A 39-year-old African American woman is admitted to the hospital following a seizure with a severe post-ictal headache. She was diagnosed with breast cancer 1 year ago when she presented with a hard, rock-like, immobile mass with irregular borders accompanied by changes in the breast skin, including erythema and dimpling. She had ipsilateral mobile axillary lymphadenopathy at that time. A biopsy confirmed the diagnosis of stage 2B invasive breast cancer. Her mother died at 42 years of age due to the same type of breast cancer. A CT scan done during this admission reveals multiple metastatic lesions in the brain and liver, along with the involvement of supra- and infra-clavicular lymph nodes. Which of the following molecular profile most likely characterizes this patient?

Progesterone receptor (PR) positive

Estrogen receptor (ER) positive

A 55-year-old female presents to her primary care physician complaining of a mass in her mid-thigh. The mass has grown slowly over the past six months and is not painful. The patient’s past medical history is notable for hypertension and hyperlipidemia. She takes lisinopril and rosuvastatin. On examination, there is a firm, immobile mass on the medial aspect of the distal thigh. She has full range of motion and strength in her lower extremities and patellar reflexes are 2+ bilaterally. A biopsy of the mass reveals multiple pleomorphic smooth muscle cells with nuclear atypia. The patient subsequently initiates radiation therapy with plans to undergo surgical resection. This tumor will most strongly stain for which of the following?

Glial fibrillary acidic protein

A 52-year-old man presents with 2 months of diarrhea, abdominal pain, and fatigue. He reports a weight loss of 4 kg (8 lb). He also says his joints have been hurting recently, as well. Past medical history is unremarkable. Review of systems is significant for problems with concentration and memory. Physical examination is unremarkable. A GI endoscopy is performed with a biopsy of the small bowel. Which of the following histologic finding would most likely be seen in this patient?

Non-caseating granulomas in the small intestine

Absence of nerves in the myenteric plexus

Crypt hyperplasia with increased intraepithelial lymphocytes

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?

Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen

The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT

CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy

Loss of IDH1 mutation suggests new primary tumor requiring re-resection only

Microvascular proliferation mandates anti-angiogenic therapy with bevacizumab

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?

It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy

It suggests prion-like propagation requiring anti-aggregation compounds

It demonstrates autoimmune etiology requiring immunosuppression

It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation

It indicates concurrent alpha-synuclein pathology requiring dual-target therapy

A 70-year-old man with progressive dementia undergoes autopsy. Microscopy shows neuritic plaques and neurofibrillary tangles meeting criteria for Alzheimer disease (AD). However, sections also reveal Lewy bodies in the substantia nigra and cortex, moderate atherosclerosis with old lacunar infarcts, and TDP-43 positive inclusions in the hippocampus. He had no parkinsonian features clinically. What is the most appropriate neuropathologic interpretation?

Alzheimer disease with multiple contributing pathologies (mixed dementia)

Dementia with Lewy bodies with concurrent Alzheimer pathology

Vascular dementia with incidental Alzheimer changes

Frontotemporal dementia with secondary Alzheimer pathology

Primary age-related tauopathy with multiple comorbidities

Metastatic CNS tumors | Neuropathology

Metastatic CNS Tumors - Brain Invaders

Most common intracranial tumors in adults, often multiple and well-circumscribed.
Typically found at the gray-white matter junction.
Primary sources: Lung > Breast > Skin (melanoma) > Kidney (renal cell) > GI tract.
- 📌 Mnemonic: Lots of Bad Stuff Kills Glia.
Imaging reveals ring-enhancing lesions with significant vasogenic edema on contrast-enhanced CT/MRI.

MRI: Multiple ring-enhancing metastatic brain lesions

⭐ While primary CNS tumors are typically solitary, the presence of multiple intraparenchymal lesions is the hallmark of metastasis.

Primary Suspects - The Usual Culprits

Lung Cancer: The most common source, causing >50% of CNS metastases. Typically presents with multiple lesions.
Breast Cancer: Second most frequent primary. Often metastasizes to the cerebellum and posterior fossa.
Melanoma: Has a very high propensity to metastasize to the brain. Lesions are often hemorrhagic.
Renal Cell Carcinoma (RCC): Characteristically forms solitary, large, vascular metastases prone to bleeding.
GI Tract (Colorectal): Less common, but an important source.

📌 Mnemonic: "Lovely Bold Men Know Greatness" (Lung, Breast, Melanoma, Kidney, GI).

⭐ Metastases are the most common intracranial tumors in adults. They characteristically appear as multiple, well-circumscribed lesions at the gray-white matter junction.

Signs & Scans - Finding the Foe

Clinical Presentation: Headaches (often worse in AM), seizures, focal neurologic deficits, or cognitive changes. Symptoms depend on tumor location and number.
Imaging is Key: Contrast-enhanced MRI is the gold standard.
- Hallmarks: Multiple, well-circumscribed lesions, typically at the gray-white matter junction.
- Appearance: Ring-enhancing lesions with significant vasogenic edema.

Axial T1 MRI: Multiple metastatic brain lesions

⭐ High-Yield Fact: Metastases often occur in arterial "watershed" areas, where blood vessels terminate, making it easier for tumor emboli to lodge and grow. This explains the characteristic location at the gray-white junction.

Pathology & Management - Cellular Clues & Battle Plans

Pathology: Often multiple, well-demarcated lesions at the gray-white junction. Histology mirrors the primary tumor (e.g., glands in lung adenocarcinoma, melanin in melanoma).
- Look for a distinct border between tumor cells and surrounding brain parenchyma, often with significant vasogenic edema.

Brain MRI: Metastatic CNS tumor with necrosis and edema

⭐ High-Yield Pearl: For patients with 1-4 metastatic lesions and good performance status, Stereotactic Radiosurgery (SRS) is often preferred over Whole Brain Radiation Therapy (WBRT) to better preserve neurocognitive function.

Management Flow:

High‑Yield Points - ⚡ Biggest Takeaways

Metastatic tumors are the most common intracranial neoplasms in adults.

Primary sources are typically lung cancer, breast cancer, melanoma, and renal cell carcinoma.

Lesions are characteristically multiple and located at the gray-white matter junction.

On imaging, they appear as well-circumscribed, ring-enhancing lesions with significant vasogenic edema.

Common presentation includes headaches, seizures, and focal neurological deficits, reflecting the lesion's location.