medulloblastoma SHH activated

Medulloblastoma, SHH Activated Tumors

Medulloblastoma, sonic hedgehog (SHH) activated tumors are a type of malignant tumor that affects the central nervous system. They are the second most common subtype of medulloblastomas, making up about 27% of these tumors [3].

Characteristics and Symptoms

These tumors typically present as pink to gray, soft and friable masses arising in the cerebellar hemisphere or vermis [5]. The symptoms of SHH activated medulloblastoma can include:

• Headaches
• Nausea
• Weakness or numbness in the arms and/or legs
• A change in normal bowel or bladder habits [2]

Causes and Genetics

The sonic hedgehog (SHH) subtype is often caused by mutations of PTCH1 or SMO, which encode key components of the SHH signaling pathway [6]. These mutations can lead to an overactive SHH pathway, contributing to tumor development.

Prevalence and Distribution

SHH activated medulloblastomas show a bimodal distribution of presentation, with the first peak occurring in infants and a second peak in adults [4].

References:

• [1] Medulloblastoma, sonic hedgehog (SHH) activated tumors are malignant tumors of the central nervous system.
• [2] Symptoms can include headaches, nausea, weakness or numbness in the arms and/or legs, and changes in bowel or bladder habits.
• [3] The SHH subtype is the second most common subtype of medulloblastomas, making up about 27% of these tumors.
• [4] SHH activated medulloblastomas show a bimodal distribution of presentation, with peaks in infants and adults.
• [5] Tumors typically present as pink to gray, soft and friable masses arising in the cerebellar hemisphere or vermis.
• [6] Mutations of PTCH1 or SMO can lead to an overactive SHH pathway, contributing to tumor development.

Common Signs and Symptoms of Medulloblastoma (SHH Activated)

Medulloblastoma, a type of brain cancer, can exhibit various symptoms depending on the location and size of the tumor. In cases where the tumor is SHH-activated, the following signs and symptoms are commonly observed:

• Morning Headaches: A sudden and severe headache, often occurring in the morning, due to increased intracranial pressure [1].
• Nausea and Vomiting: Feeling extremely tired and experiencing nausea and vomiting, which may be worst in the morning [5].
• Loss of Balance and Coordination: Difficulty walking, stumbling, and falling due to problems with balance and coordination [3].
• Weakness or Numbness in Arms and/or Legs: Weakness or numbness in the arms and/or legs, indicating nerve damage caused by the tumor [1].
• Seizures: In some cases, seizures may occur as a result of the tumor's impact on brain function [6].

These symptoms can vary in severity and may not be present in all individuals with SHH-activated medulloblastoma. If you or someone you know is experiencing these symptoms, it is essential to seek medical attention promptly.

References: [1] Medulloblastoma: Diagnosis and Treatment; WNT-activated; SHH-activated [Context 1] [3] What are the symptoms of medulloblastoma? [Context 3] [5] Medulloblastoma symptoms [Context 5] [6] Symptoms of medulloblastoma [Context 6]

Medulloblastoma, specifically the SHH-activated subtype, can be diagnosed using various diagnostic tests. Here are some of the key tests used to diagnose this type of tumor:

• MRI with gadolinium contrast: This is the test of choice for initial evaluation of possible medulloblastoma [4][5]. MRI can obtain multiplanar images and provide detailed information about the tumor's location, size, and extent.
• Histological examination: A neuropathologist reviews a piece of tumor tissue to confirm the diagnosis. Histological analysis is essential to determine the tumor's grade and subtype [2].
• FISH testing: Fluorescence in situ hybridization (FISH) can be used to detect genetic abnormalities, such as MYC or MYCN amplification, which are associated with SHH-activated medulloblastoma [1].
• Molecular diagnostic tests: These tests can identify specific genetic mutations, such as PTCH1 and SMO, that are characteristic of SHH-activated medulloblastoma [6][13].

It's worth noting that the diagnosis of medulloblastoma, including the SHH-activated subtype, often involves a combination of these diagnostic tests. A comprehensive evaluation by a multidisciplinary team of healthcare professionals is essential to determine the best course of treatment.

References:

[1] Context result 1 [2] Context result 2 [4] Context result 4 [5] Context result 5 [6] Context result 6

Current Drug Treatments for Medulloblastoma with SHH Activation

Medulloblastoma, a type of brain cancer, can be classified into four subgroups based on the genetic alterations present in the tumor. The SHH (Sonic Hedgehog) subgroup is characterized by constitutive activation of the SHH pathway, leading to uncontrolled cell growth and tumor formation.

SHH Inhibitors

The most widely used drug treatment for SHH-activated medulloblastoma is vismodegib, an SMO (Smoothened) inhibitor. Vismodegib targets the SMO protein, which plays a crucial role in the SHH signaling pathway. By inhibiting SMO, vismodegib effectively blocks the SHH pathway, leading to tumor growth inhibition.

• Sonidegib: Another SMO inhibitor, sonidegib has also been shown to be effective against SHH-activated medulloblastoma.
• SMO mutations: However, resistance to these inhibitors often develops due to SMO mutations, which can render the treatment less effective.

Other Treatment Options

While vismodegib and sonidegib are the most widely used drugs for treating SHH-activated medulloblastoma, other treatment options may be considered based on individual patient needs. These include:

• Chemotherapy: Chemotherapy is often used in combination with radiation therapy to treat medulloblastoma.
• Targeted therapies: Targeted therapies, such as those targeting the VEGF pathway, may also be used in some cases.

Recent Advances

A newly identified component of the Sonic Hedgehog pathway offers another target for precision medicine for treatment of SHH medulloblastoma. This discovery provides new avenues for developing targeted therapies against this type of cancer.

References:

• [1] by A Samkari · 2015 · Cited by 61 — SHH inhibitors for the treatment of medulloblastoma
• [6] by H Slika · 2024 — Vismodegib, an SMO inhibitor, is the most widely used drug in SHH-activated medulloblastoma.
• [7] by Y Li · 2019 · Cited by 103 — Sonidegib and vismodegib were well tolerated and demonstrated anti-tumour activity in SHH-driven paediatric and adult MB
• [9] Nov 2, 2017 — A newly identified component of the Sonic Hedgehog pathway offers another target for precision medicine for treatment of SHH medulloblastoma

Medulloblastoma, particularly the SHH-activated subtype, can be challenging to differentiate from other brain tumors due to its overlapping clinical and histological features with other entities. Here are some key points to consider for differential diagnosis:

• Atypical aggressive meningioma: This type of tumor arises from the meningeal coverings of the brain and spinal cord. It is essential to rule out meningiomas, especially in cases where the SHH pathway is activated (see [7], [9]). Meningiomas can present with similar symptoms, such as headaches, nausea, and weakness or numbness in the arms and/or legs.
• Ependymoma: Ependymomas are a type of brain tumor that originates from the ependymal cells lining the ventricles and central canal. They can be distinguished from medulloblastoma by their strong expression of GFAP (glial fibrillary acidic protein) and synaptophysin immunohistochemistry markers (see [9]). Ependymomas may also show a different histological pattern, with a more uniform cell morphology.
• Classic medulloblastoma: While SHH-activated medulloblastoma shares some similarities with classic medulloblastoma, there are distinct differences in their molecular and histological profiles. Classic medulloblastoma typically lacks SHH pathway activation and may exhibit different genetic alterations (see [11], [12]).
• MBEN (Medulloblastoma with extensive Nodularity): MBEN is a rare subtype of medulloblastoma characterized by its nodular growth pattern and strong expression of NeuN antigen. It is essential to rule out MBEN in cases where the SHH pathway is activated, as both conditions share similar histological features (see [10]).

To accurately diagnose SHH-activated medulloblastoma, it is crucial to perform a comprehensive evaluation, including:

• Immunohistochemistry for SHH target proteins and other relevant markers
• Molecular testing to identify specific genetic alterations associated with SHH pathway activation
• Clinical correlation with imaging studies and patient history

By considering these factors and performing a thorough diagnostic workup, clinicians can accurately differentiate SHH-activated medulloblastoma from other brain tumors and provide appropriate treatment recommendations.