using standard histological, immunohistochemical and ultrastructural methods. No features of malignancy (high mitotic count, atypia or necrosis) were found in the primary tumours. The follow-up period ranged from 3 to 7 years. Malignant clinical behaviour was clear-cut in four cases: three patients died from metastases to various sites and one presented several discrete spinal tumours of the same type seven years after the first operation. Only one patient presented no recurrence and was free of disease 6 years after initial diagnosis. The review of 57 cases of the literature (including our cases), showed that 15% of the cases had recurrences and 26.3% were complicated by metastasis. Only 53% of the cases followed for more than 5 years, were free of disease vs. 67.5% of the cases with shorter follow-up. Twenty additional cases had no follow-up.



Conclusion

Appropriate long-term follow-up is required for all melanotic schwannomas, as it may recur or metastasize after more than 5 years, even in the absence of overt malignant histological features.

Spinal melanotic schwannoma: a tumour with poor prognosis.

Nervous system tumors represent unique neoplasms that arise within the central and peripheral nervous system. While the vast majority of nervous system neoplasm occur sporadically, most of the adult and pediatric forms have a hereditary equivalent. In a little over a decade, we have seen a tremendous increase in knowledge of the primary genetic basis of many of the familial cancer syndromes that involve the nervous system, syndromes that are mostly inherited as autosomal dominant traits. In this review, we discuss the most recent findings on the genetic basis of hereditary nervous system tumors. The identification of genes associated with familial cancer syndromes has in some families enabled a “molecular diagnosis” that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at-risk for disease. © 2004 Wiley-Liss, Inc.

Genetic insights into familial tumors of the nervous system

Psammomatous melanotic schwannoma is a rare variant of schwannoma. The authors present histological and immunohistochemical findings in two cases of the tumor arising in the spinal nerve roots region at a 56-year-old woman and a 58-year-old man. The latter recurred locally. Microscopically the tumor was composed of polygonal epithelioid or spindle-shaped cells. Some of these cells contained melanin. Small calcifications were dispersed throughout the lesion. Ultrastructural examination of one of these cases revealed nerve sheath origin of the tumor cells and identified premelanosomes and melanosomes within the cytoplasm of neoplastic cells. Histogenesis and relationship of the tumor to Carney complex are discussed.

M Syrůcek

Papers

Psammomatous melanotic schwannoma