Plexiform Neurofibroma Infiltrating the Facial Nerve William
Osebold, MD, Kenneth C. Moore, MF
\s=b\ A plexiform neurofibroma was unusual in that it extensively infiltrated the main trunk and branches of the left facial nerve without compromising function, rather than forming a circumscribed, compressive mass. Histologic sections showed diffuse involvement of even minute branches of the facial nerve. Electron microscopy disclosed Schwann cell and fibroblastic proliferation in a collagenous matrix. Collagen fibrogenesis by fibroblasts, but not by Schwann cells, was noted. Many of the Schwann cells were free of any association with nerve axons, which suggests that some release of the Schwann cell from its usually well-defined functions is involved in neurofibroma formation.
(Arch Neurol 36:35-37, 1979)
plexiform neurofibroma is characby proliferation of endoneurial and epineurial Schwann cells, with thickening, degeneration, and tortuosity of the nerve of origin. -^*· terized
Unlike more circumscribed neurofibromas that are localized to a specific region of a nerve trunk, the plexiform neurofibroma proliferates to involve surrounding tissue and nerve trunks much more extensively, often with
perineurial proliferation surrounding swollen, tortuous nerve axons.
Plexiform neurofibromas have been reported on the head, neck, trunk, limbs,1 and in the viscera.2:1 Common sites include the eyelid, orbit, cheek, and neck, with aggressive prolifer¬ ation located centrally along the crani¬ al nerve trunks to compress brain stem structures.
There are several excellent studies the clinical manifestations of neurofibromatosis4" and the histolo¬ gy'-7 s and electron microscopy7"1- of neurofibromas. A profusely illuson
Accepted for publication Oct 19, 1977. From the Departments of Orthopaedic Surgery (Dr Osebold) and Biochemistry (Dr Moore), The University of Iowa, Iowa City. Reprint requests to Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA 52242 (Dr Osebold).
trated discussion of the histology of plexiform neurofibroma is available.1 The present report correlates the clin¬ ical, histologie, and electron micro¬ scopic observations of a boy in whom a plexiform neurofibroma had diffusely infiltrated along the entire trunk and branches of the left facial nerve, rath¬ er than proliferating outward from the nerve into surrounding tissues. MATERIALS AND METHODS of Histologie Sections
Preparation
Tissue obtained at operation was finely sectioned, fixed in 10% formaldehyde, dehydrated in 95% ethanol, and embedded in paraffin. Paraffin blocks were sectioned with a microtome, and specimens were stained with hematoxylin-eosin. Electron Microscopy Tissue obtained at operation was imme¬ diately immersed in cold 3% glutaraldehyde in 0.1M sodium cacodylate buffer at a pH of 7.4, and then sectioned into
5 x 1 x 1-mm blocks and allowed to remain in cold fixative for at least one hour. The tissue blocks were washed with 0.1M sodium cacodylate buffer at a pH of 7.4 and postfixed in cold 2% osmium tetroxide in veronal-acetate-HCl buffer at a pH of 7.4 for one hour, dehydrated in ethanol and embedded in epoxy resin (Epon 812). Thin sections were cut on an ultramicrotome equipped with a diamond knife. Sil¬
ver-to-light-gold sections were mounted on 300-mesh copper grids; they were then stained with 5% uranyl acetate, followed by lead citrate. The sections were examined and photographed in an electron micro¬ scope.
REPORT OF A CASE
The patient, a boy, was first seen at age 10 months for congenital pseudarthrosis of the right tibia. He and his mother have multiple café au lait spots. Gradual enlargement of the left side of the face was noted since the patient was 15 months old, with preservation of cranial nerve motor and sensory function. At age 11 years, nodular enlargement of the left side of the face extended deep to the masseter muscle, with enlargement of the left side of the floor of the mouth and tongue. Basilar tomograms of the skull showed widening of the left superior orbital fissure, pterygopalatine fossa, and foramen ovale, sugges-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
tive of neurofibromatous involvement of multiple cranial nerves. At operation to excise the tumor, the left facial nerve was seen to be three times its normal diameter and intimately involved with the neurofibroma. Rather than spreading outward into surrounding tissue from a localized segment of the nerve of origin, the proliferative tissue had dis¬ sected extensively along the trunk of the facial nerve and its branches so that tumor tissue could not be excised without sacrific¬ ing functioning nerve tissue. Sections of tumor from cervical and subcutaneous branches were taken for microscopic exam¬ ination. No further dissection was per¬ formed. Histologie examination disclosed tor¬ tuous, coarse, edematous neurofibromatous tissue that was unencapsulated and per¬ meating parotid tissue (Fig 1). Electron microscopy revealed Schwann cells with basement membranes, large nuclei, and scant cytoplasm. The Schwann cell configu¬ rations ranged from ovoid cells lying free in the tumor matrix, to long, drawn out cytoplasmic processes (Fig 2, and 3). Sur¬ rounding each Schwann cell was an amor¬ phous extracellular basement membrane. Another feature of all Schwann cells was their intimate relationship to bundles of collagen fibers immediately exterior to the basement membrane. Although intracytoplasmic microfibrils were encountered, there were no micrographs suggestive of intracellular fibrogenesis, even in sections showing collagen bundles enclosed in Schwann cell cytoplasmic indentations (Fig 3). We observed none of the unique banded structures reported by Luse," Waggener,1" and Chino and Tsuruhara," nor the segment-long-spacing fibers reported by Fisher and Vuzevski12 and by Ramsey.1' Several Schwann cells were enveloping nerve axons with sparsely fibrillar cyto¬ plasm containing few organelles. No myelin formation was observed. Despite the frequency of Schwann cells, no desmosomes
were
seen
bridging cytoplasmic
membranes. Several dense structures sug¬ gestive of desmosomes were seen at junc¬ tions of abutting, fibroblast cytoplasmic membranes (Fig 4). COMMENT
Plexiform neurofibroma is an un¬ common manifestation of neurofibromatosis, occurring in only 3% of the 61 adult patients studied by Preston et
al.e These arise from neous
large, aggressive tumors deep nerve trunks, cuta¬ twigs (as in the upper eyelid),
and from the autonomie nervous system (as in the gut myenteric plexus), with a high incidence of sarcomatous degeneration. Our patient showed no cranial nerve abnormality, which was consistent with the prolif¬ eration of the tumor along the nerve and its branches, rather than the formation of a large compressive mass.
Normally, the Schwann cell is inti¬ mately associated with nerve axons; it either envelops them, forms myelin sheaths, or contributes to the peri¬ neurial sheath.1 Although many of the
Schwann cells in
sections were encountered many without associated axons or cytoplasmic processes." As noted by other observers, the Schwann cells had a homogeneous, amorphous basement membrane and did not form mye¬ lin.1"-12
enveloping
Fig 1.—Involvement of small branches of cervical portion of facial nerve within parotid gland. Neuronal degeneration with perineurial thickening and coarse bundles of collagen and spindle cells (hematoxylin-eosin, original magnification 320).
axons,
our
we
Fig 2.—Schwann cell with large nucleus, scant cytoplasm, and amorphous basement membrane lying in collagenous matrix (2% osmium tetroxide in veronal-acetate-hydrochloride buffer [pH, 7.4]; 25,000).
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
6. Preston FW, Walsh WS, Clarke TH: Cutaneurofibromatosis (von Recklinghausen's disease). Arch Surg 64:813-827, 1952. 7. Aegerter EE: The possible relationship of neous
neurofibromatosis, congenital pseudarthrosis, dysplasia. J Bone Joint Surg [Am] 32:618-626, 1950. 8. Feigin I: The nerve sheath tumor, solitary and in von Recklinghausen's disease: A unitary mesenchymal concept. Acta Neuropathol 17:188\x=req-\ 200, 1971. 9. Luse SA: Electron microscopic studies of brain tumors. Neurology 10:481-505, 1960. 10. Waggener JD: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699\x=req-\ 709, 1966. 11. Chino F, Tsuruhara T: Electron microscopic study on von Recklinghausen's disease. Jpn J and fibrous
3.—Thin Schwann cell cytoplasmic processes lie in close association with collagen fibrils (2% osmium tetroxide in veronal-acetate-hydrochloride buffer [pH, 7.4]; original magnification
Fig 4.—At right, between crisscrossing collagen bundles, is thin, tortuous cytoplasm of a histiocyte (h). Top left, abutting fibroblast membranes demonstrate densities suggestive of desmosomes (d) (2% osmium tetroxide in veronal-acetate-hydrochloride buffer
Fig
26,000).
[pH, 7.4]; original magnification
Although the Schwann cell is thought to be ectodermal in origin,1-8 its mesenchymal function of collagen formation has been carefully docu¬ mented.1117' Despite previously pub¬ lished micrographs that show unique banded structures"11 and segment-
long-spacing fibrils,12
''
we
saw
no
clear evidence of fibril extrusion Schwann cells.
by
The neurofibroma is tous rather than
a
a
hamartoma-
neoplastic tumor,
and plexiform neurofibroma may be considered to be a further degenera¬ than proliferative, tive, rather change.' * What initially stimulates endoneurial matrix production, and then Schwann cell and fibroblastic proliferation, in the incipient plexi¬ form neurofibroma remains unknown.
23,000).
The autosomal dominant mode of inheritance suggests disturbance of a structural protein, such as collagen, though none of the fibrils examined by us appeared abnormal. M. V. Connelly, MD, of the Department of Otorhinolaryngology, The University of Iowa, assisted in obtaining tumor tissue, and Mae Ewalt, orthopedic pathology technician, helped prepare the histologie sections.
References 1. Harkin JC, Reed RJ: Tumors of the Peripheral Nervous System. Atlas of Tumor Pathology, Armed Forces Institute of Pathology, 1969, pp 72-87, 116-120. 2. Hochberg FH, Dasilva AB, Galdabini J, et al: Gastrointestinal involvement in von Reck-
linghausen's
neurofibromatosis.
24:1144-1151, 1974.
Neurology
3. Staple TW, McAlister WH, Anderson MS: Plexiform neurofibromatosis of the colon simulating Hirschsprung's disease. Am J Roentgenol 91:840-845, 1964. 4. Crowe FW, Schull WJ, Neel JV: A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis. Springfield, Ill, Charles C Thomas Publisher, 1956. 5. Fienman NL, Yakovac WC: Neurofibromatosis in childhood.J Pediatr 76:339-346, 1970.
6. Preston FW, Walsh WS, Clarke TH: Cutaneurofibromatosis (von Recklinghausen's disease). Arch Surg 64:813-827, 1952. 7. Aegerter EE: The possible relationship of neous
neurofibromatosis, congenital pseudarthrosis, dysplasia. J Bone Joint Surg [Am] 32:618-626, 1950. 8. Feigin I: The nerve sheath tumor, solitary and in von Recklinghausen's disease: A unitary mesenchymal concept. Acta Neuropathol 17:188\x=req-\ 200, 1971. 9. Luse SA: Electron microscopic studies of brain tumors. Neurology 10:481-505, 1960. 10. Waggener JD: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699\x=req-\ 709, 1966. 11. Chino F, Tsuruhara T: Electron microscopic study on von Recklinghausen's disease. Jpn J and fibrous
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
Med Sci Biol 21:249-257, 1968. 12. Fisher ER, Vuzevski VD: Cytogenesis of schwannoma (neurilemoma), neurofibroma, dermatofibroma, and dermatofibrosarcoma as revealed by electron microscopy. Am J Clin Pathol 49:141-154, 1968. 13. Ramsey HJ: Fibrous long-spacing collagen in tumors of the nervous system. J Neuropathol Exp Neurol 24:40-48, 1965. 14. Nathaniel EJH, Pease DC: Collagen and basement membrane formation by Schwann cells during nerve regeneration. J Ultrastruct Res 9:550-560, 1963. 15. Thomas PK: The deposition of collagen in relation to Schwann cell basement membrane during peripheral nerve regeneration. J Cell Biol 23:375-382, 1964.
Osebold, MD, Kenneth C. Moore, MF
\s=b\ A plexiform neurofibroma was unusual in that it extensively infiltrated the main trunk and branches of the left facial nerve without compromising function, rather than forming a circumscribed, compressive mass. Histologic sections showed diffuse involvement of even minute branches of the facial nerve. Electron microscopy disclosed Schwann cell and fibroblastic proliferation in a collagenous matrix. Collagen fibrogenesis by fibroblasts, but not by Schwann cells, was noted. Many of the Schwann cells were free of any association with nerve axons, which suggests that some release of the Schwann cell from its usually well-defined functions is involved in neurofibroma formation.
(Arch Neurol 36:35-37, 1979)
plexiform neurofibroma is characby proliferation of endoneurial and epineurial Schwann cells, with thickening, degeneration, and tortuosity of the nerve of origin. -^*· terized
Unlike more circumscribed neurofibromas that are localized to a specific region of a nerve trunk, the plexiform neurofibroma proliferates to involve surrounding tissue and nerve trunks much more extensively, often with
perineurial proliferation surrounding swollen, tortuous nerve axons.
Plexiform neurofibromas have been reported on the head, neck, trunk, limbs,1 and in the viscera.2:1 Common sites include the eyelid, orbit, cheek, and neck, with aggressive prolifer¬ ation located centrally along the crani¬ al nerve trunks to compress brain stem structures.
There are several excellent studies the clinical manifestations of neurofibromatosis4" and the histolo¬ gy'-7 s and electron microscopy7"1- of neurofibromas. A profusely illuson
Accepted for publication Oct 19, 1977. From the Departments of Orthopaedic Surgery (Dr Osebold) and Biochemistry (Dr Moore), The University of Iowa, Iowa City. Reprint requests to Department of Orthopaedic Surgery, University of Iowa, Iowa City, IA 52242 (Dr Osebold).
trated discussion of the histology of plexiform neurofibroma is available.1 The present report correlates the clin¬ ical, histologie, and electron micro¬ scopic observations of a boy in whom a plexiform neurofibroma had diffusely infiltrated along the entire trunk and branches of the left facial nerve, rath¬ er than proliferating outward from the nerve into surrounding tissues. MATERIALS AND METHODS of Histologie Sections
Preparation
Tissue obtained at operation was finely sectioned, fixed in 10% formaldehyde, dehydrated in 95% ethanol, and embedded in paraffin. Paraffin blocks were sectioned with a microtome, and specimens were stained with hematoxylin-eosin. Electron Microscopy Tissue obtained at operation was imme¬ diately immersed in cold 3% glutaraldehyde in 0.1M sodium cacodylate buffer at a pH of 7.4, and then sectioned into
5 x 1 x 1-mm blocks and allowed to remain in cold fixative for at least one hour. The tissue blocks were washed with 0.1M sodium cacodylate buffer at a pH of 7.4 and postfixed in cold 2% osmium tetroxide in veronal-acetate-HCl buffer at a pH of 7.4 for one hour, dehydrated in ethanol and embedded in epoxy resin (Epon 812). Thin sections were cut on an ultramicrotome equipped with a diamond knife. Sil¬
ver-to-light-gold sections were mounted on 300-mesh copper grids; they were then stained with 5% uranyl acetate, followed by lead citrate. The sections were examined and photographed in an electron micro¬ scope.
REPORT OF A CASE
The patient, a boy, was first seen at age 10 months for congenital pseudarthrosis of the right tibia. He and his mother have multiple café au lait spots. Gradual enlargement of the left side of the face was noted since the patient was 15 months old, with preservation of cranial nerve motor and sensory function. At age 11 years, nodular enlargement of the left side of the face extended deep to the masseter muscle, with enlargement of the left side of the floor of the mouth and tongue. Basilar tomograms of the skull showed widening of the left superior orbital fissure, pterygopalatine fossa, and foramen ovale, sugges-
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
tive of neurofibromatous involvement of multiple cranial nerves. At operation to excise the tumor, the left facial nerve was seen to be three times its normal diameter and intimately involved with the neurofibroma. Rather than spreading outward into surrounding tissue from a localized segment of the nerve of origin, the proliferative tissue had dis¬ sected extensively along the trunk of the facial nerve and its branches so that tumor tissue could not be excised without sacrific¬ ing functioning nerve tissue. Sections of tumor from cervical and subcutaneous branches were taken for microscopic exam¬ ination. No further dissection was per¬ formed. Histologie examination disclosed tor¬ tuous, coarse, edematous neurofibromatous tissue that was unencapsulated and per¬ meating parotid tissue (Fig 1). Electron microscopy revealed Schwann cells with basement membranes, large nuclei, and scant cytoplasm. The Schwann cell configu¬ rations ranged from ovoid cells lying free in the tumor matrix, to long, drawn out cytoplasmic processes (Fig 2, and 3). Sur¬ rounding each Schwann cell was an amor¬ phous extracellular basement membrane. Another feature of all Schwann cells was their intimate relationship to bundles of collagen fibers immediately exterior to the basement membrane. Although intracytoplasmic microfibrils were encountered, there were no micrographs suggestive of intracellular fibrogenesis, even in sections showing collagen bundles enclosed in Schwann cell cytoplasmic indentations (Fig 3). We observed none of the unique banded structures reported by Luse," Waggener,1" and Chino and Tsuruhara," nor the segment-long-spacing fibers reported by Fisher and Vuzevski12 and by Ramsey.1' Several Schwann cells were enveloping nerve axons with sparsely fibrillar cyto¬ plasm containing few organelles. No myelin formation was observed. Despite the frequency of Schwann cells, no desmosomes
were
seen
bridging cytoplasmic
membranes. Several dense structures sug¬ gestive of desmosomes were seen at junc¬ tions of abutting, fibroblast cytoplasmic membranes (Fig 4). COMMENT
Plexiform neurofibroma is an un¬ common manifestation of neurofibromatosis, occurring in only 3% of the 61 adult patients studied by Preston et
al.e These arise from neous
large, aggressive tumors deep nerve trunks, cuta¬ twigs (as in the upper eyelid),
and from the autonomie nervous system (as in the gut myenteric plexus), with a high incidence of sarcomatous degeneration. Our patient showed no cranial nerve abnormality, which was consistent with the prolif¬ eration of the tumor along the nerve and its branches, rather than the formation of a large compressive mass.
Normally, the Schwann cell is inti¬ mately associated with nerve axons; it either envelops them, forms myelin sheaths, or contributes to the peri¬ neurial sheath.1 Although many of the
Schwann cells in
sections were encountered many without associated axons or cytoplasmic processes." As noted by other observers, the Schwann cells had a homogeneous, amorphous basement membrane and did not form mye¬ lin.1"-12
enveloping
Fig 1.—Involvement of small branches of cervical portion of facial nerve within parotid gland. Neuronal degeneration with perineurial thickening and coarse bundles of collagen and spindle cells (hematoxylin-eosin, original magnification 320).
axons,
our
we
Fig 2.—Schwann cell with large nucleus, scant cytoplasm, and amorphous basement membrane lying in collagenous matrix (2% osmium tetroxide in veronal-acetate-hydrochloride buffer [pH, 7.4]; 25,000).
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
6. Preston FW, Walsh WS, Clarke TH: Cutaneurofibromatosis (von Recklinghausen's disease). Arch Surg 64:813-827, 1952. 7. Aegerter EE: The possible relationship of neous
neurofibromatosis, congenital pseudarthrosis, dysplasia. J Bone Joint Surg [Am] 32:618-626, 1950. 8. Feigin I: The nerve sheath tumor, solitary and in von Recklinghausen's disease: A unitary mesenchymal concept. Acta Neuropathol 17:188\x=req-\ 200, 1971. 9. Luse SA: Electron microscopic studies of brain tumors. Neurology 10:481-505, 1960. 10. Waggener JD: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699\x=req-\ 709, 1966. 11. Chino F, Tsuruhara T: Electron microscopic study on von Recklinghausen's disease. Jpn J and fibrous
3.—Thin Schwann cell cytoplasmic processes lie in close association with collagen fibrils (2% osmium tetroxide in veronal-acetate-hydrochloride buffer [pH, 7.4]; original magnification
Fig 4.—At right, between crisscrossing collagen bundles, is thin, tortuous cytoplasm of a histiocyte (h). Top left, abutting fibroblast membranes demonstrate densities suggestive of desmosomes (d) (2% osmium tetroxide in veronal-acetate-hydrochloride buffer
Fig
26,000).
[pH, 7.4]; original magnification
Although the Schwann cell is thought to be ectodermal in origin,1-8 its mesenchymal function of collagen formation has been carefully docu¬ mented.1117' Despite previously pub¬ lished micrographs that show unique banded structures"11 and segment-
long-spacing fibrils,12
''
we
saw
no
clear evidence of fibril extrusion Schwann cells.
by
The neurofibroma is tous rather than
a
a
hamartoma-
neoplastic tumor,
and plexiform neurofibroma may be considered to be a further degenera¬ than proliferative, tive, rather change.' * What initially stimulates endoneurial matrix production, and then Schwann cell and fibroblastic proliferation, in the incipient plexi¬ form neurofibroma remains unknown.
23,000).
The autosomal dominant mode of inheritance suggests disturbance of a structural protein, such as collagen, though none of the fibrils examined by us appeared abnormal. M. V. Connelly, MD, of the Department of Otorhinolaryngology, The University of Iowa, assisted in obtaining tumor tissue, and Mae Ewalt, orthopedic pathology technician, helped prepare the histologie sections.
References 1. Harkin JC, Reed RJ: Tumors of the Peripheral Nervous System. Atlas of Tumor Pathology, Armed Forces Institute of Pathology, 1969, pp 72-87, 116-120. 2. Hochberg FH, Dasilva AB, Galdabini J, et al: Gastrointestinal involvement in von Reck-
linghausen's
neurofibromatosis.
24:1144-1151, 1974.
Neurology
3. Staple TW, McAlister WH, Anderson MS: Plexiform neurofibromatosis of the colon simulating Hirschsprung's disease. Am J Roentgenol 91:840-845, 1964. 4. Crowe FW, Schull WJ, Neel JV: A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis. Springfield, Ill, Charles C Thomas Publisher, 1956. 5. Fienman NL, Yakovac WC: Neurofibromatosis in childhood.J Pediatr 76:339-346, 1970.
6. Preston FW, Walsh WS, Clarke TH: Cutaneurofibromatosis (von Recklinghausen's disease). Arch Surg 64:813-827, 1952. 7. Aegerter EE: The possible relationship of neous
neurofibromatosis, congenital pseudarthrosis, dysplasia. J Bone Joint Surg [Am] 32:618-626, 1950. 8. Feigin I: The nerve sheath tumor, solitary and in von Recklinghausen's disease: A unitary mesenchymal concept. Acta Neuropathol 17:188\x=req-\ 200, 1971. 9. Luse SA: Electron microscopic studies of brain tumors. Neurology 10:481-505, 1960. 10. Waggener JD: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699\x=req-\ 709, 1966. 11. Chino F, Tsuruhara T: Electron microscopic study on von Recklinghausen's disease. Jpn J and fibrous
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/14/2015
Med Sci Biol 21:249-257, 1968. 12. Fisher ER, Vuzevski VD: Cytogenesis of schwannoma (neurilemoma), neurofibroma, dermatofibroma, and dermatofibrosarcoma as revealed by electron microscopy. Am J Clin Pathol 49:141-154, 1968. 13. Ramsey HJ: Fibrous long-spacing collagen in tumors of the nervous system. J Neuropathol Exp Neurol 24:40-48, 1965. 14. Nathaniel EJH, Pease DC: Collagen and basement membrane formation by Schwann cells during nerve regeneration. J Ultrastruct Res 9:550-560, 1963. 15. Thomas PK: The deposition of collagen in relation to Schwann cell basement membrane during peripheral nerve regeneration. J Cell Biol 23:375-382, 1964.
