| Disease | Neurofibromatosis type 1 (NF1) is an autosomal genetic disease caused by heterozygous dysfunction of the NF1 tumor suppressor gene on the long arm of chromosome 17. |
| Embryonic origin | Neurocrest. |
| Etiology | The genetic cause for neurofibromas is the bi-allelic inactivation of the NF1 tumor suppressor gene. |
| Epidemiology | Both sex can be affected. Neurofibromas are rare in children, but start develop in puberty. Up to thousands of neurofibromas can develop in one adult NF1 patient. In contrast to dermal neurofibromas, PNF are often congenital and may develop already before birth. |
| Clinics | Neurofibromas are mostly benign. These tumors can lead to transient stinging, itching, and pain. Multiplicity of these tumors often cause disfigurement with psychological impact on the individual's selfesterm, partnerships and social relations.
However, dermal neurofibromas usually do not cause any further serious dysfunction. There is no evidence for malignant transformation of dermal neurofibromas.
In contrast, PNF often lead to pain, disfigurement, neurological and other clinical deficits. PNF mostly show net-like growth pattern along nerve roots extending from a main nerve root to a small distal branch, and can be divided into two main types: internal tumors and superficial ones.
Superficial PNF do not cross tissue planes and are amenable to complete or nearly complete surgical resection.
Internal PNF extend through multiple tissue planes and can not be completely removed in most cases without damaging tissues and organs. PNF located in the chest, abdomen or pelvis are frequently detected as paraspinal masses that involves multiple spinal levels. These tumors may also appear as anterior mediastinal masses, sciatic nerve lesions with pelvic extension, and perirectal plexiform and uterine tumors, all leading to sever clinical complications. Furthermore, there is a risk of malignant progression in PNF, especially the internal ones. While dermal neurofibromas mostly appear during adolescence, PNF are mainly congenital though some of them become apparent later. Growth of PNF is slows down with increasing age. |
| Pathology | According to the WHO classification dermal and plexiform neurofibromas are grade I tumours. Histologically they consist of transformed Schwann cells with wavy contours and ovoid to elongated nuclei with fine dense heterochromatin. The tumours show a diffuse growth or an arrangement of cells in streams. The Schwann cells are intermingled with fibroblasts and perineurial-like cells in a matrix of muco-substances and a varying amount of collagen fibres. Within the tumour, especially in dermal neurofibromas, mast cells and perivascular lymphocytic infiltrates may be demonstrated. In some patients focal palisading of small groups of nuclei may resemble Meissner corpuscles and arrangement of cells in dense whorls may resemble Pacini corpuscles. Plexiform tumours typically show a low cellularity, loose texture and an abundant myxoid matrix. Degenerating nerve fibres may be seen within the tumour. There are no signs of malignancy and proliferative activity is low or absent in both, dermal and plexiform neurofibroma.
Some cases may show a mixed Schwannoma-neurofibroma differentiation, these tumours are termed Schwannoma in Neurofibroma.
Immunohistochemical labelling of tumour cells with antibodies against S-100 protein is particularly helpful in tumours with extremely low cellularity like in dermal neurofibromas of the mamilla. |
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| Labelling of tumour cells in dermal (left) and plexiform neurofibroma (right)with antibodies against S-100 protein. |
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| Treatment | Surgery: Plastic surgeons should be consulted for surgical resection of neurofibromas, especially for those of face and neck. The result of the surgery dipendends on the size, localization, and structure (diffuse, nodular, or pendunculated) of the tumors. Pendunculated neurofibromas can be excised with a very satisfactory result. Various techniques can be applied for resection of neurofibromas: conventional scalpel, laser or electrocauterization. According to our experience, conventional scalpel is suitable for larger, exophytic tumors. Laser and electrocauterization are useful for tumors with intracutaneous localization with abundent blood vessels. There is no proven benefit for carbon dioxide laser treatment for neurofibromas. No relapse will occur upon completely resection. Anti-histamine is not always satisfactory as a treatment for itching of neurofibromas.
Hormones: Hormonal factors seem to contribute to the growth of neurofibromas, as neurofibroma growth is stimulated by puberty and pregnancy. A recent study has shown that 75% of neurofibromas carry progesterone receptors. However, there is no evidence that progesterone and combined oral contraceptive pill stimulate growth of neurofibromas. For pregnant NF1 patient, obstetrician and clinicians should be aware that spinal and pelvic neurofibromas may progress rapidly and thus need to be monitored closely.
Plexiform neurofibromas: Deeply located tumors PNF often lead to pain and neurological deficits and thus need special attention and closely monitoring. Patients developing deficits or pain should undergo surgery whenever a positive outcome is suggested. Annual examination helps to detect first indication of possible spinal cord compression. Regular MRI is important for early detection of malignant transformation. Results of surgery of PNF are usually unsatisfactory because of the network-like growth of the tumors often involve multiple nerve fascicles and other adjacent tissues. Typically surgical interventions for PNF are restricted to debulking procedures of large tumors causing significant clinical complications or aesthetic disfigurement. However, successful subtotal resections of the superficial PNF with significant improvement in cosmetic appearance are possible. Furthermore, a recent study reported the advantage of early surgical intervention of small PNF in children under 15 years of age. Total resection was achieved in all 7 cases without causing any neurological or organic deficit. Annual control within four years with magnetic resonance tomography did not reveal any relapse of the tumors. |
| Prognosis | Neurofibromas are benign tumors. However, there is a risk of malignant transformation in PNF, leading to malignant peripheral nerve sheath tumors. |
| Concurrent chemoradiotherapy with low dose weekly gemcitabine in stage III non-small cell lung cancer. |
| Abacioglu U, Yumuk PF, Caglar H, Sengoz M, Turhal NS |
| BMC cancer. 2005 ; 5 : page 71. |
| PMID 16000167 |
| |
| The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. |
| Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F |
| Cell. 1990 ; 63 (4) : 851-859. |
| PMID 2121371 |
| |
| A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. |
| Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P |
| Cell. 1990 ; 62 (1) : 193-201. |
| PMID 2114220 |
| |
| NF1 tumor suppressor gene function: narrowing the GAP. |
| Cichowski K, Jacks T |
| Cell. 2001 ; 104 (4) : 593-604. |
| PMID 11239415 |
| |
| Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. |
| Colman SD, Williams CA, Wallace MR |
| Nature genetics. 1995 ; 11 (1) : 90-92. |
| PMID 7550323 |
| |
| Subtotal and total resection of superficial plexiform neurofibromas of face and neck: four case reports. |
| Friedrich RE, Schmelzle R, Hartmann M, Mautner VF |
| Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2005 ; 33 (1) : 55-60. |
| PMID 15694151 |
| |
| Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. |
| Kluwe L, Friedrich R, Mautner VF |
| Genes, chromosomes & cancer. 1999 ; 24 (3) : 283-285. |
| PMID 10451710 |
| |
| Mutation and cancer: statistical study of retinoblastoma. |
| Knudson AG Jr |
| Proceedings of the National Academy of Sciences of the United States of America. 1971 ; 68 (4) : 820-823. |
| PMID 5279523 |
| |
| Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. |
| Lammert M, Friedman JM, Kluwe L, Mautner VF |
| Archives of dermatology. 2005 ; 141 (1) : 71-74. |
| PMID 15655144 |
| |
| Adenocarcinoma in bladder diverticulum, metastatic from gastric cancer. |
| Matsuhashi N, Yamaguchi K, Tamura T, Shimokawa K, Sugiyama Y, Adachi Y |
| World journal of surgical oncology. 2005 ; 3 : page 55. |
| PMID 16117837 |
| |
| MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. |
| Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Fünsterer C |
| Neuroradiology. 2006 ; 48 (3) : 160-165. |
| PMID 16432718 |
| |
| Progesterone receptor expression in neurofibromas. |
| McLaughlin ME, Jacks T |
| Cancer research. 2003 ; 63 (4) : 752-755. |
| PMID 12591720 |
| |
| Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. |
| Serra E, Puig S, Otero D, Gaona A, Kruyer H, Ars E, Estivill X, Lázaro C |
| American journal of human genetics. 1997 ; 61 (3) : 512-519. |
| PMID 9326316 |
| |
| Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. |
| Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, Lenard HG, Lázaro C |
| Human molecular genetics. 2000 ; 9 (20) : 3055-3064. |
| PMID 11115850 |
| |
| CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. |
| Tonsgard JH, Kwak SM, Short MP, Dachman AH |
| Neurology. 1998 ; 50 (6) : 1755-1760. |
| PMID 9633723 |
| |
| Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. |
| Upadhyaya M, Han S, Consoli C, Majounie E, Horan M, Thomas NS, Potts C, Griffiths S, Ruggieri M, von Deimling A, Cooper DN |
| Human mutation. 2004 ; 23 (2) : 134-146. |
| PMID 14722917 |
| |
| Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. |
| Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA |
| Cell. 1990 ; 62 (1) : 187-192. |
| PMID 1694727 |
| |
| World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Nervous System. |
| Woodruff JM, Kourea HP, Louis DN, Scheithauer BW |
| Neurofibroma.In : page I. |
| |
