Dermal Neurofibromas Research Articles

Malignant Peripheral Nerve Sheath Tumors of the Skin

We report two cases of cutaneous malignant peripheral nerve sheath tumors. One occurred in a patient without neurofibromatosis and manifested as a recurrent scalp nodule. Histologically, the lesion began as a benign-appearing, dermal neurofibroma and progressed to a highly cellular, pleomorphic neoplasm with prominent mitotic activity and invasion of the subcutis. Immunohistochemical and ultrastructural examination confirmed the nerve sheath origin of this tumor. The other case presented as a large scalp mass in a patient with an established diagnosis of neurofibromatosis; its immunohistochemical characteristics were identical to those of case 1. Although malignant peripheral nerve sheath tumors are uncommon in the skin, they can be effectively separated from other spindle cell neoplasms by specialized pathologic studies.

Nerve growth factor receptor immunoreactivity in human benign peripheral nerve sheath tumor

In situ expression of nerve growth factor (NGF) receptors in human dermal and plexiform neurofibroma, schwannoma and traumatic neuroma was examined by an immunohistochemical method using a monoclonal anti-human NGF receptor antibody. Immunoreactivity for the NGF receptor was observed on the principal cells of both neurofibroma and schwannoma. Immunostaining by the anti-S-100 beta protein antibody in adjacent sections suggested that the vast majority of NGF receptor-positive cells were also positive for S-100 beta protein. In traumatic neuroma, staining for the NGF receptor was more intense in the perineurium than in the endoneurial cells.

Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales.

A population-based study in south-east Wales (population 668,100) identified 135 patients with von Recklinghausen neurofibromatosis (prevalence 20/10(5]. In addition to multiple café-au-lait spots and/or dermal neurofibromas, freckling was present in the axilla (67%), groin (44%) or submammary areas (29% of adult females). Although not a criterion for diagnosis, Lisch nodules were almost invariably present in the iris (93% of patients overall; 96% of those aged greater than or equal to 20 yrs). The complications of von Recklinghausen neurofibromatosis in this cohort (n = 135 unless stated) were plexiform neurofibromas (40/125), severe mental retardation (1), epilepsy (6), optic glioma (2), spinal neurofibroma (2), aqueduct stenosis (2), meningioangiomatosis (1), scoliosis requiring surgery (6), pseudoarthrosis (3), delayed puberty (2), visceral and endocrine tumours (6), and congenital glaucoma (1). There were no cases of acoustic neuroma. Considering all living family members aged greater than or equal to 18 yrs, together with their deceased relatives, the frequency of CNS and malignant tumours related to the disease was 4.4-5.2%. Uncomplicated von Recklinghausen neurofibromatosis is disfiguring but not a major cause of morbidity. The management of the disease relates to its complications which can be divided into three categories: those which occur in childhood and cause lifelong morbidity (moderate-severe mental handicap, facial plexiform neurofibromas, orthopaedic), those which can occur at any time but are 'treatable' (benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis), and malignant or CNS tumours. The combined frequency for each category based on this survey was 12%, 16% and 4.4-5.2%, respectively.

Schwann-like cells cultured from human dermal neurofibromas. Immunohistological identification and response to Schwann cell mitogens.

Primary cultures prepared from dermal and plexiform neurofibromas contain Schwann-like cells and fibroblast-like cells. SLC are elongated and bipolar or multipolar. By indirect immunofluorescence light microscopy, living SLC bind antibodies against laminin and against nerve growth factor receptor to their surface, but not antibodies against fibronectin. In these respects, cultured SLC are indistinguishable from cultured human adult Schwann cells. FLC are flat and pleomorphic. By indirect immunofluorescence light microscopy, living FLC bind antibodies against fibronectin but not against laminin or NGFR. In these respects, cultured FLC are indistinguishable from cultured human adult endoneurial fibroblasts. Considerable purification of viable SLC from SLC/FLC mixed cultures can be achieved by flow cytofluorometry using a monoclonal anti-NGFR antibody. Tritiated thymidine radioautography indicated that mitosis of SLC in mixed SLC/FLC cultures prepared from dermal neurofibromas is infrequent in MEM with 10% calf serum, more frequent in RPMI 1640 medium with 15% fetal calf serum. Central nervous system axolemmal fragments (rat or human) elicited a greater than 10-fold SLC proliferative response in mixed SLC/FLC cultures from three of seven dermal neurofibromas (from six patients with neurofibromatosis), but had no effect on SLC mitosis in cultures from the other four dermal neurofibromas. SLC mitosis was inhibited by concentrations of cyclic adenosine 3',5'-monophosphate analogues known to stimulate proliferation of normal rat Schwann cells. Glial growth factor partially purified from bovine pituitaries stimulated SLC mitosis both in SLC/FLC mixed cultures and in cultures of purified SLC. The studies we have described indicate that neurofibroma SLC can be cultured, unequivocally identified in culture by morphological and immunohistological criteria, purified, and stimulated to proliferate by several Schwann cell mitogens. Further quantitative comparisons of the baseline and mitogen-stimulated rates of proliferation of SLC and age-matched control human Schwann cells are needed, however, to determine which of the two alternate pathogenetic mechanisms for formation of neurofibromas mentioned in the introduction is correct.

Tissue culture studies of neurofibromatosis: effects of axolemmal fragments and cyclic adenosine 3',5'-monophosphate analogues on proliferation of Schwann-like and fibroblast-like neurofibroma cells.

Six dermal neurofibromas obtained from 5 patients with neurofibromatosis were dissociated and the cells were plated on polylysine-coated glass. Two principal cell types were observed in the cultures: elongated and bipolar Schwann-like cells (SLCs), and polymorphic flattened fibroblast-like cells (FLCs). Indirect immunofluorescence demonstrated that SLCs expressed surface laminin but not surface fibronectin; FLCs expressed surface fibronectin but were only weakly positive for surface laminin. Tritiated thymidine autoradiography demonstrated that cultured SLCs proliferated slowly (labeling index, 0.7 to 4.0%), whereas FLCs divided more rapidly (labeling index, 7.5 to 26.4%). Axolemmal fragments prepared from human or rat central nervous system specimens adhered to SLCs derived from each of the 6 neurofibromas, but not to FLCs. Axolemmal fragments induced a marked proliferative response of SLCs from 2 of the 6 neurofibromas but had no effect on proliferation of SLCs from the other 4 neurofibromas or FLCs from any of the 6 neurofibromas. In one patient from whom 2 neurofibromas were obtained, SLCs from one neurofibroma responded to axolemmal fragments, while SLCs from the other did not. Treatment of the cultures with 0.1 mM cyclic adenosine 3'5'-monophosphate (cAMP) analogue, 8-bromo cAMP, caused marked inhibition of proliferation of both SLCs and FLCs derived from all 6 neurofibromas. The same concentration of another cAMP analogue, dibutyryl cAMP, inhibited proliferation of SLCs but not of FLCs.

Tissue Culture Studies of Schwann Cell Proliferation and Differentiation

Neonatal rat sciatic nerve Schwann cells in monolayer culture are stimulated to proliferate and to express a lipid and a protein characteristic of myelin by agents which raise intracellular cyclic adenosine 3',5'-monophosphate. Both glial growth factor and axolemmal fragments increase the rate of mitosis of cultured rat and human Schwann cells. Rat Schwann cell mitosis is enhanced by a soluble factor produced by concanavalin A-stimulated blood mononuclear cells and inhibited by lead salts. Schwann-like cells cultured from human dermal and plexiform neurofibromas resemble normal human Schwann cells in phenotype and response to mitogens.

Neurotransmitter analysis of dermal neurofibromas: implications for the pathogenesis and treatment of neurofibromatosis.

We examined 15 dermal neurofibromas from five adults with disseminated neurofibromatosis. All tumors contained axons that reacted for catecholamines and tyrosine hydroxylase on histochemical stains. Assay of tissue homogenates identified norepinephrine as the catecholamine. Assays for dopamine and choline acetyltransferase were negative. Some axonal components of dermal neurofibromas may originate in sympathetic adrenergic neurons. Most dermal neurofibromas do not contain neuronal cell bodies, and some of the axons may maintain functional connections with proximal sympathetic neuronal cell bodies. Sympathetic denervation may therefore affect the growth of these dermal neurofibromas.

The distinction between central neurofibromatosis and tuberose sclerosis.

Central neurofibromatosis and tuberose sclerosis are genetically distinct diseases but both produce hamartomas of the supporting cells of the central nervous system and malformation of other tissues. A case of central neurofibromatosis previously reported as tuberose sclerosis is presented and the distinguishing features of the two diseases reviewed. Earlier reports of their co-existence are re-examined and only one indisputable case found. Double diagnosis has frequently been made on the basis of non-specific changes common to both diseases, e. g. glial proliferation, fibrous dermal tumours; the misdiagnosis of dermal neurofibroma or adenoma sebaceum in the absence of histological proof or the misinterpretation of X-ray appearances of bone.