Molecular analysis of malignant triton tumors.

Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.     

Granular cell variant of neurofibromatosis: ultrastructure of benign and malignant tumors

A case of neurofibromatosis with a metastasizing malignant tumor is presented. The benign lesions were identified by light microscopy as neurofibromas containing granular cells typical of granular cell tumors. The malignant tumor was classified as a malignant granular cell tumor. Ultrastructural studies demonstrated common histogenetic and subcellular features of the benign and malignant tissues. The case is the first reported in which granular cells are seen in the lesions. The typical granular cell morphologic features of the malignant lesion support the concept of Schwann cell derivation of this group of tumors.     

ELMO蛋白家族与恶性肿瘤侵袭转移关系的研究进展

It is one of the main characters of malignant tumors that malignant tumor cells invade surrounding tissues and metastasize to distant tissues. Multiple factors are involved in this complicated dynamic process. Metastasis is the major factor influencing recurrence and prognosis. Therefore, it is important to explore the mechanism of invasion and metastasis for reducing recurrence rate and mortality of malignant tumors. Engulfment and cell mobility (ELMO) family is one kind of conserved protein in evolutional process. It includes 3 members, ELMO1, ELMO2 and ELMO3. The members of ELMO family play an important role in cell phagocytosis and cell migration, and they also have close correlation with malignant tumor cell invasion and metastasis. In this paper, we review the progress of the relationship between ELMO family and malignant tumor invasion and metastasis.     

A Young Male with Parafibromin-Deficient Parathyroid Carcinoma Due to a Rare Germline <Emphasis Type="Italic">HRPT2/CDC73</Emphasis> Mutation

Hyperparathyroidism, commonly observed in asymptomatic middle-aged women, with mild hypercalcemia, is usually caused by a benign adenoma. Some cases present with more severe manifestation and greater hypercalcemia. Within this spectrum, several familial/genetic associations have been discovered. While the majority are caused by benign disease, adenomas, or hyperplasia, a small proportion (<?1%) are associated with malignant tumors and present with more severe symptoms. Although usually sporadic, recent reports document various gene mutations that strongly predispose to the development of parathyroid carcinoma. An increasing number of cases of hyperparathyroidism, benign or malignant, require and benefit from genetic analysis. We describe a 25-year-old male with hyperparathyroidism presenting with a pathological fracture, brown tumors, hypercalcemia, and markedly elevated parathyroid hormone levels. There was no family history of hyperparathyroidism or jaw tumors. Surgical removal revealed a single large tumor confirmed to be malignant. Immunohistochemical analysis revealed the absence of parafibromin and decreased APC (adenomatosis polyposis coli) expression. Genetic analysis revealed a rare germline nonsense mutation (R76X) in the parafibromin gene, HRPT2/CDC73. Parathyroid carcinoma should be suspected as a cause of hyperparathyroidism when clinical manifestations are severe, particularly in young individuals, <?59 years. Immunohistochemistry may lead to suspicion for a germline mutation as a significant contributor despite absence of a family history. The discovery of a germline mutation in parathyroid carcinoma alters the clinical management of the index case and that of family members. Long-term follow-up studies of such patients are necessary to develop evidence-based clinical guidelines.     

Neurofibromatosis in monozygotic twins: a case report of spontaneous mutation

We report female monozygotic twins with neurofibromatosis. The family history is unremarkable, and careful examination of other family members did not show evidence of the condition. It is concluded that the occurrence in this family is due to a spontaneous mutation arising in one of the parental gametes. This article examines the similarity and difference in manifestations of the disorder in this pair of monozygotic twins.     

Malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation (malignant triton tumor) with balanced t(7;9)(q11.2;p24) and unbalanced translocation der(16)t(1;16)(q23;q13)

Malignant peripheral nerve sheath tumors (MPNST) with skeletal muscle differentiation are termed malignant triton tumors. A case of malignant triton tumor arising in a patient without signs of neurofibromatosis with two consistent chromosomal abnormalities is described. The first was of a balanced translocation between the long arm of chromosome 7 and the short arm of chromosome 9. The second was an unbalanced rearrangement between chromosomes 1 and 16, leading to partial trisomy for the long arm of chromosome 1 and partial monosomy for the long arm of chromosome 16. Review of previous reports on chromosomal abnormalities in malignant triton tumors revealed consistent abnormalities involving chromosome 1, regardless of the presence or absence of neurofibromatosis. This finding may relate to the observed poor prognostic outcome in this type of sarcoma. Also unique to our case is the translocation involving 7q and 9p, both regions may play a role in MPNST.     

A case of familial angiolipomatosis with Lisch nodules.

Familial angiolipomatosis is a rare syndrome that may be confused clinically with neurofibromatosis type 1. This condition is most often inherited in an autosomal recessive manner; however, several reports have been published suggesting an autosomal dominant mode of inheritance. Angiolipomatosis, although somewhat disfiguring, is a benign condition with no known association with malignant neoplasms. This is in contradistinction to neurofibromatosis, an autosomal dominant syndrome associated with a myriad of benign and malignant neoplasms. It is, therefore, important to discriminate this entity from neurofibromatosis when a patient presents with multiple subcutaneous tumors and a family history of similar lesions. Described is a case of a prison inmate with a history of seizures and "neurofibromatosis" without clinical documentation. Lisch nodules were noted on the irides. Postmortem examination showed multiple subcutaneous yellow tumors on the chest and arms. Fine-needle aspiration of 1 mass yielded adipose tissue with prominent vessels; histologic sections of another mass showed angiolipoma. The remainder of the autopsy showed significant coronary artery disease and a remote cerebral infarction of the temporal lobe but no signs of neurofibromatosis. We feel that the presence of multiple angiolipomas in combination with Lisch nodules lends credence to the proposed relationship between fatty tumors and neurofibromatosis suggested by other authors.     

Neonatal neurofibromatosis: unusual manifestations with malignant clinical course

A family with neurofibromatosis is reported in which the proband was an infant in whom the diagnosis was established at birth. In this case, the presenting symptom was a large tumor of the tongue and macrocephaly. Cafe-aula it spots appeared early, as did additional subcutaneous tumors, with skeletal involvement and severe psychomotor retardation. The rapid growth of the tumor, its spread within the mediastinum, neck and oral cavity, led to a strangulating death at one year of age. The disease originates from early embryonic involvement of the neural crest and from tissues derived from its caudal end. It is probably caused by a single pleiotropic gene transmitted as an autosomal dominant trait, with varying expression of the disease in different members of the same family.     

Primary malignant peripheral nerve tumors (malignant schwannomas). A clinicopathologic and electron microscopic study.

A clinicopath-logic and electron microscopic study was performed on 35 cases of primary malignant peripheral nerve tumors, among which 12 developed in association with neurofibromatosis (von Recklinghausen's disease) and further 11 in keeping with anatomically discernible nerves in patients without neurofibromatosis. Depending upon the histologically predominant pattern, these tumors were subdivided into three groups: 23 compact spindle cell, 6 myxoid, and 6 epithelioid varieties of the tumor. The common ultrastructures in three of the 35 tumors were as follows: 1) The cell membranes manifested characteristic infoldings and lamellar configuation. 2) The tumor cell surfaces were coated by occasional basal lamina or homogeneously electron-dense membranous material. 3) The cytoplasms contained well-developed organelles and a few neurosecretory-type granules. Differential points from other soft-tissue sarcomas were briefly discussed on the histologic basis.     

PRIMARY MALIGNANT PERIPHERAL NERVE TUMORS (MALIGNANT SCHWANNOMAS)

A clinicopathologic and electron microscopic study was performed on 35 cases of primary malignant peripheral nerve tumors, among which 12 developed in association with neurofibromatosis (von Recklinghausen's disease) and further 11 in keeping with anatomically discernible nerves in patients without neurofibromatosis. Depending upon the histologically predominant pattern, these tumors were subdivided into three groups: 23 compact spindle cell, 6 myxoid, and 6 epithelioid varieties of the tumor. The common ultrastructures in three of the 35 tumors were as follows: 1) The cell membranes manifested characteristic infoldings and lamellar configuration. 2) The tumor cell surfaces were coated by occasional basal lamina or homogeneously electron-dense membranous material. 3) The cytoplasms contained well-developed organelles and a few neurosecretory-type granules. Differential points from other soft-tissue sarcomas were briefly discussed on the histologic basis. ACTA PATH. JAP. 29 : 363–375, 1979.     

Non-neurogenic sarcomas in four children and young adults with neurofibromatosis type 1

It is well known that children and young adults with neurofibromatosis type 1 (NF1) have a higher risk for non-neurogenic sarcomas than the general population, in addition to an increased risk for malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas occur in early childhood, a subsequent malignant peripheral nerve sheath tumor can occur as a second malignant neoplasm, especially after alkylating agent chemotherapy and irradiation. This report includes the clinicopathologic features of non-neurogenic sarcomas and secondary malignant peripheral nerve sheath tumor in the context of four cases of NF1. The purpose is to emphasize that early diagnosis of NF1 and recognition of potential manifestations of non-neurogenic sarcomas are important for clinical care of these patients and their families.     

Phyllodes tumor of the breast: EGFR family expression and relation to clinicopathological features

The expression of EGFR family members was examined by immunohistochemistry in 22 phyllodes tumors, and the results were evaluated together with immunohistochemical findings for proliferation markers Ki67 and BM28, and the tumor suppressor gene product p53. Light and electron microscopy were performed in all cases. Clinical information was obtained from the medial records. We did find that expression of EG FR, c-erbB-3 and c-erbB-4 proteins could be detected in the neoplastic mesenchymal cells, and that the expression increased with increasing malignancy. Increased expressions of Ki67, BM28, p53 and EGFR family members in neoplastic cells were associated with malignancy and unfavorable clinical course. Furthermore, the expression of ER-alpha and PR in the epithelial cells of phyllodes tumors was increased compared to that in normal breast epithelium. Finally, the application of electron microscopy helped to identify a group of malignant tumors, revealing neoplastic cells with characteristic nuclear indentations, as well as an increasing number of myofibroblasts.     

The infrequency of malignant disease in diaphyseal aclasis and neurofibromatosis.

The association of diaphyseal aclasis and neurofibromatosis with malignant neoplasms has been variously reported as between 5 and 28% of all cases, but malignant disease invariably presents at hospital and the true frequency from an unselected group is unknown. The current survey reviews not only hospital patients but also their affected relatives, with particular reference to malignant disease and the cause of death in all family members. A survey of 36 index patients and 80 known affected relatives with diaphyseal aclasis and 37 index patients and 33 known affected relatives with neurofibromatosis has been carried out. The observed proportions with associated malignant disease were 0.9% of all cases of diaphyseal aclasis and 4.3% of neurofibromatosis. The authors consider this is still too high an estimate in view of the number of persons in the families only mildly affected by the inherited disease who cannot be identified, although their malignant disease will be known. A more likely figure for malignant change in diaphyseal aclasis is calculated at 0.5% (or 1.3% of those over 21 years) and in neurofibromatosis 2.0% (or 4.2% of those over 21 years).     

NEUROFIBROMATOSIS COMPLICATED BY INTRACRANIAL TUMORS

Four cases of neurofibromatosis complicated by intracranial tumors are reported. Case 1 showed an intracranial neurofibromatosis while the other three cases contained gliomas in various stages of malignancy.
Japanese autopsy records for 11 years from 1958 to 1968 were investigated from a statistical point of view. Meningiomas and neurinomas associated with neurofibromatosis show an earlier peak of age distribution than that of those tumors without neurofibromatosis. There is no different age distribution between gliomas related to neurofibromatosis and the ones not related to it.
These facts suggest that both neurinomas and meningiomas associated with neurofibromatosis are intracranial manifestations of neurofibromatosis perse , while complicated gliomas are thought to be an incidental neoplasm, probably associated with transformation of disoriented neuroglial rests.     

Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation (malignant triton tumor)

Malignant peripheral nerve sheath tumors arise from Schwann cells or within existing neurofibromas and have a strong association with type 1 neurofibromatosis. These tumors are histologically diverse and may contain malignant areas of divergent mesenchymal differentiation, the most common of which is skeletal muscle (rhabdomyosarcoma). Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation is also known as malignant triton tumor. Malignant triton tumor has a worse prognosis than classic malignant peripheral nerve sheath tumor does, and the correct diagnosis requires attention to the clinical history and knowledge of the complexities regarding its differential diagnosis. In this review we discuss the clinical, histopathological, immunohistochemical, and prognostic features of this rare neoplasm.     

Identification of a breast tumor with microsatellite instability in a potential carrier of the hereditary non-polyposis colon cancer trait

Allelic expansion at microsatellite loci in colorectal tumor DNA indicates a genomic instability caused by defects in DNA mismatch repair. This is observed in a high proportion of tumors from individuals affected by hereditary non-polyposis colorectal carcinoma, but to a lesser extent in sporadic colorectal tumors. In this study we screened 46 colorectal tumors for replication errors (RER). Tumors from six patients were found to be RER positive, two of which had a marked family history of colon cancer. In both cases the RER+ phenotype was detected in colon tumors from other family members, suggesting a germline mutation in mismatch repair genes. Additionally, RER+ phenotype, distinct from that of the colon and sporadic breast tumors, was found in malignant breast tissue from the mother of one proband.     

Two epithelioid malignant schwannomas in a patient with neurofibromatosis. Cytology, histology and DNA-flow-cytometry

Cytological, histological and DNA-ploidy findings of 2 epithelioid malignant schwannomas arising in a patient with von Recklinghausen's neurofibromatosis are described. In both primary tumors, i.e. in the thigh and in the thoracic wall, origin from a neurofibromatous nerve could be established. Within 2 years after the manifestation of the first malignant tumor the patient died of widely metastasized disease. DNA-flow cytometry of several neurofibromas revealed diploid stemlines, but both malignant primary tumors and a lung metastasis appeared to be aneuploid. Presumably, the primary tumors also contained cell populations with a diploid stem line.     

Clinical and genetic aspects of neurofibromatosis 1

Neurofibromatosis 1 is an autosomal dominant disorder characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with neurofibromatosis 1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy. The diagnosis of neurofibromatosis 1 is usually based on clinical findings. Neurofibromatosis 1, one of the most common Mendelian disorders, is caused by heterozygous mutations of the NF1 gene. Almost one half of all affected individuals have de novo mutations. Molecular genetic testing is available clinically but is infrequently needed for diagnosis. Disease management includes referral to specialists for treatment of complications involving the eye, central or peripheral nervous system, cardiovascular system, spine, or long bones. Surgery to remove both benign and malignant tumors or to correct skeletal manifestations is sometimes warranted. Annual physical examination by a physician familiar with the disorder is recommended. Other recommendations include ophthalmologic examinations annually in children and less frequently in adults, regular developmental assessment in children, regular blood pressure monitoring, and magnetic resonance imaging for follow-up of clinically suspected intracranial and other internal tumors.