This article presents 2 cases of TFG::MET-rearranged mesenchymal tumor, an extremely rare molecular subset among an emerging group of mesenchymal neoplasms with kinase gene (NTRK, BRAF, RET and others) alterations. Both tumors were congenital, occurred in female patients and presented as huge masses on the trunk and thigh, measuring 18 and 20 cm in the largest dimension. Both cases showed identical areas with a distinctive triphasic morphology resembling fibrous hamartoma of infancy (FHI), consisting of haphazardly arranged ovoid to spindled cells traversed by variably cellular and hyalinized fascicles admixed with (most likely non-neoplastic) adipose tissue. In other areas, a high-grade infantile fibrosarcoma/malignant peripheral nerve sheath tumor-like (IFS/MPNST-like) morphology was present in both cases. While the first case co-expressed CD34 and S100 protein, the other case did not. When combined with the three previously reported MET-rearranged cases (of which two harbored TFG::MET fusion), 3/5 and 3/4 of MET-rearranged and TFG::MET fusion-associated tumors, respectively exhibited similar triphasic FHI-like low-grade morphology. This points toward the existence of a relatively distinct morphological subset among kinase-fusion-associated tumors which seems to be strongly associated with MET fusions. It seems some of these low-grade cases may transform into a high-grade variant with IFS/MPNST-like morphology as has been observed in other tumors with kinase gene fusions. While most cases seem to follow an indolent clinical course, the recognition of these tumors is clinically relevant as MET tyrosine kinase inhibitors might represent an effective treatment option for clinically aggressive or unresectable cases.
- MeSH
- Fibrosarcoma * genetics MeSH
- Gene Fusion MeSH
- Humans MeSH
- Biomarkers, Tumor genetics MeSH
- Skin Neoplasms * MeSH
- Soft Tissue Neoplasms * genetics pathology MeSH
- Neoplasms, Connective and Soft Tissue * MeSH
- Neurofibrosarcoma * MeSH
- Proteins genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that arise from neural tissues and carry a poor prognosis. Previously, we found that the glutamine amidotransferase inhibitor JHU395 partially impeded tumor growth in preclinical models of MPNST. JHU395 inhibits de novo purine synthesis in human MPNST cells and murine tumors with partial decreases in purine monophosphates. On the basis of prior studies showing enhanced efficacy when glutamine amidotransferase inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. Given the known toxicity associated with 6-MP, we set out to develop a more efficient and well-tolerated drug that targets the purine salvage pathway. Here, we report the discovery of Pro-905, a phosphoramidate protide that delivered the active nucleotide antimetabolite thioguanosine monophosphate (TGMP) to tumors over 2.5 times better than equimolar 6-MP. Pro-905 effectively prevented the incorporation of purine salvage substrates into nucleic acids and inhibited colony formation of human MPNST cells in a dose-dependent manner. In addition, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft (PDX) and murine flank MPNST models. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.
- MeSH
- Antimetabolites therapeutic use MeSH
- Glutamine MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Nerve Sheath Neoplasms * drug therapy MeSH
- Neurofibrosarcoma * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Humans MeSH
- Granular Cell Tumor MeSH
- Neurilemmoma MeSH
- Neurofibroma * MeSH
- Neurofibrosarcoma MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Chondrosarcoma genetics MeSH
- Neoplastic Syndromes, Hereditary * MeSH
- Sarcoma, Ewing genetics MeSH
- Gastrointestinal Stromal Tumors genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Testing * MeSH
- Genes MeSH
- Humans MeSH
- Li-Fraumeni Syndrome diagnosis genetics prevention & control MeSH
- Mutation MeSH
- Neurofibrosarcoma genetics MeSH
- Osteosarcoma etiology genetics MeSH
- Rhabdomyosarcoma genetics MeSH
- Sarcoma * genetics classification MeSH
- Check Tag
- Humans MeSH
U feny středního knírače se ve věku 10 let objevilo tumorózní zvětšení na 3. prstu pravé hrudní končetiny a prst byl amputován. Za šest měsíců byla zjištěna léze stejného typu na 5. prstu pravé pánevní končetiny a za dalších šest měsíců jsme diagnostikovali stejné postižení 5. prstu na levé hrudní končetině. Histopatologicky byl vyšetřen pouze prst pravé pánevní končetiny. Diagnostikovali jsme spinocelulární karcinom prorůstající do kosti. Přibližně v polovině údobí mezi postižením prstů na pravé pánevní a levé hrudní končetině byl zjištěn tumor v oblasti metatarzu levé pánevní končetiny, který byl diagnostikován jako neurofibrosarkom. V rámci předoperačního vyšetření amputace 5. prstu na levé hrudní končetině jsme diagnostikovali karcinom laryngu. Za dva měsíce od stanovení diagnózy jsme psa utratili vzhledem k progredující dyspnoi způsobené progresí tumoru laryngu. Pitvou jsme odhalili drobné metastázy spinocelulárního karcinomu v plicích.
Tumourous enlargement on the third digit of the right thoracic limb developed in a female Schnauzer at the age of 10 years. The digit was amputated. Six months later, a lesion of the same type appeared on the fifth digit of the right pelvic limb, and after another six months we diagnosed the same disability on the 5th digit of the left thoracic limb. Histopathologically was examined only the digit on the right pelvic limb. We diagnosed squamous cell carcinoma infiltrating into the bone. Approximately at half time of the period between occurence of these the lesions on digits of the right pelvic and left thoracic limbs a tumor in metatarsus on the left pelvic limb appeared, and it was diagnosed as neurofibrosarcoma. During preoperative examination for amputation of the 5th digit on the left thoracic limb we diagnosed cancer of the larynx. Two months after the diagnosis, we euthanized the dog due to progressive dyspnea caused by laryngeal tumour progression. Necropsy revealed small metastases of squamous cell carcinoma in the lungs.
- MeSH
- Laryngeal Neoplasms diagnosis pathology secondary veterinary MeSH
- Neurofibrosarcoma * diagnosis pathology veterinary MeSH
- Forelimb MeSH
- Toes MeSH
- Dogs MeSH
- Carcinoma, Squamous Cell * diagnosis surgery pathology veterinary MeSH
- Hindlimb MeSH
- Animals MeSH
- Check Tag
- Dogs MeSH
- Animals MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Antineoplastic Agents, Phytogenic administration & dosage MeSH
- Neoplasm Recurrence, Local MeSH
- Vaginal Neoplasms drug therapy surgery pathology veterinary MeSH
- Vulvar Neoplasms drug therapy surgery pathology veterinary MeSH
- Neurofibrosarcoma * surgery pathology veterinary MeSH
- Peritoneal Neoplasms surgery pathology veterinary MeSH
- Dogs MeSH
- Vincristine administration & dosage MeSH
- Animals MeSH
- Venereal Tumors, Veterinary * drug therapy surgery pathology MeSH
- Check Tag
- Dogs MeSH
- Animals MeSH
- Publication type
- Case Reports MeSH
Neurofibromatóza je relativně časté autozomálně dominantně dědičné neurokutánní onemocnění způsobené mutací tumor supresorových genů se vznikem mnohočetných hamartomů, benigních a maligních nádorů. Onemocnění se v současné době dělí na 3 samostatné jednotky s odlišným klinickým obrazem, podmíněným mutací různých genů – neurofibromatózu typu 1 (NF1), neurofibromatózu typu 2 (NF2) a schwannomatózu. Nejčastějším typem je NF1. Projevy onemocnění jsou věkově vázané, závažnost klinického obrazu je variabilní. Kožní projevy se vyskytují zejména u NF1, méně u ostatních typů. Jedná se o mnohočetné skvrny charakteru „café-au-lait“ a drobné skvrnité hyperpigmentace („freckling“) v axillách a tříslech. U NF1 se nachází neurofibromy a plexiformní neurofibromy, gliomy optiku, patognomický je nález Lischových nodulů na duhovce. U NF2 se nachází vestibulární schwannomy, u schwannomatózy mnohočetné schwannomy periferních nervů. Prognóza je individuální podle klinického obrazu a komplikací. K diagnostice jednotlivých forem neurofibromatóz slouží diagnostická kritéria, klíčovou roli hraje vyšetření dermatologem. Pacienti by měli být koncentrováni ve specializovaných centrech. Léčba neurofibromatózy je symptomatická. Klíčová slova: neurofibromatóza – café-au-lait – freckling – neurofibrom – schwannom – gliom – specializovaná centra odborné péče
Neurofibromatosis is a relatively common autosomal dominant hereditary neuro-cutaneous disease caused by mutation in tumor-suppressor genes. It results in the development of multiple hamartomas, benign and malignant tumors. The disease is currently classified into 3 individual subunits with different clinical presentations based on mutations of different genes – neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. The most common type is NF1. The symptoms are age-dependent, the severity of clinical picture is variable. Cutaneous symptoms are present namely in NF1, they are less common in other types. They include multiple café-au-lait spots and axillary and inguinal freckling. Neurofibromas, plexiform neurofibromas and optic gliomas are present in NF1, Lisch nodules in the iris are pathognomonic. Vestibular schwannomas are typical for NF2, and multiple schwannomas in peripheral nerves are present in schwannomatosis. The prognosis differs and is based on the clinical picture and complications. Diagnostic criteria play a key role in differentiating various types of neurofibromatosis and dermatological examination plays a key role. Patients should be concentrated in specialized centers. The treatment of neurofibromatosis is symptomatic. Key words: neurofibromatosis – café-au-lait spot – freckling – neurofibroma – schwannoma – glioma – specialized centers specialized care
- Keywords
- freckling, schwannomatóza,
- MeSH
- Diagnosis, Differential MeSH
- Long-Term Care MeSH
- Genetic Testing MeSH
- Optic Nerve Glioma etiology MeSH
- Hyperpigmentation etiology complications MeSH
- Humans MeSH
- Interdisciplinary Communication MeSH
- Central Nervous System Neoplasms complications MeSH
- Neoplasms complications MeSH
- Central Nervous System Diseases complications MeSH
- Iris Diseases complications MeSH
- Bone Diseases complications MeSH
- Neurilemmoma etiology complications MeSH
- Neurofibroma etiology complications MeSH
- Neurofibromatosis 1 * diagnosis etiology physiopathology therapy MeSH
- Neurofibromatosis 2 diagnosis etiology physiopathology MeSH
- Neurofibromatoses classification MeSH
- Neurofibrosarcoma complications MeSH
- Neurofibroma, Plexiform etiology MeSH
- Cafe-au-Lait Spots etiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Adult MeSH
- Humans MeSH
- Neurofibromatosis 1 * complications MeSH
- Neurofibrosarcoma * drug therapy surgery mortality pathology MeSH
- Retroperitoneal Neoplasms * surgery pathology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
