Primary CNS tumors — MCQs

10 questions

A 3-year-old boy is brought to the emergency department after losing consciousness. His parents report that he collapsed and then had repetitive, twitching movements of the right side of his body that lasted approximately one minute. He recently started to walk with support. He speaks in bisyllables and has a vocabulary of almost 50 words. Examination shows a large purple-colored patch over the left cheek. One week later, he dies. Which of the following is the most likely finding on autopsy of the brain?

A 57-year-old man is brought to the emergency department by his wife 20 minutes after having had a seizure. He has had recurrent headaches and dizziness for the past 2 weeks. An MRI of the brain shows multiple, round, well-demarcated lesions in the brain parenchyma at the junction between gray and white matter. This patient's brain lesions are most likely comprised of cells that originate from which of the following organs?

A 23-year-old man comes to the physician for evaluation of decreased hearing, dizziness, and ringing in his right ear for the past 6 months. Physical examination shows multiple soft, yellow plaques and papules on his arms, chest, and back. There is sensorineural hearing loss and weakness of facial muscles bilaterally. His gait is unsteady. An MRI of the brain shows a 3-cm mass near the right internal auditory meatus and a 2-cm mass at the left cerebellopontine angle. The abnormal cells in these masses are most likely derived from which of the following embryological structures?

A 5-year-old boy is brought to the physician because of early morning headaches for the past 6 months. During this period, he has had severe nausea and occasional episodes of vomiting. For the past month, he has had difficulty walking and intermittent double vision. He was born at term and has been healthy apart from an episode of sinusitis 8 months ago that resolved spontaneously. He is at the 60th percentile for height and 50th percentile for weight. His temperature is 37.1°C (98.8°F), pulse is 80/min, and blood pressure is 105/64 mm Hg. Examination shows normal muscle strength and 2+ deep tendon reflexes bilaterally. He has a broad-based gait and impaired tandem gait. Fundoscopy shows bilateral swelling of the optic disc. There is esotropia of the left eye. Which of the following is the most likely diagnosis?

A 10-year-old boy is brought to his pediatrician over concern for a 2-month history of headaches. Recently, the patient has been experiencing nausea and vomiting, along with some difficulty with coordination during soccer practice last week. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 110/80 mmHg, pulse is 72/min, and respirations are 14/min. On further evaluation, the patient is found to have a well-encapsulated posterior fossa mass. The patient undergoes surgical resection, and the mass is found to be positive for GFAP. Which of the following is derived from the same embryologic germ layer as the cells that comprise this tumor?

An 8-year-old boy is brought to the pediatrician because his mother is concerned about recent behavioral changes. His mother states that she has started to notice that he is slurring his speech and seems to be falling more than normal. On exam, the pediatrician observes the boy has pes cavus, hammer toes, and kyphoscoliosis. Based on these findings, the pediatrician is concerned the child has a trinucleotide repeat disease. Which of the following trinucleotide repeats is this child most likely to possess?

A 47-year-old woman comes to the physician because of a 2-month history of a lump on her neck and a 1-week history of hoarseness. Examination shows a 3-cm, firm, non-tender nodule on the anterior neck. Further evaluation confirms a thyroid malignancy, and she undergoes thyroidectomy. Histopathologic examination of the surgical specimen shows lymphatic invasion. Genetic analysis shows an activating mutation in the RET/PTC genes. Microscopic examination of the surgical specimen is most likely to also show which of the following?

A 12-year-old boy is brought to the emergency department after he vomited and said he was having double vision in school. He also says that he has been experiencing morning headaches, nausea, and dizziness over the last month. He has no past medical history and is not taking any medications. Physical exam reveals a broad-based gait, dysmetria on finger-to-nose testing, and nystagmus. Both serum and urine toxicology are negative, and radiography reveals a solid mass in the midline cerebellum that enhances after contrast administration. Biopsy of this lesion reveals cells of primitive neuroectodermal origin. Which of the following would most likely be seen on histology of this lesion?

A 35-year-old woman presents with headaches and seizures. MRI shows a well-circumscribed, calcified frontal lobe mass. Histology reveals oligodendroglioma with 1p/19q codeletion and IDH1 mutation. She undergoes gross total resection. Two years later, surveillance MRI shows a new enhancing nodule at the resection margin. Biopsy shows increased mitotic activity, microvascular proliferation, and retained 1p/19q codeletion but new CDKN2A/B homozygous deletion. What is the most critical factor in determining management strategy?

Q10

A 55-year-old man presents with progressive supranuclear gaze palsy, axial rigidity, and frequent falls. MRI shows midbrain atrophy with hummingbird sign. He dies 7 years later. Autopsy reveals globose neurofibrillary tangles in the basal ganglia and brainstem. Tau immunostaining shows 4-repeat tau predominance. His brother had similar symptoms. Genetic testing reveals a MAPT mutation. How does this change the pathogenic understanding and potential therapeutic approach?

Primary CNS tumors US Medical PG Practice Questions and MCQs

Question 1: A 3-year-old boy is brought to the emergency department after losing consciousness. His parents report that he collapsed and then had repetitive, twitching movements of the right side of his body that lasted approximately one minute. He recently started to walk with support. He speaks in bisyllables and has a vocabulary of almost 50 words. Examination shows a large purple-colored patch over the left cheek. One week later, he dies. Which of the following is the most likely finding on autopsy of the brain?

A. Subependymal giant cell astrocytoma
B. Periventricular calcification
C. Brainstem glioma
D. Leptomeningeal vascular malformation (Correct Answer)
E. Intraparenchymal cyst

Explanation: ***Leptomeningeal vascular malformation*** - The constellation of **seizures** and a **large purple patch** on the face (**port-wine stain** or nevus flammeus) strongly suggests **Sturge-Weber syndrome**. - **Leptomeningeal angioma** (vascular malformation) is the characteristic brain finding in Sturge-Weber syndrome, often leading to neurological deficits, seizures, and increased intracranial pressure. *Subependymal giant cell astrocytoma* - This tumor is pathognomonic for **tuberous sclerosis complex**, which is typically associated with **facial angiofibromas** (adenoma sebaceum) and other skin lesions like ash-leaf spots. - While tuberous sclerosis can present with seizures, the facial lesion described in the patient (large purple patch, or port-wine stain) is not consistent with the typical skin findings of tuberous sclerosis. *Periventricular calcification* - **Periventricular calcifications** are a hallmark sign of **congenital cytomegalovirus (CMV)** infection. - While CMV can cause neurological sequelae and developmental delay, the clinical presentation with a distinct facial lesion and recent onset seizures is more indicative of Sturge-Weber syndrome. *Brainstem glioma* - **Brainstem gliomas** typically present with **cranial nerve deficits**, **ataxia**, and long tract signs, rather than focal seizures and a port-wine stain. - The sudden onset of seizures and collapse, along with the characteristic facial lesion, points away from a primary brainstem tumor. *Intraparenchymal cyst* - An **intraparenchymal cyst** is a non-specific finding that could result from various causes, such as infection, trauma, or developmental anomalies. - It does not specifically account for the combination of seizures and the facial **port-wine stain** seen in this patient.

Question 2: A 57-year-old man is brought to the emergency department by his wife 20 minutes after having had a seizure. He has had recurrent headaches and dizziness for the past 2 weeks. An MRI of the brain shows multiple, round, well-demarcated lesions in the brain parenchyma at the junction between gray and white matter. This patient's brain lesions are most likely comprised of cells that originate from which of the following organs?

A. Kidney
B. Skin
C. Lung (Correct Answer)
D. Thyroid
E. Prostate

Explanation: ***Lung (Correct Answer)*** - **Lung cancer** is the most common cause of **brain metastases** in adults, accounting for approximately **50% of all cases** - The clinical presentation—seizure, headaches, dizziness, and **multiple, round, well-demarcated lesions at the gray-white matter junction**—is classic for metastatic lung cancer - Both **small cell and non-small cell lung cancers** have high propensity for hematogenous spread to the brain - The watershed areas at the gray-white junction are common sites due to lodging of tumor emboli in terminal arterioles *Kidney (Incorrect)* - **Renal cell carcinoma (RCC)** can metastasize to the brain but accounts for only **5-10% of brain metastases** - While RCC metastases can appear similar on imaging, lung cancer is statistically more likely given its higher prevalence - RCC metastases are often **highly vascular and may hemorrhage**, which is not mentioned in this case *Skin (Incorrect)* - **Melanoma** has the **highest propensity per case** to metastasize to the brain among all cancers - However, the **overall incidence of melanoma is much lower** than lung cancer, making it a less probable primary source - Melanoma brain metastases often present as **hemorrhagic lesions** and would typically have skin findings or history *Thyroid (Incorrect)* - **Thyroid cancer** rarely metastasizes to the brain (accounts for <1% of brain metastases) - Brain metastases from thyroid cancer typically occur in **advanced papillary or follicular carcinoma** or in **anaplastic thyroid cancer** - More common metastatic sites for thyroid cancer are lung and bone *Prostate (Incorrect)* - **Prostate cancer very rarely metastasizes to the brain** (<1% of cases) - Prostate cancer preferentially metastasizes to **bone (especially axial skeleton), lymph nodes, and liver** - Brain metastases from prostate cancer suggest extremely advanced, aggressive disease and are exceptionally uncommon

Question 3: A 23-year-old man comes to the physician for evaluation of decreased hearing, dizziness, and ringing in his right ear for the past 6 months. Physical examination shows multiple soft, yellow plaques and papules on his arms, chest, and back. There is sensorineural hearing loss and weakness of facial muscles bilaterally. His gait is unsteady. An MRI of the brain shows a 3-cm mass near the right internal auditory meatus and a 2-cm mass at the left cerebellopontine angle. The abnormal cells in these masses are most likely derived from which of the following embryological structures?

A. Surface ectoderm
B. Neural tube
C. Neural crest (Correct Answer)
D. Notochord
E. Mesoderm

Explanation: ***Neural crest*** - The patient's symptoms (bilateral sensorineural hearing loss, facial weakness, unsteady gait, central masses) along with cutaneous lesions (soft, yellow plaques) are highly suggestive of **Neurofibromatosis type 2 (NF2)**. - NF2 is characterized by **vestibular schwannomas** (acoustic neuromas) and other CNS tumors, which are derived from **Schwann cells**. Schwann cells, along with melanocytes and other peripheral nervous system components, originate from the **neural crest**. *Surface ectoderm* - The surface ectoderm forms structures such as the **epidermis**, hair, nails, and anterior pituitary. - While the skin lesions are present, the primary tumors (schwannomas) are not derived from the surface ectoderm. *Neural tube* - The neural tube gives rise to the **central nervous system** (brain and spinal cord) and motor neurons. - While the tumors affect the brain and cranial nerves, the specific cell type forming schwannomas (Schwann cells) does not originate directly from the neural tube. *Notochord* - The notochord induces the formation of the neural tube and eventually degenerates, contributing to the **nucleus pulposus** of the intervertebral discs. - It is not involved in the pathogenesis or cellular origin of schwannomas. *Mesoderm* - The mesoderm gives rise to connective tissues, blood, bone, muscle, and most internal organs. - While some tumors can have mesodermal origins, schwannomas are neuroectodermal in origin.

Question 4: A 5-year-old boy is brought to the physician because of early morning headaches for the past 6 months. During this period, he has had severe nausea and occasional episodes of vomiting. For the past month, he has had difficulty walking and intermittent double vision. He was born at term and has been healthy apart from an episode of sinusitis 8 months ago that resolved spontaneously. He is at the 60th percentile for height and 50th percentile for weight. His temperature is 37.1°C (98.8°F), pulse is 80/min, and blood pressure is 105/64 mm Hg. Examination shows normal muscle strength and 2+ deep tendon reflexes bilaterally. He has a broad-based gait and impaired tandem gait. Fundoscopy shows bilateral swelling of the optic disc. There is esotropia of the left eye. Which of the following is the most likely diagnosis?

A. Schwannoma
B. Optic glioma
C. Meningioma
D. Hemangioblastoma
E. Medulloblastoma (Correct Answer)

Explanation: ***Medulloblastoma*** - The constellation of **early morning headaches**, **nausea/vomiting**, **papilledema** (swelling of the optic disc), **ataxia** (difficulty walking, broad-based gait, impaired tandem gait), and **cranial nerve palsy** (esotropia from abducens nerve dysfunction) in a young child strongly indicates increased intracranial pressure secondary to a posterior fossa tumor. **Medulloblastoma** is the most common malignant posterior fossa tumor in children. - The location in the **cerebellum** explains the gait abnormalities (ataxia), and its rapid growth often leads to **hydrocephalus** and raised ICP symptoms. *Schwannoma* - **Schwannomas** typically arise from cranial nerves (most commonly the vestibular nerve, causing acoustic neuromas) and are rare in children. - They tend to be **slow-growing** and usually present with localized symptoms like hearing loss or facial nerve weakness, rather than diffuse signs of increased ICP and ataxia. *Optic glioma* - **Optic gliomas** arise from the optic nerve and primarily cause **vision loss**, proptosis, and strabismus. - While they can cause hydrocephalus if large and compressive, they typically do not cause pronounced cerebellar signs like ataxia, and primary presentation with early morning headaches and vomiting would be less common than vision issues. *Meningioma* - **Meningiomas** are typically **benign tumors** arising from the meninges that are rare in children and usually occur in older adults. - They are slow-growing and often present with focal neurological deficits related to their location, but they are an improbable diagnosis given the age and constellation of rapidly developing symptoms of increased ICP and cerebellar dysfunction. *Hemangioblastoma* - **Hemangioblastomas** are vascular tumors, often associated with **von Hippel-Lindau disease**, and are typically found in the cerebellum, brainstem, or spinal cord. - While they can cause cerebellar symptoms and increased ICP, they are more commonly seen in **adults** and are much rarer than medulloblastomas in children of this age.

Question 5: A 10-year-old boy is brought to his pediatrician over concern for a 2-month history of headaches. Recently, the patient has been experiencing nausea and vomiting, along with some difficulty with coordination during soccer practice last week. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 110/80 mmHg, pulse is 72/min, and respirations are 14/min. On further evaluation, the patient is found to have a well-encapsulated posterior fossa mass. The patient undergoes surgical resection, and the mass is found to be positive for GFAP. Which of the following is derived from the same embryologic germ layer as the cells that comprise this tumor?

A. Ependymal cells (Correct Answer)
B. Nucleus pulposus
C. Schwann cells
D. Microglia
E. Melanocytes

Explanation: ***Ependymal cells*** - The tumor described is a **pilocytic astrocytoma**, a common **posterior fossa tumor** in children, characterized by its **well-encapsulated** nature and **GFAP positivity**, indicating an **astrocytic origin**. - **Astrocytes** develop from the **neuroectoderm/neural tube**, as do **ependymal cells**, which line the ventricles and central canal of the spinal cord. *Nucleus pulposus* - The **nucleus pulposus** is a remnant of the **notochord**, which originates from the **mesoderm**. - This embryological origin is distinct from the **neuroectodermal** origin of the tumor cells. *Schwann cells* - **Schwann cells** are derived from the **neural crest**, which is also **ectodermal** but represents a different lineage than the **neural tube**. - While both contribute to the nervous system, **neural crest cells** form the peripheral nervous system, whereas the **neural tube** forms the central nervous system. *Microglia* - **Microglia** are the immune cells of the CNS and are derived from the **mesoderm**, specifically from **monocytes** in the yolk sac. - Their origin is distinct from the **neuroectodermal** lineage of astrocytes. *Melanocytes* - **Melanocytes** are pigment-producing cells found in the skin, hair, and eyes, and they are derived from the **neural crest**. - This makes their embryological origin different from the **neural tube** cells that give rise to astrocytes.

Question 6: An 8-year-old boy is brought to the pediatrician because his mother is concerned about recent behavioral changes. His mother states that she has started to notice that he is slurring his speech and seems to be falling more than normal. On exam, the pediatrician observes the boy has pes cavus, hammer toes, and kyphoscoliosis. Based on these findings, the pediatrician is concerned the child has a trinucleotide repeat disease. Which of the following trinucleotide repeats is this child most likely to possess?

A. CTG
B. GAA (Correct Answer)
C. CGG
D. CAG
E. GCC

Explanation: ***GAA*** - This trinucleotide repeat is associated with **Friedreich's ataxia**, an autosomal recessive neurodegenerative disorder. - The presented symptoms of **ataxia** (slurred speech, falling), **pes cavus**, **hammer toes**, and **kyphoscoliosis** are classic features of Friedreich's ataxia. *CTG* - This trinucleotide repeat is associated with **myotonic dystrophy type 1**, an autosomal dominant disorder. - While it causes muscle weakness, it is characterized by **myotonia** (delayed muscle relaxation), cataracts, and frontal baldness, which are not described here. *CGG* - This trinucleotide repeat is associated with **fragile X syndrome**, an X-linked dominant disorder. - Fragile X syndrome primarily causes intellectual disability, behavioral issues (e.g., autism spectrum disorder), and characteristic facial features, but not the specific neurological and orthopedic findings seen in this patient. *CAG* - This trinucleotide repeat is associated with several neurodegenerative diseases, including **Huntington's disease**, spinocerebellar ataxias, and **dentatorubral-pallidoluysian atrophy**. - Huntington's disease, for example, presents with chorea, cognitive decline, and psychiatric symptoms, differing from the patient's presentation. *GCC* - This trinucleotide repeat is associated with **fragile X-associated tremor/ataxia syndrome (FXTAS)**. - FXTAS typically affects older adult carriers of premutation alleles for fragile X, presenting with intention tremor and gait ataxia, not the early childhood onset and specific orthopedic deformities seen here.

Question 7: A 47-year-old woman comes to the physician because of a 2-month history of a lump on her neck and a 1-week history of hoarseness. Examination shows a 3-cm, firm, non-tender nodule on the anterior neck. Further evaluation confirms a thyroid malignancy, and she undergoes thyroidectomy. Histopathologic examination of the surgical specimen shows lymphatic invasion. Genetic analysis shows an activating mutation in the RET/PTC genes. Microscopic examination of the surgical specimen is most likely to also show which of the following?

A. Pleomorphic giant cells with numerous atypical mitotic figures
B. Cuboidal cells arranged spherically around colloid lakes
C. Hyperplastic epithelium with colloid scalloping
D. Calcified spherules and large oval cells with empty-appearing nuclei (Correct Answer)
E. Sheets of polygonal cells surrounding amyloid deposition

Explanation: ***Calcified spherules and large oval cells with empty-appearing nuclei*** - The presence of an **activating mutation in RET/PTC genes**, **lymphatic invasion**, and a new neck lump with hoarseness (suggesting nerve involvement) are highly characteristic of **papillary thyroid carcinoma**. - Microscopic features of papillary thyroid carcinoma include **Psammoma bodies (calcified spherules)**, **Orphan Annie eye nuclei (large oval cells with empty-appearing nuclei)**, and nuclear grooves. *Pleomorphic giant cells with numerous atypical mitotic figures* - This description typically refers to **anaplastic thyroid carcinoma**, a highly aggressive and undifferentiated tumor. - While anaplastic carcinoma can present with rapid growth and hoarseness, it is less commonly associated with a **RET/PTC mutation** (BRAF mutations are more common) and typically has a much poorer prognosis, often presenting with a rapidly enlarging mass rather than a 2-month history suggestive of a more indolent tumor. *Cuboidal cells arranged spherically around colloid lakes* - This morphology is characteristic of **follicular thyroid carcinoma** or **follicular adenoma**. - While follicular tumors can have RET/PTC mutations in some variants, the classic features described (empty-appearing nuclei and psammoma bodies) are absent here. *Hyperplastic epithelium with colloid scalloping* - This describes the histologic features seen in **Graves' disease** or **diffuse toxic goiter**, a benign condition. - It is not indicative of malignancy, and the patient's presentation with a solitary nodule and hoarseness points to a malignant process. *Sheets of polygonal cells surrounding amyloid deposition* - This is the classic microscopic appearance of **medullary thyroid carcinoma**. - Medullary thyroid carcinoma is also associated with **RET mutations**, but these are typically **germline or somatic RET point mutations** (e.g., RET M918T), not RET/PTC rearrangements, and it arises from parafollicular C cells, producing calcitonin, not thyroid hormones.

Question 8: A 12-year-old boy is brought to the emergency department after he vomited and said he was having double vision in school. He also says that he has been experiencing morning headaches, nausea, and dizziness over the last month. He has no past medical history and is not taking any medications. Physical exam reveals a broad-based gait, dysmetria on finger-to-nose testing, and nystagmus. Both serum and urine toxicology are negative, and radiography reveals a solid mass in the midline cerebellum that enhances after contrast administration. Biopsy of this lesion reveals cells of primitive neuroectodermal origin. Which of the following would most likely be seen on histology of this lesion?

A. Rosettes with small blue cells (Correct Answer)
B. Rosenthal fibers
C. Tooth enamel-like calcification
D. Foamy cells and high vascularity
E. Perivascular pseudorosettes

Explanation: ***Rosettes with small blue cells*** - The description of a **midline cerebellar mass** in a child, presenting with signs of **increased intracranial pressure (headaches, vomiting, double vision)** and **cerebellar dysfunction (broad-based gait, dysmetria, nystagmus)**, is classic for **medulloblastoma**. - **Medulloblastomas** are primitive neuroectodermal tumors (PNETs) known for their distinctive histology of **small, round, blue cells** forming **Homer-Wright rosettes**. *Rosenthal fibers* - **Rosenthal fibers** are eosinophilic, corkscrew-shaped structures that are characteristic histological features of **pilocytic astrocytomas**. - While pilocytic astrocytomas can be cerebellar and common in children, the question describes a "solid mass of primitive neuroectodermal origin" rather than the typical cystic lesion with mural nodule associated with pilocytic astrocytomas, and the aggressive presentation points away from pilocytic astrocytoma. *Tooth enamel-like calcification* - **Tooth enamel-like calcification** is a pathognomonic feature of **craniopharyngiomas**, which are typically supratentorial (in the sellar region) and cause symptoms related to pituitary dysfunction and optic chiasm compression, not cerebellar dysfunction. - The location and symptoms provided in the vignette do not match the typical presentation of a craniopharyngioma. *Foamy cells and high vascularity* - **Foamy cells and high vascularity** are characteristic features of **hemangioblastomas**, which are typically seen in adults, often associated with **von Hippel-Lindau disease**, and are more commonly located in the cerebellum. - However, the patient's age (12-year-old) and the description of cells of "primitive neuroectodermal origin" do not align with the typical presentation or origin of hemangioblastomas. *Perivascular pseudorosettes* - **Perivascular pseudorosettes** are the classic histological finding in **ependymomas**, another common pediatric brain tumor. - While ependymomas can occur in the posterior fossa, they typically arise from the floor of the fourth ventricle and are not described as having primitive neuroectodermal origin in the same way medulloblastomas are, and the specific rosettes formed by medulloblastomas are Homer-Wright rosettes.

Question 9: A 35-year-old woman presents with headaches and seizures. MRI shows a well-circumscribed, calcified frontal lobe mass. Histology reveals oligodendroglioma with 1p/19q codeletion and IDH1 mutation. She undergoes gross total resection. Two years later, surveillance MRI shows a new enhancing nodule at the resection margin. Biopsy shows increased mitotic activity, microvascular proliferation, and retained 1p/19q codeletion but new CDKN2A/B homozygous deletion. What is the most critical factor in determining management strategy?

A. The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT
B. CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy
C. Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen (Correct Answer)
D. Loss of IDH1 mutation suggests new primary tumor requiring re-resection only
E. Microvascular proliferation mandates anti-angiogenic therapy with bevacizumab

Explanation: ***Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen*** - The preservation of **1p/19q codeletion** in a recurrent tumor is the strongest predictor of clinical response to alkylating chemotherapy, specifically the **PCV (Procarbazine, Lomustine, Vincristine)** regimen. - While the tumor shows histological progression, the underlying molecular subtype remains an **oligodendroglioma**, which generally carries a better prognosis and higher chemosensitivity than non-codeleted gliomas. *The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT* - While the histology suggests a higher grade, the standard of care for 1p/19q codeleted tumors frequently favors **PCV** over **Temozolomide** due to more robust long-term survival data from clinical trials like RTOG 9402. - Grading alone does not dictate management as much as the **molecular profile** does in modern neuro-oncology guidelines. *CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy* - Under the current WHO classification, **glioblastoma** is defined as an **IDH-wildtype** tumor; since this tumor has an **IDH1 mutation**, it cannot be classified as a glioblastoma. - **CDKN2A/B homozygous deletion** is a marker of high-grade malignancy (WHO Grade 4) in IDH-mutant astrocytomas, but its presence in an **oligodendroglioma** does not change the lineage-defining 1p/19q status. *Loss of IDH1 mutation suggests new primary tumor requiring re-resection only* - **IDH1 mutations** are early, trunk events in gliomagenesis and are almost never

Question 10: A 55-year-old man presents with progressive supranuclear gaze palsy, axial rigidity, and frequent falls. MRI shows midbrain atrophy with hummingbird sign. He dies 7 years later. Autopsy reveals globose neurofibrillary tangles in the basal ganglia and brainstem. Tau immunostaining shows 4-repeat tau predominance. His brother had similar symptoms. Genetic testing reveals a MAPT mutation. How does this change the pathogenic understanding and potential therapeutic approach?

A. It suggests prion-like propagation requiring anti-aggregation compounds
B. It demonstrates autoimmune etiology requiring immunosuppression
C. It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation
D. It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy (Correct Answer)
E. It indicates concurrent alpha-synuclein pathology requiring dual-target therapy

Explanation: ***It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy*** - The presence of **MAPT mutations** and **4-repeat (4R) tau** predominance confirms that tau dysfunction is the primary driver of the neurodegenerative process in this **Progressive Supranuclear Palsy (PSP)** phenotype. - Targeting the underlying genetic cause with **antisense oligonucleotides (ASOs)** can reduce the expression of toxic tau protein, offering a disease-modifying approach rather than just symptomatic relief. *It suggests prion-like propagation requiring anti-aggregation compounds* - While **prion-like seeding** occurs in tauopathies, the discovery of a **MAPT mutation** specifically points to a genetic production error rather than isolated misfolding propagation. - **Anti-aggregation compounds** are a general strategy, but they do not address the primary genetic driver identified by the mutation in this specific case. *It demonstrates autoimmune etiology requiring immunosuppression* - **PSP** and related **tauopathies** are degenerative proteinopathies, not autoimmune conditions, and show no response to **immunosuppressive therapy**. - The **hummingbird sign** and **globose tangles** are classic markers of protein deposition, not inflammatory-mediated demyelination or vasculitis. *It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation* - Although some **mitochondrial deficit** is seen in neurodegeneration, it is a downstream effect and not the primary cause identified by a **MAPT mutation**. - **Coenzyme Q10** has failed to show significant disease-modifying efficacy in clinical trials for primary tauopathies like **PSP**. *It indicates concurrent alpha-synuclein pathology requiring dual-target therapy* - The **MAPT mutation** and **4R tau** findings are specific to tauopathies; **alpha-synuclein** is the hallmark of synucleinopathies like **Parkinson’s disease** or **Multiple System Atrophy (MSA)**. - Clinical features like the **hummingbird sign** (midbrain atrophy) and **axial rigidity** without resting tremors strongly favor a pure tau pathology over a dual-pathology state.

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