Non-RMS comprise of at least 50 different histological subtypes originating from mesenchymal cells.
There are two major types:
1. Those with widespread genomic instability
- Pleomorphic sarcoma (known previously as malignant fibrous histiocytoma or MFH)
2. Those with specific chromosomal rearrangements:
- Translocations which generate a specific chimeric "fusion" protein from two different transcription factors
- Proteins can drive the generation of sarcomas in mouse models
- Specific histological subtype arises from expression of a transcription factor
- Example: synovial sarcoma
Non-RMS arise in associated with:
- Underlying genetic conditions
- Environmental exposures
Underlying genetic conditions associated with an increased risk for the development of non-RMS:
Neurofibromatosis 1
Also called von Recklinghausen's Neurofibromatosis.
Hamartoneoplastic syndrome:
- hamartomas are localized tissue proliferations with faulty differentiation
- mixture of component tissues
- potential towards neoplasia
- embryonic origin of dysgenetic tissues involved in NF1 is ectoblastic
Autosomal dominant with almost complete penetrance and is one of the most frequent genetically inheritable disease.
- 30/105 newborns
- 1 /200 people with a developmental disability have this condition
- 50% cases arise as a sporadic mutation
- highly variable expressivity:
- very mild to very severe
- expressivity is also age-related
The NF1 gene:
- Mapped to chromosome 17q11.2.
- Encodes for Neurofibromin protein which is expressed in many tissues, including brain, kidney, spleen, and thymus.
- Neurofibromin belongs to a family of GTPase-activating proteins that down regulate a proto-oncogene, p21-ras, an important determinant of cell growth and regulation (tumor suppressor gene).
The clinical diagnosis of neurofibromatosis is based on the presence of at least two of the following criteria:
NIH criteria for NF1 (Patients must have more then two of the following):
Six or more café-au-lait macules larger than 5 mm in greatest diameter in prepubertal persons and larger than 15 mm in greatest diameter in postpubertal persons |
Two or more neurofibromas of any type or one plexiform neurofibroma |
Freckling in the axillary or inguinal region |
Optic glioma |
Two or more Lisch nodules (iris hamartomas) |
A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis |
A first-degree relative (parent, sibling or offspring) with NF-1 by the above criteria |
- Neurofibromas are benign tumors that are comprised of a mixture of Schwann cells, fibroblasts, and mast cells. They may be cutaneous (soft fleshy tumors arising from cells in the peripheral nerve sheath, mostly on trunk), subcutaneous (firm, tender nodules along the course of peripheral nerves) or nodular plexiform (complex clusters along proximal nerve roots and major nerves).
- 15-20% of children with neurofibromatosis develop central nervous system neoplasms, usually as gliomas of the visual pathway or low-grade astrocytomas of the diencephalon, cerebral hemispheres, or posterior fossa.
- 5% of patients with NF develop a malignant neoplasm - this is often a malignant peripheral nerve sheath neoplasm.
Resources:
Neurofibromatosis type 1 (NF1) at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Li-Fraumeni syndrome
- Autosomal dominant.
- Germline mutation of the p53 tumor suppressor gene (70% of families have a mutation of the p53 gene on chromosome 17).
- Associated with an increased incidence of CNS astrocytomas in children.
- Young adults with this syndrome have an increased incidence of breast cancer, sarcomas, and brain tumors. There is also an increased risk of leukemia, and adrenocortical cancer occurring before the age of 45.
Li-Fraumeni Syndrome at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Familial adenomatous polyposis (Gardner syndrome)
- Autosomal dominant disorder
- Frequency about 2.5/105 newborns
- Penetrance close to 100% by the age of 40 years
- Associated with:
- Multiple adenomatous polyps of the colon and rectum
- Colorectal cancer is the major cause of death with a median age of onset at 40 years
- Desmoid tumors (fibromatosis) are very common in this disease
- Hepatoblastomas
- Osteomas
Familial adenomatous polyposis at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Bilateral Retinoblastoma
- Autosomal dominant disorder
- Caused by mutations in the RB1 gene
- Associated with:
- Bilateral multifocal retinoblastoma
- Pineoblastoma
- Osteogenic sarcoma
- Leiomyosarcomas and lipomas
Bilateral retinoblastoma at the Atlas of Genetics and Cytogenetics in Oncology and Haematology
Environmental causes of non-RMS
Radiation therapy
- Associated with an increased risk of non-RMS in the radiation therapy field many years later
- Often malignant fibrous histiocytoma (pleomorphic sarcoma)
- Risk increased in the presence of underlying genetic conditions such as Li-Fraumeni
Other environmental exposures:
- Epstein-Barr virus infection in patients with AIDS can be associated with leiomyosarcoma
- Arsenic
- Polyvinyl chloride
- Thorotrast
References:
Malignant peripheral nerve sheath tumors in neurofibromatosis 1 Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A
