2017 NPA-08

This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 66-year-old man went for a run, began to feel dizzy and fell backwards. He was admitted to the emergency department of his local hospital after sustaining a fall. He had a history of well-controlled hypertension and hyperlipidemia. Initial management included cardiovascular workup with no significant findings. The patient was discharged. Subsequent complaints of abdominal discomfort prompted an MRI of the abdomen which demonstrated a T2 hyperintense, non-enhancing, 1.4 cm cystic lesion of the pancreatic body. Neuroimaging studies revealed two small masses with heterogeneous enhancement in the right posterior inferior frontal and right lateral temporal lobes. Two weeks after his fall, the patient underwent craniotomy for excisional biopsy.

Tissue Site
Right frontal and temporal lobes

The whole slide image provided is an H&E stain from a brain biopsy.

The diagnosis is subacute cerebral infarct. The clinical, radiologic, macroscopic, and microscopic findings of a brain infarct vary, depending upon the onset of the hypoxic-ischemic event (temporality), magnitude of the insult, location of the lesion, status of collateral circulation, and vulnerability of the brain cells involved. Most infarcts result from thromboembolic occlusion of intracranial arteries. The vast majority of brain infarcts are managed without tissue diagnosis. However, atypical presentations like the one illustrated here may involve surgical intervention and histologic diagnosis. Differential diagnostic considerations in such cases include infections, primary tumors, metastases, demyelinating lesions, and vasculitides, among other entities.

The typical radiologic findings of an ischemic cerebral infarct evolve over time. During the first few hours after the ischemic event, there is no discernable CT or MRI findings. Within six to eight hours, the infarcted area becomes hypodense and appears as a zone of enhancement after contrast administration. After 24 hours, the lesion often appears as a wedge-shaped hypodense lesion on CT and T1-weighted MRI. Enhancement after contrast administration, often with gyral pattern and mass effect, is evident within one week of the event and may persist up to two months. After months to years, the lesion undergoes cystic degeneration and accompanying hydrocephalus ex-vacuo may be present. In atypical presentations, generally in the subacute phase, infarcts may appear as other mass forming lesions (Image A) such as infections or neoplasms.

Neuropathologic features are generally not evident earlier than eight to twelve hours after the ischemic event. Macroscopically, within 12-24 hours and up to approximately four days (acute phase), there is congestion and a well-circumscribed area of swelling and hyperemia in the gray matter of a well-defined vascular territory. Regions of pallor with vacuolization of the neuropil and eosinophilic neuronal cell change ("red" neurons) can be seen microscopically. Neutrophils can occasionally be appreciated if the tissue is examined within the first 72 hours. If reperfusion occurs during this phase, hemorrhage within the ischemic area may be seen.

During the subacute or organizing stage (five to 30 days), liquefactive necrosis and artifactual separation of infarcted from noninfarcted brain parenchyma (“cracking artifact”) may be evident grossly. Microglia undergo activation and transformation into foamy macrophages that infiltrate the area to remove the necrotic material. During the first two weeks, capillary proliferation and reactive astrocytosis become evident at the edge of the lesion, along with neuronal ghosts and foamy histiocytes (lipid-laden macrophages) (Image B and Image C). In comparison with demyelinating lesions, loss of axons in the lesion and axonal spheroids at the edge are evident. After two to four weeks, eosinophilic neurons disappear.

Chronic changes of an infarct are apparent within weeks and persist for years after the initial insult. The lesion becomes “organized” once the macrophages scavenge the necrotic parenchyma, resulting in a cavity which is traversed by thin strands of residual blood vessels and shows scattered reactive astrocytes at the periphery of the lesion. Remaining neurons and axons may undergo ferruginization or calcinosis. Rarely, thrombosed vessels adjacent to the infarct can be evident.

The differential diagnostic considerations include brain hemorrhage, glioma, active demyelination, necrotizing infections, and metastasis. The use of ancillary stains is not usually necessary since the characteristic histopathologic features of cerebral infarct are readily discernible on H&E staining (Image B and Image C). However, in cases where the clinical and/or radiologic presentations suggest an infectious or neoplastic process, additional studies may be helpful. In a subacute brain infarct with reactive gliosis and an inflammatory infiltrate, the identification of numerous CD68-immunoreactive macrophages supports the diagnosis of organizing necrosis (Image D). GFAP highlights reactive astrocytes (Image E) and IDH-1 R132H is nonimmunoreactive (nonmutant) (Image F). In demyelinating disease, LFB/H&E stain shows loss of myelin (Image G), while axonal stains like Bielschowsky silver or neurofilament protein IHC demonstrate the relative sparing of axons, contrary to the complete loss of both myelin and axons in organizing necrosis. PAS-D-positive macrophages are seen in both demyelination and organizing necrosis (Image H).

• An atypical radiologic presentation of a brain infarct prompts differential diagnoses of glioma, infection, metastasis, demyelination, CNS lymphoma, and vasculitis, among other entities.
• Based on their histologic evolution, brain infarcts are categorized as acute (1-4 days), subacute (5-30 days), and chronic (weeks to months/years).
• The defining histopathologic changes of a subacute infarct include microglial activation and foamy macrophages (CD68) at the center of the lesion with surrounding capillary proliferation and reactive astrocytes (GFAP), as well as loss of axons (Bielschowsky and neurofilament), myelin (LFB), and neurons.

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