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SEOM Clinical Guideline for Management of Adult Medulloblastoma (2020)

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SEOM Clinical Guideline for Management of Adult Medulloblastoma (2020) Clinical and Translational Oncology https://doi.org/10.1007/s12094-021-02581-1 CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline for management of adult medulloblastoma (2020) R. Luque1 · M. Benavides2 · S. del Barco3 · L. Egaña4 · J. García‑Gómez5 · M. Martínez‑García6 · P. Pérez‑Segura7 · E. Pineda8 · J. M. Sepúlveda9 · M. Vieito10 Accepted: 2 March 2021 © The Author(s) 2021 Abstract Recent advances in molecular profling, have reclassifed medulloblastoma, an undiferentiated tumor of the posterior fossa, in at least four diseases, each one with diferences in prognosis, epidemiology and sensibility to diferent treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm 2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular fndings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients beneft from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered pal- liative and inclusion on clinical trials, focusing on the molecular alterations that defne each subgroup, should be encouraged. Selected patients can beneft from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of signifcant sequelae is common and patients must undergo lifelong follow-up. Keywords Medulloblastoma · Adults · Treatment * R. Luque 1 Department of Medical Oncology, Hospital Universitario [email protected] Virgen de Las Nieves, Granada, Spain M. Benavides 2 Department of Medical Oncology, Hospital Regional [email protected] Universitario Carlos Haya, Malaga, Spain S. del Barco 3 Department of Medical Oncology, Hospital Universitari [email protected] Dr. Josep Trueta. ICO Girona, Girona, Spain L. Egaña 4 Department of Medical Oncology, Hospital [email protected] Donostia-Donostia Ospitalea, San Sebastián, Spain J. García-Gómez 5 Department of Medical Oncology, Complexo Hospitalario de [email protected] Ourense (CHUO), Orense, Spain M. Martínez-García 6 Department of Medical Oncology, Hospital del Mar - Parc de [email protected] Salut Mar, Barcelona, Spain P. Pérez-Segura 7 Department of Medical Oncology, Hospital Universitario [email protected] Clínico San Carlos, Madrid, Spain E. Pineda 8 Department of Medical Oncology, Hospital Clinic I [email protected] Provincial de Barcelona, Barcelona, Spain J. M. Sepúlveda 9 Department of Medical Oncology, Hospital Universitario 12 [email protected] de Octubre, Madrid, Spain M. Vieito 10 Department of Medical Oncology, Hospital Universitario [email protected] Vall D’Hebron, Barcelona, Spain Vol.:(0123456789)1 3 Clinical and Translational Oncology Methodology following CSF pathways, it is classifed by WHO as grade IV tumor. This guideline has been developed based on the consensus The four long-established histological variants (classic, of ten medical oncologists, designated by the Spanish Soci- desmoplastic/nodular, extensive nodularity, large cell/ana- ety of Medical Oncology (SEOM) and the Spanish Neuro- plastic) have been more recently genetically defned in four Oncology Research Group (GEINO), with the purpose of diferent molecular which have divergent genetics, clinical reviewing and summarizing the available evidence regard- behavior, and patient outcomes and can be used for an inte- ing the management of meduloblastoma (MB), as well as grated diagnosis [2]. generating evidence-based statements on diagnostics and therapeutic strategies. To be in accordance with previous Epidemiology SEOM guidelines, the rating system for quality of the evi- dence (I–III) and strength of the recommendation (A–E) Consistently with its embryonal origin, MB is much more criteria are summarized in Table 1. common in childhood, and extremely rare (about 1% of pri- mary CNS tumors) in adults. The majority of medulloblastomas are sporadic but some Introduction cases might be traced to a hereditary cancer syndrome, namely Turcot, Li Fraumeni and Gorlin syndrome in SHH Among the more than 100 diferent types of primary cen- MB and familiar polyposis coloni in WNT MB [3]. tral nervous system (CNS) tumors, MB, sometimes referred Although MBs are potentially curable tumors by apply- as primitive neuroectodermal tumor of the posterior fossa ing a multimodal treatment approach, the survival is largely [1] is a subtype of embryonal tumor. Due to its high prolif- infuenced by age (adults worse), the extent of the disease, erative index and risk of metastatization thorough the CNS residual disease after resection and the molecular subtype. Table 1 Levels of evidence 1 3 Clinical and Translational Oncology Histology and molecular biology desmoplastic. TP53 mutations have been found in 10–20% of this subgroup and this molecular alteration has important As most embryonal tumors, MB displays difuse and high prognostic consequences since the fve-year overall survival cellularity. Cells are small, poor-diferentiated, round or rate is approximately 40% while the TP53wt SHH-activated oval, forming difuse masses or, sometimes well-defned MBs have a fve-year survival rate of 80%. SHH-activated nodes. Rossettes are typical structures of medulloblastomas MBs with TP53 mutations have a peak incidence in ado- and are characterized by groups of cells set in a circle with lescence while TP53wt SHH are more common in infants a fbrillary center. Although they typically remain undif- and adults. It is possible that in further classifcations SHH- ferentiated, some MBs contain cells with neuronal or glial activated MBs will be split within two independent groups diferentiation. depending on TP53. Immunohistochemical staining frequently demonstrates 3. Group 3: expression of neuronal markers, such as synaptophysin and This group is characterized by the presence of high-level enolase, and also embryonal or neuroepithelial markers, MYC amplifcation and signifcant genomic instability and such as nestin. Other immunohistochemistry studies are other alterations (see Table 2). This group (25% of MB) is important to diferentiate the subgroups, in fact, MB diag- very rare in adults, but not in children. Morphologically, nosis must integrate morphological and molecular features. most of the cases are large cell/anaplastic variant. The prog- The last WHO classifcation of the tumors of the CNS nosis is poor with frequent metastases at diagnosis and a (2016) diferentiates four sub-types[1] that are summarized 5-year survival rate of only 50% [5]. in Table 2: 4. Group 4: 1. WNT-activated medulloblastoma: This group comprises 35% of MBs and its main feature is This subgroup is the most uncommon type of MB and the amplifcation of both MYCN and cyclin-dependent kinase represents about 10% of cases. WNT-activated MBs are very 6 (CDK6) genes [6]. The histology uses to be the classic pat- rare in infants but can be seen in adults or children. tern. Group 4 tumors are more common in males with a peak The Wnt protein can deactivate the protein complex that incidence in adolescence. The prognosis is diferent in chil- eliminates Beta-catenin. The activation of this pathway turns dren and adults, while the prognosis is similar to the SHH into an accumulation of beta-catenin in the nucleus where it group in children, fve-year survival rate of 75%, in adults is acts as a transcription factor of proliferation genes, such as worse, even with the large cell/anaplastic morphology [1]. Cyclin D and c-myc. This subgroup of MB has the better prognosis in chil- dren, with a fve-year overall survival of 95%. In adults, Diagnosis and staging the prognosis is also good but the 5-year overall survival is below 95% [4]. The clinical symptoms and signs are associated with the 2. SHH-activated MB: location of the tumor in the posterior fossa, such as increased The sonic-hedgehog pathway is important in the prolifera- intracranial pressure, cerebellar dysfunction and/or obstruc- tion of the cerebellar Purkinje cells. SHH pathway activation tion of cerebrospinal fuid pathway. Symptoms evolve over is present in 30% of MBs and most of them are histologically a period of weeks to a few months. However, adult MB may Table 2 Molecular subgroups of MB according to WHO 2016 WNT-activated SHH-activated Group 3 Group 4 Gene expression and genetics WNT signaling SHH signaling: MYC amplifcation MYCN amplifcation CTNNB1 mutation PTCH11/SMO/SUFU mutation SMARCA4 mutation CDK6 amplifcation GLI2 amp OTX2 amplifcation TP53 mut GFI I enhancer activation MYCN amplifcation Demographics Children > Adults Infants and adults Infants > children Children Rarely in Infants Rarely in adults Possible in infants and adults More common in male More common in male Outcome Very good Infants: good Very poor Intermediate 5-year OS > 95% Others: Intermediate Adults: poor TP53mut worse prognosis Histology Classic Desmoplasic/nodular Classic Classic large cell/anaplastic Risk of metastases Low Low High High 1 3
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