Łagodny nowotwór nerwu obwodowego – Patofizjologia i mechanizm

Łagodny nowotwór nerwu obwodowego
Patofizjologia i mechanizm

Łagodne nowotwory osłonek nerwów obwodowych (bPNST), takie jak schwannoma i neurofibroma, wywodzą się z komórek Schwanna i innych elementów obwodowego układu nerwowego. Schwannoma, najczęstszy typ u dorosłych, zwykle rozwija się z pojedynczego pęczka nerwowego i pozostaje w osłonce nerwu, natomiast neurofibroma zawiera dodatkowo aksony, fibroblasty i komórki zapalne. Genetycznie, mutacje w genie NF2 są powiązane ze schwannoma, a mutacje w genie NF1 z neurofibromami, szczególnie w kontekście zespołu neurofibromatozy typu 1 (NF1). Neurofibromina, kodowana przez NF1, reguluje aktywność Ras, a jej utrata prowadzi do nadaktywacji szlaków proliferacyjnych mTOR, MAPK i AKT, co sprzyja rozwojowi nowotworów. Transformacja złośliwa nerwiakowłókniaków (MPNST) wiąże się z kolejnymi mutacjami, m.in. w genie CDKN2A, oraz niestabilnością genomową obejmującą liczne delecje i amplifikacje chromosomowe.

Patogeneza Łagodnego Nowotworu Nerwu Obwodowego

Łagodny nowotwór nerwu obwodowego (bPNST – benign peripheral nerve sheath tumor) to rzadka zmiana pochodzenia neuroektodermalnego, bezpośrednio związana ze strukturami nerwowymi układu obwodowego.¹² Nowotwory te są rzadkimi zmianami, które rozwijają się na nerwach obwodowych łączących mózg i rdzeń kręgowy z pozostałymi częściami ciała.³ Ich występowanie może powodować różnorodne objawy, takie jak miejscowy obrzęk, deficyty ruchowe, hipoestezja oraz ból neuropatyczny wynikający z ucisku na nieobjęte procesem chorobowym pęczki nerwowe lub utratę funkcji zajętych pęczków.⁴

Podstawy molekularne rozwoju łagodnych nowotworów nerwu obwodowego

Najczęstszymi łagodnymi nowotworami osłonek nerwów obwodowych są schwannoma i neurofibroma.⁵ Głównym typem komórki neoplastycznej w tych nowotworach jest komórka Schwanna, która cytologicznie charakteryzuje się ekspresją białka S-100 oraz falistymi obrysami jądrowymi.⁶ W przypadku nerwiakowłókniaka (neurofibroma) obecne są także inne komórki obwodowego układu nerwowego, w tym aksony, komórki peryneurialne, fibroblasty oraz różne składniki zapalne, takie jak komórki tuczne i limfocyty.⁷ Odkryto również populację komórek CD34-dodatnich o nieznanej histogenezie.⁸

Schwannoma jest najczęstszym typem łagodnego nowotworu nerwu obwodowego u dorosłych. Zazwyczaj pochodzi z pojedynczego pęczka (fascicle) w głównym nerwie i przesuwa pozostałą część nerwu. Gdy schwannoma rośnie, zajmuje więcej pęczków, co utrudnia jej usunięcie.⁹ W przeciwieństwie do nerwiakowłókniaków, schwannoma nie przechodzi przez nerw, ale pozostaje w osłonce.¹⁰

Zmiany genetyczne w patogenezie łagodnych nowotworów nerwu obwodowego

Zmiany genetyczne odgrywają istotną rolę w rozwoju nowotworów osłonek nerwowych. Modyfikacja genu NF2 jest związana z rozwojem schwannoma, podczas gdy gen NF1 jest kojarzony z nerwiakowłókniakami.¹¹ Najczęściej zmiany te są sporadyczne i występują losowo, a jedynie niewielka część schwannoma i neurofibroma jest spowodowana rzadką chorobą genetyczną występującą rodzinnie – neurofibromatozą.¹²

Badania genetyczne wykazały, że gen NF2 na chromosomie 22 odgrywa kluczową rolę w rozwoju schwannoma.¹³ Utrata funkcji genu supresorowego merlin (schwannomina) związana jest z rozwojem schwannoma.¹⁴ Bezpośrednia zmiana genetyczna obejmująca gen NF2 lub wtórnie inaktywacja merliny może prowadzić do rozwoju nowotworu.¹⁵

Merlina działa jako gen supresorowy nowotworu – jej nadekspresja może hamować proliferację komórek i zmiany indukowane przez onkogeny, natomiast jej downregulacja prowadzi do transformacji nowotworowej.¹⁶ Mutacje wpływające na gen SMARCB1 mają rolę w patogenezie niewielkiej części schwannoma rdzeniowych, a bialleliczna inaktywacja SMARCB1 może współdziałać z niedoborem funkcji NF2.¹⁷

Rola genu NF1 w patogenezie nowotworów nerwów obwodowych

Zespół NF1 jest konsekwencją mutacji w genie supresorowym nowotworów NF1 na chromosomie 17q11. Zidentyfikowano ponad 500 mutacji, z których większość prowadzi do utraty funkcji białka neurofibrominy, kodowanego przez gen NF1.¹⁸ Neurofibromina jest silnie wyrażana w licznych narządach, ale najbardziej obficie występuje w tkance mózgowej, rdzeniu kręgowym i obwodowym układzie nerwowym.¹⁹

Do wywołania zespołu NF1 wystarczająca jest zmiana w pojedynczym allelu linii zarodkowej, ale zgodnie z hipotezą „dwóch uderzeń” Knudsona, formowanie się guza wydaje się wymagać utraty funkcji drugiego allelu.²⁰ Neurofibromina uczestniczy również w regulacji histogenezy oraz utrzymania lub naprawy komórek. W związku z tym NF1 jest zaburzeniem nie tylko predyspozycji do nowotworów, ale także dysplazji.²¹

Szlaki sygnałowe w patogenezie nowotworów nerwów obwodowych

Neurofibromina to białko, które przyspiesza wewnętrzną hydrolizę Ras z jego konformacji związanej z GTP do nieaktywnej konformacji związanej z GDP. W zdrowych komórkach Ras znajduje się w nieaktywnej konformacji i jest odpowiedzialny za prawidłową proliferację, transformację, różnicowanie i apoptozę.²²

Po inaktywacji NF1 obserwuje się hiperaktywność Ras i wynikającą z tego aktywację różnych szlaków proliferacyjnych i przeżyciowych, takich jak szlaki mTOR (mammalian target of rapamycin), MAPK (mitogen-activated protein kinase) czy AKT (białko kinazy B).²³ Przyspieszając konwersję Ras-GTP do Ras-GDP, neurofibromina negatywnie reguluje kaskady sygnałowe zależne od Ras.²⁴

W patofizjologii NF1, gdy neurofibromina jest wadliwa, Ras-GTP jest stale aktywowany, co prowadzi do nieograniczonej stymulacji różnych szlaków prowzrostowych.²⁵ Inaktywacja NF1 i utrata ekspresji NF charakteryzują większość transformacji złośliwych, ale bialleliczna utrata NF1 jest niewystarczająca do transformacji złośliwej.²⁶

Mechanizmy transformacji złośliwej

Bialleliczna utrata neurofibrominy jest odpowiedzialna za rozwój nowotworów osłonek nerwów obwodowych (PNST) u pacjentów z zespołem NF1. Jednak droga do onkogenezy jest znacznie bardziej skomplikowana – same mutacje NF1 prawdopodobnie nie wystarczają do wywołania zmiany nowotworowej.²⁷

Eksperymenty na myszach wykazały również znaczenie haploniewystarczalnych komórek tucznych NF1 dla przyspieszenia wzrostu pleksusowych nerwiakowłókniaków (PNF). Oprócz aktywacji Ras, dojrzewanie, rekrutacja i proliferacja komórek tucznych jest mediowana przez czynnik komórek macierzystych (SCF), ligand dla receptora kinazy tyrozynowej KIT, sugerując zależne od SCF/KIT tumorigenne interakcje guza ze zrębem w PNF.²⁸

Dla złośliwej progresji aktywowane są dodatkowe szlaki wynikające z utraty heterogeniczności locus NF1, takie jak SCF, PI3K/mTOR, P-TEN i MAPK. Te ostatecznie prowadzą do zaburzenia regulacji epigenetycznej, mitozy i angiogenezy, powodując agresywny wzrost komórek nowotworowych.²⁹

Geny RAS/RAF są proto-onkogenami charakteryzującymi się transdukcją sygnału w biologii komórki. Główną funkcją tych szlaków jest przekazywanie sygnałów z struktur zewnątrzkomórkowych (receptorów powierzchni komórkowej) do jądra komórki, co napędza szerokie spektrum fizjologicznych i patologicznych procesów komórkowych, takich jak wzrost, proliferacja, różnicowanie, migracja i apoptoza.³⁰

Sekwencyjne Nagromadzenie Zmian Genetycznych

Sekwencyjne nagromadzenie zmian genetycznych, rozpoczynające się od mutacji NF1, a następnie utraty lub inaktywacji CDKN2A oraz innych zmian molekularnych, zbiorowo napędza progresję nerwiakowłókniaków do nowotworów złośliwych.³¹ Mechanicznie gen CDKN2A koduje dwa ważne białka hamujące cykl komórkowy (p16/INK4a i p14/ARF).³² Obecne dowody wskazują, że mutacje w tych genach następują w określonej kolejności, aby przekształcić łagodne nerwiakowłókniaki pleksusowe (PN) w złośliwe nowotwory w MPNST związanych z NF1.³³

Niestabilność genomowa jest kolejną wyraźną cechą złośliwości, obejmującą rozległe zyski, straty i rearanżacje chromosomowe, które prowadzą do znaczących zmian w liczbie kopii DNA i ekspresji genów.³⁴ Częste straty chromosomowe w MPNST obejmują regiony takie jak 1p, 9p, 11, 12p, 14q i 22q, podczas gdy zyski są powszechnie obserwowane w regionach obejmujących chromosom 7, 8q, 9q, 13q, 15q i 17q.³⁵

Zgodnie z utratą funkcji NF1, ogniskowa delecja genu NF1 jest powszechnie wykrywana w MPNST. Utrata regionu 9p, gdzie znajduje się gen CDKN2A, jest również częstym zjawiskiem w MPNST, co dodatkowo potwierdza, że utrata CDKN2A jest czynnikiem napędzającym transformację.³⁶

Przypadek Nowotworów Hybrydowych Osłonek Nerwów Obwodowych

Hybrydowe nowotwory osłonek nerwów obwodowych (hybrid PNSTs) zostały niedawno rozpoznane i zostały po raz pierwszy uwzględnione w 4. edycji klasyfikacji Światowej Organizacji Zdrowia (WHO) dotyczącej guzów tkanek miękkich i kości, opublikowanej w 2013 roku.³⁷

Hybrydowe PNST są odrębnymi nowotworami i zwykle są łagodne. Jednak rzadkie doniesienia opisywały miejscowe nawroty, a co najmniej dwa niedawne raporty opisały transformację złośliwą w tych guzach.³⁸

Nawet dzisiaj dokładna patogenetyczna podstawa podwójnego (lub nawet potrójnego) różnicowania w hybrydowych PNST jest słabo zrozumiała, a to czy takie hybrydowe różnicowanie wynika z klonalnej zmiany genetycznej czy z lokalizowanej zmiany w mikrośrodowisku, nie jest znane.³⁹

Status hybrydowych PNST jako odrębnych jednostek został uznany przez WHO i uwzględniony w 4. edycji klasyfikacji WHO nowotworów tkanek miękkich i kości. Konieczne są jednak dalsze badania w celu określenia statusu hybrydowych PNST jako odrębnych jednostek oraz ustalenia dokładnej patogenetycznej podstawy hybrydowego różnicowania w PNST.⁴⁰

Implikacje Kliniczne Patogenezy

Zrozumienie patogenezy łagodnych nowotworów nerwów obwodowych ma kluczowe znaczenie dla ich właściwego leczenia. Całkowita resekcja schwannoma jest standardem opieki i jest możliwa bez utraty funkcji.⁴¹ Zachowanie funkcji musi być podstawowym celem operacji, zwłaszcza jeśli te łagodne guzy nie spowodowały żadnych deficytów neurologicznych przed operacją.⁴²

Leczenie przez doświadczonego chirurga nerwowego wykazało znacznie niższe wskaźniki niewłaściwego leczenia w porównaniu z leczeniem przez innych specjalistów.⁴³ W przypadku podejrzenia łagodnych nowotworów osłonek nerwów obwodowych ryzyko biopsji (np. nowy/pogarszający się ból neuropatyczny lub upośledzenie czuciowe/ruchowe) przewyższa korzyści z biopsji.⁴⁴

W przypadku pacjentów z NF1, którzy są narażeni na wyższe ryzyko nowotworów złośliwych, resekcja chirurgiczna i potwierdzenie patologiczne są bardzo ważne w leczeniu objawowych lub rosnących guzów.⁴⁵ Ze względu na możliwość złośliwej zmiany, wykrycie i leczenie atypowego nerwiakowłókniaka jest istotne u pacjentów z NF1.⁴⁶

Śmiertelność pacjentów z NF1 jest głównie spowodowana rozwojem złośliwych nowotworów osłonek nerwów obwodowych (MPNST), które mogą powstawać z transformacji łagodnych zmian pleksusowych nerwiakowłókniaków.⁴⁷ Całkowita resekcja zmian przednowotworowych może znacznie zmniejszyć nawroty i śmiertelność pacjentów.⁴⁸

Innowacyjne podejścia terapeutyczne

Szczegółowe zrozumienie molekularnej patogenezy nowotworów nerwów obwodowych dostarcza informacji niezbędnych do stworzenia nowej generacji terapii dostosowanych specjalnie do zapobiegania, zatrzymania lub odwrócenia stanów patologicznych na fundamentalnym poziomie dysfunkcji.⁴⁹

Badania nad szlakami molekularnymi zaangażowanymi w PNST, szczególnie MPNST, przyspieszyły eksplorację leków celowanych.⁵⁰ Pojawiające się dowody sugerują, że podejścia immunomodulacyjne lub inne leczenie ukierunkowane molekularnie mogą przynieść korzyści w podgrupie agresywnych MPNST, chociaż pozostają one eksperymentalne.⁵¹

Wykazano, że imatynib mezylat hamuje PDGF-BB-indukowaną inwazję i proliferację komórek MPNST poprzez hamowanie fosforylacji PDGFR-α. Skuteczność imatynibu mezylatu in vitro sugeruje, że celowanie w PDGFR-α może doprowadzić do ustanowienia nowych metod leczenia MPNST.⁵²

Łączne zastosowanie różnych technologii obrazowania, takich jak FDG-PET/CT i MRI, znacznie poprawiło wykrywanie MPNST. Konieczne są jednak dalsze badania i ulepszenia technologii, aby dokładnie odróżnić MPNST, atypowy neurofibroma i pleksusowy neurofibroma od tego samego pacjenta oraz odróżnić zmiany przednowotworowe i złośliwe we wczesnym stadium.⁵³

Obecnie innowacje w terapii celowanej, diagnostyce molekularnej i podejściach radiacyjnych są obiecujące dla poprawy wyników w tych rzadkich, ale złożonych nowotworach.⁵⁴

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Materiały źródłowe

#1 Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge
https://pmc.ncbi.nlm.nih.gov/articles/PMC10439084/
A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. […] A benign peripheral nerve sheath tumor (bPNST) is a rare lesion of neuroectodermal origin, directly associated with peripheral nerve structures. […] For the first time, our data shows the quantity and impact of incorrect initial diagnosis in bPNST causing a delay in causative treatment or resulting in unnecessary or potentially harmful treatment. […] A bPNST is a lesion directly associated with peripheral nervous structures and of neuroectodermal origin. […] A nervous origin might not be assumed at first due to its rarity, leading to treatment under a suspected different diagnosis. Consequently, misdiagnosis and resulting suboptimal or insufficient treatment with possible severe complications might occur.
#2
https://link.springer.com/article/10.1007/s10143-023-02107-z
A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. […] The most common bPNSTs are schwannomas and neurofibromas. Their localization can cause various symptoms such as local swelling, motor deficits, hypoesthesia, and neuropathic pain due to the ongoing pressure on the unaffected nerve fascicles or the loss of function of the affected fascicles themselves. […] A misdiagnosis occurred, if the final diagnosis was inconsistent with the diagnosis which was set up by the doctor who treated the patient at first. […] For the first time, our study presents data on rates of initial misdiagnosis and mistreatment in patients with bPNST. In our series, 44.7% of patients with sporadic bPNST presenting to our specialized institution had an initial misdiagnosis that led to inappropriate surgical treatment in most of these patients (71.1%).
#3 Benign peripheral nerve tumor | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/benign-peripheral-nerve-tumor?content_id=CON-20341913
Benign peripheral nerve tumors are tumors that form on peripheral nerves. The peripheral nerves link the brain and spinal cord to other parts of the body. These nerves control muscles that allow you to walk, blink, swallow, pick things up and do other activities. Benign tumors are not cancerous. […] Several different types of tumors may form on the peripheral nerves. While some are caused by genetics, the cause of these tumors is usually not known. […] The cause of benign peripheral nerve tumors usually isn’t known. Some are passed down in families.
#4
https://link.springer.com/article/10.1007/s10143-023-02107-z
A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. […] The most common bPNSTs are schwannomas and neurofibromas. Their localization can cause various symptoms such as local swelling, motor deficits, hypoesthesia, and neuropathic pain due to the ongoing pressure on the unaffected nerve fascicles or the loss of function of the affected fascicles themselves. […] A misdiagnosis occurred, if the final diagnosis was inconsistent with the diagnosis which was set up by the doctor who treated the patient at first. […] For the first time, our study presents data on rates of initial misdiagnosis and mistreatment in patients with bPNST. In our series, 44.7% of patients with sporadic bPNST presenting to our specialized institution had an initial misdiagnosis that led to inappropriate surgical treatment in most of these patients (71.1%).
#5
https://link.springer.com/article/10.1007/s10143-023-02107-z
A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. […] The most common bPNSTs are schwannomas and neurofibromas. Their localization can cause various symptoms such as local swelling, motor deficits, hypoesthesia, and neuropathic pain due to the ongoing pressure on the unaffected nerve fascicles or the loss of function of the affected fascicles themselves. […] A misdiagnosis occurred, if the final diagnosis was inconsistent with the diagnosis which was set up by the doctor who treated the patient at first. […] For the first time, our study presents data on rates of initial misdiagnosis and mistreatment in patients with bPNST. In our series, 44.7% of patients with sporadic bPNST presenting to our specialized institution had an initial misdiagnosis that led to inappropriate surgical treatment in most of these patients (71.1%).
#6 Nerve sheath tumor – Wikipedia
https://en.wikipedia.org/wiki/Nerve_sheath_tumor
The primary Schwann cell differentiation and neoplastic proliferations are characteristics of peripheral nerve sheath tumors. […] For instance, the Schwann cell, which is the major neoplastic cell component of neurofibroma, is cytologically distinguished by the expression of S-100 protein and wavy nuclear outlines. […] A variety of peripheral nerve cells, including axons, perineurial cells, fibroblasts, and varying inflammatory components such as mast cells and lymphocytes, are also present in neurofibromas. […] A population of CD34-positive cells with an unknown histogenesis is also found.
#7 Nerve sheath tumor – Wikipedia
https://en.wikipedia.org/wiki/Nerve_sheath_tumor
The primary Schwann cell differentiation and neoplastic proliferations are characteristics of peripheral nerve sheath tumors. […] For instance, the Schwann cell, which is the major neoplastic cell component of neurofibroma, is cytologically distinguished by the expression of S-100 protein and wavy nuclear outlines. […] A variety of peripheral nerve cells, including axons, perineurial cells, fibroblasts, and varying inflammatory components such as mast cells and lymphocytes, are also present in neurofibromas. […] A population of CD34-positive cells with an unknown histogenesis is also found.
#8 Nerve sheath tumor – Wikipedia
https://en.wikipedia.org/wiki/Nerve_sheath_tumor
The primary Schwann cell differentiation and neoplastic proliferations are characteristics of peripheral nerve sheath tumors. […] For instance, the Schwann cell, which is the major neoplastic cell component of neurofibroma, is cytologically distinguished by the expression of S-100 protein and wavy nuclear outlines. […] A variety of peripheral nerve cells, including axons, perineurial cells, fibroblasts, and varying inflammatory components such as mast cells and lymphocytes, are also present in neurofibromas. […] A population of CD34-positive cells with an unknown histogenesis is also found.
#9 Schwannoma – Overview – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/schwannoma/cdc-20352974
Benign tumors can occur in nerves, muscle and bone. This illustration shows a schwannoma of the tibial nerve in the leg. […] A schwannoma is a type of nerve tumor of the nerve sheath. It’s the most common type of benign peripheral nerve tumor in adults. It can occur anywhere in your body, at any age. […] A schwannoma typically comes from a single bundle (fascicle) within the main nerve and displaces the rest of the nerve. When a schwannoma grows larger, more fascicles are affected, making removal more difficult. In general, a schwannoma grows slowly. […] Schwannomas are rarely cancerous, but they can lead to nerve damage and loss of muscle control.
#10 Case Report of Schwannomas: Benign Tumour of the Peripheral Nerve Sheath – European Medical Journal
https://www.emjreviews.com/neurology/article/case-report-of-schwannomas-benign-tumour-of-the-peripheral-nerve-sheath/
Schwannomas, also known as neurilemmomas, are benign peripheral nerve sheath tumours arising from the Schwann cells surrounding the nerve. […] Malignant transformation of schwannomas is extremely rare. […] Schwannomas or neurilemmomas are well-encapsulated, lobulated lesions without metastatic potential, particularly if they are located in the extremities. The lesions are mostly solitary, slow-growing, painless tumours and malignant transformation is a rare event. […] Schwannomas do not transverse through the nerve but remain in the sheath, unlike neurofibromas. […] The aim of treatment is total excision of the lesion without causing nerve damage that may lead to sensorimotor deficit. […] In these cases, good magnification and good microsurgical technique under tourniquet control was extremely important to achieve this goal.
#11 Nerve Sheath Tumors: Definition & Types
https://my.clevelandclinic.org/health/diseases/22526-nerve-sheath-tumors
Genetic changes play an important role in the development of nerve sheath tumors. Alteration of the NF2 gene is linked to schwannomas, while the NF1 gene is associated with neurofibromas. […] Most often, these genetic changes are sporadic and happen randomly. A small fraction of schwannomas and neurofibromas are caused by a rare, genetic disease that runs in families called neurofibromatosis. […] Malignant peripheral nerve sheath tumors have a poor prognosis, especially if the tumor is larger than 2 inches. Fewer than half of people with this condition live five years after diagnosis.
#12 Nerve Sheath Tumors: Definition & Types
https://my.clevelandclinic.org/health/diseases/22526-nerve-sheath-tumors
Genetic changes play an important role in the development of nerve sheath tumors. Alteration of the NF2 gene is linked to schwannomas, while the NF1 gene is associated with neurofibromas. […] Most often, these genetic changes are sporadic and happen randomly. A small fraction of schwannomas and neurofibromas are caused by a rare, genetic disease that runs in families called neurofibromatosis. […] Malignant peripheral nerve sheath tumors have a poor prognosis, especially if the tumor is larger than 2 inches. Fewer than half of people with this condition live five years after diagnosis.
#13 Schwannoma: What It Is, Causes, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/17877-schwannoma
A schwannoma is a tumor that develops from Schwann cells in your peripheral nervous system or nerve roots. Theyre almost always benign and slow-growing. […] Schwannomas are almost always benign (noncancerous) but can sometimes be malignant (cancerous). Theyre usually slow-growing. […] The cause of schwannomas isnt known in most cases. Approximately 90% of cases occur sporadically (randomly). […] Genetic studies show that the NF2 gene on chromosome 22 plays an essential role in schwannoma development. […] Malignant (cancerous) schwannomas may be treated with immunotherapy and chemotherapy medications as well.
#14 Pathology Outlines – Schwannoma
https://www.pathologyoutlines.com/topic/softtissueschwannoma.html
Benign nerve sheath tumor arising from differentiated Schwann cells […] May occur spontaneously […] Can occur in familial tumor syndromes, such as neurofibromatosis type 2 (NF2), schwannomatosis or Carney complex […] Loss of function of the tumor suppressor gene merlin (schwannomin) […] Direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation […] Can occur in NF2 and spontaneous schwannomas […] Can cause other neoplasms including meningioma, mesothelioma, glioma multiforme and carcinomas of breast, colon and rectum, kidney (clear cell type), liver, prostate and skin […] Merlin acts as a tumor suppressor gene […] Overexpression can hinder cell proliferation and the changes induced by oncogenes […] Its downregulation leads to neoplastic transformation […] Mutations affecting SMARCB1 have a role in the pathogenesis of a small subset of spinal schwannomas and biallelic inactivation of SMARCB1 may cooperate with deficiency of NF2 function.
#15 Pathology Outlines – Schwannoma
https://www.pathologyoutlines.com/topic/softtissueschwannoma.html
Benign nerve sheath tumor arising from differentiated Schwann cells […] May occur spontaneously […] Can occur in familial tumor syndromes, such as neurofibromatosis type 2 (NF2), schwannomatosis or Carney complex […] Loss of function of the tumor suppressor gene merlin (schwannomin) […] Direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation […] Can occur in NF2 and spontaneous schwannomas […] Can cause other neoplasms including meningioma, mesothelioma, glioma multiforme and carcinomas of breast, colon and rectum, kidney (clear cell type), liver, prostate and skin […] Merlin acts as a tumor suppressor gene […] Overexpression can hinder cell proliferation and the changes induced by oncogenes […] Its downregulation leads to neoplastic transformation […] Mutations affecting SMARCB1 have a role in the pathogenesis of a small subset of spinal schwannomas and biallelic inactivation of SMARCB1 may cooperate with deficiency of NF2 function.
#16 Pathology Outlines – Schwannoma
https://www.pathologyoutlines.com/topic/softtissueschwannoma.html
Benign nerve sheath tumor arising from differentiated Schwann cells […] May occur spontaneously […] Can occur in familial tumor syndromes, such as neurofibromatosis type 2 (NF2), schwannomatosis or Carney complex […] Loss of function of the tumor suppressor gene merlin (schwannomin) […] Direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation […] Can occur in NF2 and spontaneous schwannomas […] Can cause other neoplasms including meningioma, mesothelioma, glioma multiforme and carcinomas of breast, colon and rectum, kidney (clear cell type), liver, prostate and skin […] Merlin acts as a tumor suppressor gene […] Overexpression can hinder cell proliferation and the changes induced by oncogenes […] Its downregulation leads to neoplastic transformation […] Mutations affecting SMARCB1 have a role in the pathogenesis of a small subset of spinal schwannomas and biallelic inactivation of SMARCB1 may cooperate with deficiency of NF2 function.
#17 Pathology Outlines – Schwannoma
https://www.pathologyoutlines.com/topic/softtissueschwannoma.html
Benign nerve sheath tumor arising from differentiated Schwann cells […] May occur spontaneously […] Can occur in familial tumor syndromes, such as neurofibromatosis type 2 (NF2), schwannomatosis or Carney complex […] Loss of function of the tumor suppressor gene merlin (schwannomin) […] Direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation […] Can occur in NF2 and spontaneous schwannomas […] Can cause other neoplasms including meningioma, mesothelioma, glioma multiforme and carcinomas of breast, colon and rectum, kidney (clear cell type), liver, prostate and skin […] Merlin acts as a tumor suppressor gene […] Overexpression can hinder cell proliferation and the changes induced by oncogenes […] Its downregulation leads to neoplastic transformation […] Mutations affecting SMARCB1 have a role in the pathogenesis of a small subset of spinal schwannomas and biallelic inactivation of SMARCB1 may cooperate with deficiency of NF2 function.
#18 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#19 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#20 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#21 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#22 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#23 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#24 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#25 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
The NF1 syndrome is the consequence of mutations in NF1 tumor suppressor gene on chromosome 17q11. More than 500 mutations have been identified, with the majority resulting in a loss of function of the neurofibromin protein, which is encoded by the NF1 gene. Neurofibromin is highly expressed in numerous organs, but is mostly abundant in the brain tissue, spinal cord, and peripheral nervous system. A variation in a single germline allele is sufficient to cause the NF1 syndrome, but according to Knudson’s 2-hit hypothesis, tumor formation appears to require the loss of function of a second allele. Neurofibromin also participates in the regulation of histogenesis, and cellular maintenance or repair. Accordingly, NF1 is a disorder of not only tumor predisposition, but also of dysplasia. […] Neurofibromin is a protein that accelerates the intrinsic hydrolysis of Ras from its GTP- to inactive GDP-bound conformation. In healthy cells, Ras is in the inactive conformation and is responsible for correct proliferation, transformation, differentiation, and apoptosis. Upon NF1 inactivation, Ras hyperactivity and the consequent activation of various downstream proliferative and survival pathways, like the mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), or AKT (Mouse breed AK thymoma, termed protein kinase B, or PKB) pathways are observed. Hence, by accelerating the conversion of Ras-GTP to Ras-GDP, neurofibromin negatively regulates Ras-dependent signaling cascades. In the pathophysiology of NF1, when neurofibromin is defective, Ras-GTP is constantly activated, which results in unrestrained stimulation of various pro-growth pathways.
#26
https://journals.lww.com/jpat/fulltext/2022/26040/an_update_on_oral_peripheral_nerve_sheath_tumors.20.aspx
For malignant progression, additional pathways gets activated due to heterogenicity loss of NF1 locus which are SCF, PI3K/mTOR, P-TEN and MAPK pathways. These eventually lead to disorder of epigenetic regulation, mitosis and angiogenesis causing aggressive growth of tumor cells. […] NF 1 inactivation and loss of NF expression characterize majority of malignant transformation but bi-allelic NF 1 loss is insufficient for malignant transformation. Generally, conditional NF1 gene inactivation in Schwann cell will result in plexiform development of neurofibroma based on this concept. […] Aberrant change in pathways due to genetic or epigenetic alteration is a common cause of cell transformation, cancer development and metastasis, and RTKs play critical roles in development/regulation stemness and proliferation. Genetic alteration that activates RTKs or component of downstream pathway such as MAPK, PI3K/AKT and JAK/STAT have been identified in progression to malignant nerve sheath tumor.
#27 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
Biallelic loss of neurofibromin is responsible for the development of PNSTs in patients with NF1 syndrome. However, the pathway to tumorigenesis is distinctly more complicated; NF1 mutations are probably not sufficient to induce neoplastic change. Murine experiments have also shown the significance of haploinsufficient NF1-mast cells for accelerating PNF growth. In addition to Ras activation, maturation, recruitment and proliferation of mast cells have been demonstrated to be mediated by the stem cell factor (SCF), the ligand for the KIT receptor tyrosine kinase (RTK), suggesting SCF/KIT-dependent tumorigenic tumor-stromal interactions in PNFs. The next molecular pathway leading from benign lesion to MPNST in NF1 syndrome remains uncertain. Figure 1 depicts the multiple major nodes engaged in the pathogenesis of MPNSTs, involving angiogenesis, intracellular signaling pathways, and interactions with the environment of the tumor.
#28 New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1817
Biallelic loss of neurofibromin is responsible for the development of PNSTs in patients with NF1 syndrome. However, the pathway to tumorigenesis is distinctly more complicated; NF1 mutations are probably not sufficient to induce neoplastic change. Murine experiments have also shown the significance of haploinsufficient NF1-mast cells for accelerating PNF growth. In addition to Ras activation, maturation, recruitment and proliferation of mast cells have been demonstrated to be mediated by the stem cell factor (SCF), the ligand for the KIT receptor tyrosine kinase (RTK), suggesting SCF/KIT-dependent tumorigenic tumor-stromal interactions in PNFs. The next molecular pathway leading from benign lesion to MPNST in NF1 syndrome remains uncertain. Figure 1 depicts the multiple major nodes engaged in the pathogenesis of MPNSTs, involving angiogenesis, intracellular signaling pathways, and interactions with the environment of the tumor.
#29
https://journals.lww.com/jpat/fulltext/2022/26040/an_update_on_oral_peripheral_nerve_sheath_tumors.20.aspx
For malignant progression, additional pathways gets activated due to heterogenicity loss of NF1 locus which are SCF, PI3K/mTOR, P-TEN and MAPK pathways. These eventually lead to disorder of epigenetic regulation, mitosis and angiogenesis causing aggressive growth of tumor cells. […] NF 1 inactivation and loss of NF expression characterize majority of malignant transformation but bi-allelic NF 1 loss is insufficient for malignant transformation. Generally, conditional NF1 gene inactivation in Schwann cell will result in plexiform development of neurofibroma based on this concept. […] Aberrant change in pathways due to genetic or epigenetic alteration is a common cause of cell transformation, cancer development and metastasis, and RTKs play critical roles in development/regulation stemness and proliferation. Genetic alteration that activates RTKs or component of downstream pathway such as MAPK, PI3K/AKT and JAK/STAT have been identified in progression to malignant nerve sheath tumor.
#30
https://journals.lww.com/jpat/fulltext/2022/26040/an_update_on_oral_peripheral_nerve_sheath_tumors.20.aspx
The RAS/RAF genes are the proto-oncogenes characterized by signal transduction in cell biology. The main function of these pathway is to transduce signals from extracellular structure (cell surface receptor) into intrinsic nucleus of cell that drives broad spectrum of physiological and pathological cellular processes such as growth, proliferation, differentiation, migration and apoptosis. Proper activation of these gene level helps in cell growth with appropriate apoptosis and it also able to stimulate the angiogenesis for formation of new blood vessels. But overactivation of RAS due to genetic or somatic mutation of NF1 leads to activation of various pathway such as serine/threonine, ERK1, ERK2 phosphorylate and MEK pathway and stimulate downstream effectors and regulate different transcription factors like neurotropic factor (NT3, Ciliary neurotrophic factor and leukemia inhibitory factor) leads to expression of gene that stimulate proliferation. Thus, the initial formation of tumor growth occurs but activation of these pathway alone will not lead to malignant progression.
#31
https://link.springer.com/article/10.1007/s13402-025-01054-9
The transformation of PN to MPNSTs involves a series of gene mutations and molecular mechanisms. […] The NF1 gene is located on chromosome 17 and encodes neurofibromin, a protein that negatively regulates the RAS (Rat sarcoma virus) signaling pathway. […] Other than the mutated NF1 gene, only rare and non-recurrent genetic mutations are identified in benign neurofibromas including DN and PN. […] The sequential accumulation of genetic alterations, beginning with NF1 mutations, followed by CDKN2A loss or inactivation, and other molecular changes, collectively drive the progression of neurofibromas to malignant tumors. […] Mechanically, the CDKN2A gene encodes two important cell cycle inhibitory proteins (p16/INK4a and p14/ARF). […] Current evidence indicates that mutations in these genes follow a specific order to drive the benign PNs to the malignancy in NF1-associated MPNSTs.
#32
https://link.springer.com/article/10.1007/s13402-025-01054-9
The transformation of PN to MPNSTs involves a series of gene mutations and molecular mechanisms. […] The NF1 gene is located on chromosome 17 and encodes neurofibromin, a protein that negatively regulates the RAS (Rat sarcoma virus) signaling pathway. […] Other than the mutated NF1 gene, only rare and non-recurrent genetic mutations are identified in benign neurofibromas including DN and PN. […] The sequential accumulation of genetic alterations, beginning with NF1 mutations, followed by CDKN2A loss or inactivation, and other molecular changes, collectively drive the progression of neurofibromas to malignant tumors. […] Mechanically, the CDKN2A gene encodes two important cell cycle inhibitory proteins (p16/INK4a and p14/ARF). […] Current evidence indicates that mutations in these genes follow a specific order to drive the benign PNs to the malignancy in NF1-associated MPNSTs.
#33
https://link.springer.com/article/10.1007/s13402-025-01054-9
The transformation of PN to MPNSTs involves a series of gene mutations and molecular mechanisms. […] The NF1 gene is located on chromosome 17 and encodes neurofibromin, a protein that negatively regulates the RAS (Rat sarcoma virus) signaling pathway. […] Other than the mutated NF1 gene, only rare and non-recurrent genetic mutations are identified in benign neurofibromas including DN and PN. […] The sequential accumulation of genetic alterations, beginning with NF1 mutations, followed by CDKN2A loss or inactivation, and other molecular changes, collectively drive the progression of neurofibromas to malignant tumors. […] Mechanically, the CDKN2A gene encodes two important cell cycle inhibitory proteins (p16/INK4a and p14/ARF). […] Current evidence indicates that mutations in these genes follow a specific order to drive the benign PNs to the malignancy in NF1-associated MPNSTs.
#34
https://link.springer.com/article/10.1007/s13402-025-01054-9
Genomic instability is another prominent feature of the malignancy, involving extensive chromosomal gains, losses, and rearrangements, that lead to significant changes in DNA copy number and gene expression. […] Frequent chromosomal losses in MPNSTs include regions such as 1p, 9p, 11, 12p, 14q, and 22q, while gains are commonly seen in regions including chromosome 7, 8q, 9q, 13q, 15q, and 17q. […] Consistent with NF1 loss of function, focal deletion of the NF1 gene is commonly detected in the MPNST. […] The loss of the 9p region, where the CDKN2A gene is located, is also a common event in MPNSTs, further supporting that the loss of CDKN2A is a driver of transformation. […] In both sporadic and NF1-associated MPNSTs, NF1 gene loss of function mutations and activation of the RAS signaling are identified.
#35
https://link.springer.com/article/10.1007/s13402-025-01054-9
Genomic instability is another prominent feature of the malignancy, involving extensive chromosomal gains, losses, and rearrangements, that lead to significant changes in DNA copy number and gene expression. […] Frequent chromosomal losses in MPNSTs include regions such as 1p, 9p, 11, 12p, 14q, and 22q, while gains are commonly seen in regions including chromosome 7, 8q, 9q, 13q, 15q, and 17q. […] Consistent with NF1 loss of function, focal deletion of the NF1 gene is commonly detected in the MPNST. […] The loss of the 9p region, where the CDKN2A gene is located, is also a common event in MPNSTs, further supporting that the loss of CDKN2A is a driver of transformation. […] In both sporadic and NF1-associated MPNSTs, NF1 gene loss of function mutations and activation of the RAS signaling are identified.
#36
https://link.springer.com/article/10.1007/s13402-025-01054-9
Genomic instability is another prominent feature of the malignancy, involving extensive chromosomal gains, losses, and rearrangements, that lead to significant changes in DNA copy number and gene expression. […] Frequent chromosomal losses in MPNSTs include regions such as 1p, 9p, 11, 12p, 14q, and 22q, while gains are commonly seen in regions including chromosome 7, 8q, 9q, 13q, 15q, and 17q. […] Consistent with NF1 loss of function, focal deletion of the NF1 gene is commonly detected in the MPNST. […] The loss of the 9p region, where the CDKN2A gene is located, is also a common event in MPNSTs, further supporting that the loss of CDKN2A is a driver of transformation. […] In both sporadic and NF1-associated MPNSTs, NF1 gene loss of function mutations and activation of the RAS signaling are identified.
#37 Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3350-1
Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. […] Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors. […] Even today the exact pathogenetic basis of dual (or even triple) differentiation in hybrid PNSTs is poorly understood and whether such hybrid differentiation results from a clonal genetic alteration or from a localized change in the microenvironment is not known.
#38 Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3350-1
Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. […] Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors. […] Even today the exact pathogenetic basis of dual (or even triple) differentiation in hybrid PNSTs is poorly understood and whether such hybrid differentiation results from a clonal genetic alteration or from a localized change in the microenvironment is not known.
#39 Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3350-1
Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. […] Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors. […] Even today the exact pathogenetic basis of dual (or even triple) differentiation in hybrid PNSTs is poorly understood and whether such hybrid differentiation results from a clonal genetic alteration or from a localized change in the microenvironment is not known.
#40 Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3350-1
The status of hybrid PNSTs as distinct entities has been recognized by the WHO and included in the 4th edition of the WHO classification of tumors of soft tissue and bone. However, further studies are required to determine the status of hybrid PNSTs as distinct entities and to determine the exact pathogenetic basis of hybrid differentiation in PNSTs.
#41 Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge
https://pmc.ncbi.nlm.nih.gov/articles/PMC10439084/
Complete resection of schwannomas is standard of care and possible without loss of function. […] Preservation of function must be the primary goal of surgery, especially if these benign tumors have not caused any neurological deficits before surgery. […] Treatment by an experienced nerve surgeon showed significantly lower rates of mistreatment compared with treatment by other specialists.
#42 Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge
https://pmc.ncbi.nlm.nih.gov/articles/PMC10439084/
Complete resection of schwannomas is standard of care and possible without loss of function. […] Preservation of function must be the primary goal of surgery, especially if these benign tumors have not caused any neurological deficits before surgery. […] Treatment by an experienced nerve surgeon showed significantly lower rates of mistreatment compared with treatment by other specialists.
#43 Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge
https://pmc.ncbi.nlm.nih.gov/articles/PMC10439084/
Complete resection of schwannomas is standard of care and possible without loss of function. […] Preservation of function must be the primary goal of surgery, especially if these benign tumors have not caused any neurological deficits before surgery. […] Treatment by an experienced nerve surgeon showed significantly lower rates of mistreatment compared with treatment by other specialists.
#44 Peripheral nerve sheath tumor | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/peripheral-nerve-sheath-tumour-2?lang=us
Surgical resection is the treatment of choice, not only for diagnostic confirmation (i.e. histopathology) and also with curative intent. […] Pre-surgical biopsy of peripheral nerve sheath tumors (usually an ultrasound-guided core biopsy) is typically reserved for lesions with indeterminate or malignant clinical and/or radiological features; the risk of biopsy (e.g. new/worsening neuropathic pain or sensory/motor impairment) outweighs the benefit of biopsy in suspected benign peripheral nerve sheath tumors.
#45 Different Pathology of Peripheral Nerve Sheath Tumor in Neurofibromatosis Type 1: 3 Cases
https://www.thenerve.net/DOIx.php?id=10.21129/nerve.2021.7.2.92
Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that predisposes affected individuals to tumors. Neurofibroma is a benign peripheral nerve sheath tumor (PNST) that can transform into atypical neurofibroma, a premalignant tumor, or malignant PNST (MPNST). Because NF1 patients are at higher risk of malignancy, which is the most common cause of death, surgical resection and pathologic confirmation are very important to the treatment of symptomatic or growing tumors in NF1 patients. […] The incidence of MPNST is approximately 0.001% in the general population. The recurrence rate is approximately 40% to 65%, and metastasis is found in 16% to 39% of patients. The 5-year survival rate is approximately 25% to 42%. Factors related prognosis include tumor size, the extent of resection in surgery, and rate of mitosis. Total resection or wide tumor excision is considered appropriate because chemotherapy and radiotherapy tend to be ineffective.
#46 Different Pathology of Peripheral Nerve Sheath Tumor in Neurofibromatosis Type 1: 3 Cases
https://www.thenerve.net/DOIx.php?id=10.21129/nerve.2021.7.2.92
NF1 patients are at high risk of neoplastic disease; the overall risk of cancer in NF1 patients is 2.7 times higher and the risk of malignancy in 50-year-olds is approximately 20%. Also, approximately 50% of MPNSTs are related to NF1. In NF1 patients, MPNST is less rare than in the general population. The incidence is around 4.6% and the lifetime risk is 8% to 13%. Furthermore, the prognosis of MPNST with NF1 is poorer. […] Because of the possibility of malignant change, detection and treatment of atypical neurofibroma are important in NF1 patients. Serial MRI and 18F-fluorodeoxyglucose-positron emission tomography can be used for detection of atypical neurofibroma.
#47 Neural-crest Stem Cells and Malignant Peripheral Nerve Sheath Tumor (MPNST) | Zhu (Yuan) Lab | UT Southwestern, Dallas, Texas
https://labs.utsouthwestern.edu/zhu-yuan-lab/research/neural-crest-stem-cells-and-malignant-peripheral-nerve-sheath-tumor-mpnst
MPNST, a sarcoma arising from the neural-crest stem cell lineage in the peripheral nerve, is the leading cause of death for individuals with NF1. […] The presence of benign and premalignant lesions, namely, plexiform neurofibromas (PNF) and atypical neurofibroma (ANF), makes this cancer uniquely suitable for investigating the mechanisms underlying tumor initiation and progression from benign to malignant tumors, and more importantly, designing a preventive therapeutic strategy. […] Inactivation of NF1 drives benign PNF formation by abnormal activation of the RAS-mediated MEK-ERK/MAPK signaling pathway. […] Thus, the CDKN2A/ARF-MDM2-p53 regulatory axis is the major tumor suppressive pathway(s) that inhibits the malignant transformation of benign PNFs. […] In addition to the loss of NF1 and CDKN2A, more than half of MPNSTs also harbor additional oncogenic driver mutations, in components of the POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), most frequently SUZ12 or EED.
#48
https://link.springer.com/article/10.1007/s13402-025-01054-9
Almost all patients of Neurofibromatosis Type I (NF1) develop benign peripheral nerve tumors called neurofibromas, which are derived from neural crest Schwann cell lineage progenitors with biallelic NF1 gene mutations. […] In 813% of individuals with NF1, PN can transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of nerve soft tissue sarcoma that is the main cause of mortality of NF1 patients. […] During the progression from benign neurofibromas to malignancy, a variety of changes including tumor morphology, genetic mutations, expression of multiple signaling pathways-related proteins and genome instability gradually occur. […] However, full resection of the premalignant lesions can largely reduce the recurrence and mortality of patients. […] While there are no recurrent genetic mutations detected present in benign neurofibromas (except the NF1 gene mutation), MPNST has a diverse mutational spectrum including multiple gene mutations and DNA fragment deletions or duplications.
#49 Experimental therapeutic approaches to peripheral nerve tumors in: Neurosurgical Focus Volume 22 Issue 6 (2007) Journals
https://thejns.org/focus/view/journals/neurosurg-focus/22/6/foc.2007.22.6.3.xml
Discovery that the Schwann cell is the primary cell type responsible for both the neurofibroma as well as the schwannoma has proven to represent a crucial milestone in understanding the pathogenesis of peripheral nerve tumor development. […] Recent discoveries in the laboratory have clarified an understanding of the molecular mechanisms underlying the pathogenesis of benign peripheral nerve tumors. […] Similarly, the mechanisms whereby idiopathic and syndromic (NF1- and NF2-associated) nerve sheath tumors progress to malignancy are being elucidated. […] This detailed understanding of the molecular pathogenesis of peripheral nerve tumors provides the information necessary to create a new generation of therapies tailored specifically to the prevention, cessation, or reversal of pathological conditions at the fundamental level of dysfunction. […] The authors review the data that have helped to elucidate the molecular pathogenesis of this category of conditions, explore the current progress toward exploitation of these findings, and discuss potential therapeutic avenues for future research.
#50 PERIPHERAL NERVE TUMORS – Dr Prem Pillay
https://singaporebrain.org/en/nerves/peripheral-nerve-tumors/
Research into molecular pathways involved in PNSTs, especially MPNSTs, has propelled the exploration of targeted agents. […] Emerging evidence suggests that immunomodulatory approaches or other molecularly guided treatments may benefit a subset of aggressive MPNSTs, though these remain experimental. Clinical trials continue to assess efficacy. […] Peripheral nerve tumors, encompassing benign entities such as schwannomas and neurofibromas and malignant variants like MPNSTs, represent a diverse group requiring careful workup and multidisciplinary treatment. Accurate diagnosis via imaging and biopsy, alongside precision surgical techniques, can often lead to remission in benign lesions and offer the best chance for disease control in malignant ones. Meanwhile, current innovations in targeted therapy, molecular diagnostics, and radiation approaches hold promise for improving outcomes in these rare yet complex tumors.
#51 PERIPHERAL NERVE TUMORS – Dr Prem Pillay
https://singaporebrain.org/en/nerves/peripheral-nerve-tumors/
Research into molecular pathways involved in PNSTs, especially MPNSTs, has propelled the exploration of targeted agents. […] Emerging evidence suggests that immunomodulatory approaches or other molecularly guided treatments may benefit a subset of aggressive MPNSTs, though these remain experimental. Clinical trials continue to assess efficacy. […] Peripheral nerve tumors, encompassing benign entities such as schwannomas and neurofibromas and malignant variants like MPNSTs, represent a diverse group requiring careful workup and multidisciplinary treatment. Accurate diagnosis via imaging and biopsy, alongside precision surgical techniques, can often lead to remission in benign lesions and offer the best chance for disease control in malignant ones. Meanwhile, current innovations in targeted therapy, molecular diagnostics, and radiation approaches hold promise for improving outcomes in these rare yet complex tumors.
#52 Imatinib mesylate inhibits cell invasion of malignant peripheral nerve sheath tumor induced by platelet-derived growth factor-BB | Laboratory Investigation
https://www.nature.com/articles/3700591
Malignant peripheral nerve sheath tumor (MPNST) is an uncommon and highly progressive soft tissue tumor arising from either neurofibromatosis type 1 (NF1) or de novo from peripheral nerves, accounting for about 5% of malignant tumors of soft tissue. The overall 5- and 10-year survival rate were 34 and 22%, respectively. Overexpression of growth factors and/or their receptors is believed to play an important role in cellular transformation. However, their role in the pathogenesis of MPNST remains unclear. It was reported that PDGF-BB is mitogenic for two human MPNST cell lines, but not for a Schwann cell line derived from a schwannoma. Significantly high expression levels of both PDGF receptor (PDGFR)-Î± and -Î² were found in the two MPNST cell lines compared to non-NF1 Schwann cell lines. PDGF-BB induced higher levels of proliferation in MPNST cell lines than in normal human adult Schwann cells. The present study was designed to identify motogenic factor(s) involved in MPNST cell invasion and find effective inhibitor(s) of the invasive activity. PDGF-BB was identified as the most effective MPNST cell invasion-inducing factor. Our results indicated that PDGF-BB enhanced the invasive activity of MPNST cells through PDGFR phosphorylation and that imatinib inhibited such activity. This PDGF-BB-induced invasion was dependent on phosphorylation of PDGFR-Î± in MPNST cells and was effectively inhibited by imatinib mesylate. Expression of PDGFR-Î± was upregulated at both mRNA and protein levels in MPNST tissues compared with benign Schwannomas and neurofibromas. The mechanisms leading to tumorigenesis for MPNST remain unclear. However, it is considered that MPNST cells seem to acquire multiple genetic changes during their progression toward the malignant phenotype, which may be responsible for the aberrant expression of growth factor receptors or their responsiveness. PDGF-BB but not PDGF-AA stimulated MPNST cell invasion of Matrigel. This finding suggests the predominant involvement of PDGFR-Î± in this PDGF-BB-induced invasion process. Imatinib mesylate is a selective low-molecular-weight inhibitor of the PDGF receptor tyrosine kinase and inhibits both PDGF-AA and PDGF-BB-induced receptor phosphorylation. In our study, PDGFR-Î± phosphorylation was less inhibited by herbimycin A than by imatinib. In conclusion, our study has shown that imatinib mesylate inhibits PDGF-BB-induced invasion and proliferation of MPNST cells by suppressing phosphorylation of PDGFR-Î±. The effectiveness of imatinib mesylate in vitro suggests that targeting PDGFR-Î± may result in the establishment of novel treatments for MPNST.
#53
https://link.springer.com/article/10.1007/s13402-025-01054-9
The combined application of different imaging technologies, such as FDG-PET/CT and MRI, has greatly improved the detection of MPNST. […] However, further research and improvement of the technology are still needed to accurately distinguish the MPNST, ANF, and PN from the same patient and to distinguish the pre-malignant and malignancy lesions at an early stage.
#54 PERIPHERAL NERVE TUMORS – Dr Prem Pillay
https://singaporebrain.org/en/nerves/peripheral-nerve-tumors/
Research into molecular pathways involved in PNSTs, especially MPNSTs, has propelled the exploration of targeted agents. […] Emerging evidence suggests that immunomodulatory approaches or other molecularly guided treatments may benefit a subset of aggressive MPNSTs, though these remain experimental. Clinical trials continue to assess efficacy. […] Peripheral nerve tumors, encompassing benign entities such as schwannomas and neurofibromas and malignant variants like MPNSTs, represent a diverse group requiring careful workup and multidisciplinary treatment. Accurate diagnosis via imaging and biopsy, alongside precision surgical techniques, can often lead to remission in benign lesions and offer the best chance for disease control in malignant ones. Meanwhile, current innovations in targeted therapy, molecular diagnostics, and radiation approaches hold promise for improving outcomes in these rare yet complex tumors.