medulloblastoma SHH activated and TP53 wild-type

Medulloblastoma SHH Activated and TP53 Wild-Type: A Molecular Subtype

Medulloblastoma SHH activated and TP53 wild-type is a molecular subtype of medulloblastoma, a type of brain cancer that primarily affects children. This subtype is characterized by the activation of the sonic hedgehog (SHH) pathway and the absence of TP53 mutations.

Key Features:

• Activation of SHH Pathway: The SHH pathway plays a crucial role in the development and progression of medulloblastoma. In this subtype, the SHH pathway is activated, leading to the promotion of tumor growth.
• Absence of TP53 Mutations: Unlike other subtypes of medulloblastoma, TP53 mutations are not present in this subtype. TP53 is a tumor suppressor gene that helps regulate cell growth and division.
• Intermediate Risk Disease: Medulloblastoma SHH activated and TP53 wild-type is associated with intermediate risk disease, with a 5-year overall survival rate of around 76% [4].

Risk Stratification:

Medulloblastomas are classified into four subtypes based on their molecular characteristics:

• Standard Risk: Wild-type TP53, no MYCN amplification, and non-metastatic.
• High-Risk SHH MBs: Metastatic, have MYCN amplification, or have both [6].

Key Markers of Poor Prognosis:

In medulloblastoma SHH activated and TP53 wild-type tumors, key markers of poor prognosis include:

• MYCN Amplification
• GLI2 Amplification
• Chromosome 14q Loss [8]

These markers indicate a higher risk of tumor recurrence and poorer overall survival.

References: [1] [3] [4] [6] [7] [8]

Medulloblastoma, particularly the SHH (sonic hedgehog) activated and TP53 wild-type subtype, can exhibit a range of signs and symptoms due to its growth in the brain. Here are some possible indicators:

• Increased head circumference: This is often one of the earliest signs, as the tumor grows and puts pressure on the surrounding brain tissue.
• Bulging anterior fontanel: The increased intracranial pressure can cause the front part of the skull to bulge, leading to a visible indentation in the soft spot (fontanel) at the top of the head.
• Headache: As the tumor grows and puts pressure on the brain, it can cause headaches that may be severe or persistent.
• Irritability: Children with medulloblastoma may become irritable or restless due to the discomfort caused by the growing tumor.
• Nausea and vomiting: The increased intracranial pressure can also lead to nausea and vomiting.
• Papilledema: This is a condition where the optic disc (the part of the eye responsible for vision) becomes swollen, often due to increased pressure in the brain.

These symptoms are not unique to medulloblastoma and can be caused by other conditions. However, if you suspect that someone may have this type of tumor, it's essential to seek medical attention promptly.

References:

• [6] Such signs and symptoms include headache, irritability, nausea/vomiting, papilledema, and macrocephaly.
• [2] Increase in head circumference. On examination, there may be bulging of the anterior fontanel due to increased intracranial pressure and ...
• [10] Clinical manifestations are initially related to intracranial hypertension and to the tumor's mass effect in the posterior fossa, including headaches, nausea, ...

Medulloblastoma, specifically the SHH (sonic hedgehog) activated and TP53 wild-type subtype, requires a comprehensive diagnostic approach to confirm the diagnosis.

Histological Analysis A pathologist or neuropathologist should perform microscopic analysis (histology) of the primary tumor in the brain to confirm the diagnosis [8]. Ideally, the completely resected tumor should be examined by a pathologist to determine the histopathological features and molecular characteristics of the tumor.

Molecular Testing Testing for TP53 abnormalities, such as IHC or sequencing, has an important prognostic role in SHH medulloblastoma [2]. This testing should be routinely performed in tumors falling within this subgroup. Additionally, SUFU mutations can further subdivide this subgroup into different risk categories, particularly in infants (0-4 years) [4].

Other Diagnostic Tests While not specifically mentioned in the context provided, other diagnostic tests such as imaging studies and clinical evaluation are also essential for diagnosing medulloblastoma.

It's worth noting that the diagnosis of SHH activated and TP53 wild-type medulloblastoma is often made based on a combination of histological and molecular features. A multidisciplinary team approach involving pathologists, neuropathologists, and other specialists is typically required to confirm the diagnosis and determine the optimal treatment plan.

References: [1] Not applicable [2] by BA Orr · 2020 · Cited by 136 — Testing for TP53 abnormalities, by IHC or sequencing has important prognostic role in SHH MB and should be routinely performed in tumors falling ... [3] Not applicable [4] Sep 27, 2022 — SHH activation: This subgroup is further subdivided by presence of TP53 mutation and by age groups. For infants (0–4 years) the SUFU mutations ... [5] Not applicable [6] Not applicable [7] Not applicable [8] by RH Eibl · 2023 · Cited by 8 — A pathologist or neuropathologist needs to confirm the diagnosis of the primary tumor in the brain by microscopic analysis (histology). Ideally, the completely ... [9] Not applicable [10] Not applicable

Medulloblastoma, a type of brain cancer, can be classified into different subgroups based on the genetic mutations present in the tumor cells. One such subgroup is SHH-activated medulloblastoma, which accounts for approximately 60-70% of cases in adults and is characterized by the activation of the Sonic Hedgehog (SHH) signaling pathway.

Treatment Options

For patients with SHH-activated medulloblastoma who have wild-type TP53, several treatment options are available. These include:

• Targeted therapies: Inhibitors of the HH pathway, such as vismodegib and sonidegib, have shown promise in clinical trials for treating medulloblastoma. These drugs work by blocking the activity of the SHH signaling pathway, which is essential for tumor growth.
• Itraconazole: This antifungal medication has also been shown to inhibit Hh signaling in SMO-mutant models and may be a potential treatment option for patients with SHH-activated medulloblastoma.

Current Research

Research on the treatment of SHH-activated, TP53 wild-type medulloblastoma is ongoing. Studies have compared different treatment approaches, including intraventricular and oral administration of vismodegib, to evaluate their effectiveness in treating this type of cancer.

Prognosis

Unfortunately, patients with germline TP53-mutated medulloblastoma have a very poor prognosis, and there is currently no consensus on the best treatment approach for these individuals.

References:

• [2] by E Franceschi · 2021 · Cited by 18 — ... In adults, SHH-activated, TP53 wild-type medulloblastomas represent the most frequent type with ∼60%-70% of cases.
• [3] by H MAIER · 2021 · Cited by 29 — Summary and Conclusion​​ Currently, HH pathway inhibitors, already FDA-approved for treatment of other types of tumors, deliver promising clinical trials for the ...
• [8] by E Franceschi · 2021 · Cited by 18 — In adults, SHH-activated, TP53 wild-type medulloblastomas represent the most frequent type with ∼60%-70% of cases.
• [9] by L Gatto · 2022 · Cited by 9 — In a mouse model for SHH medulloblastoma, they have compared intraventricular and oral treatment with vismodegib, evaluating the effects on ...

Medulloblastoma, particularly the SHH-activated and TP53 wild-type subtype, can be challenging to diagnose differentially due to its overlapping features with other brain tumors. However, several key markers and characteristics can help in distinguishing it from other types of medulloblastomas.

• SHH-activated and TP53 wild-type tumors: These are associated with an intermediate risk disease, with a 5-year overall survival rate of around 76% [2]. Key markers of poor prognosis among these tumors include MYCN amplification, GLI2 amplification, chromosome 14q loss [4].
• Desmoplastic/nodular medulloblastoma: This subtype shares morphologic and IHC features with SHH-activated and TP53 wild-type tumors [5]. However, the presence of desmoplasia and nodules can help differentiate it from other subtypes.
• WNT-activated group: While this group is present in some classifications, SHH-activated tumors (TP53 wild type) are divided among four subgroups discovered in more recent studies [7].
• CGNPs and mutant Daoy cells: These cells demonstrate Chk1 signaling axis requirements but may no longer represent MB patients. Targeting Chk1 could be a potential therapeutic option, but its effectiveness is still being researched [8].

To make a differential diagnosis of medulloblastoma SHH-activated and TP53 wild-type, it's essential to consider the following:

• Histopathological examination: A thorough histopathological examination is crucial in identifying the characteristic features of SHH-activated and TP53 wild-type tumors.
• Immunohistochemistry (IHC): IHC can help identify specific markers such as MYCN, GLI2, and chromosome 14q loss, which are associated with poor prognosis in this subtype.
• Genetic analysis: Genetic analysis can confirm the presence of SHH activation and TP53 wild-type status.

It's worth noting that the differential diagnosis of medulloblastoma is complex and requires a multidisciplinary approach. A team of experts, including neuropathologists, neurosurgeons, and medical oncologists, should be involved in making an accurate diagnosis.

References:

[1] V Ramaswamy · 2016 [2] BA Orr · 2020 [4] JA Cotter · 2022 [5] The morphologic and IHC features of this tumor are consistent with desmoplastic/nodular medulloblastoma, SHH-activated and TP53 wild-type. [7] JS Rechberger · 2023 [8] LF McSwain · 2022