Differential Diagnosis of Intracranial Masses
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An informed differential diagnosis requires analyzing the imaging features in the context of the clinical presentation of the patient. A wedge-shaped cortical lesion, involving both gray and white-matter, presenting with an acute neurologic deficit is probably an ischemic infarction. Multiple cortical/subcortical round nodular enhancing lesions are likely metastatic. Large deep white-matter masses suggest a diffuse glioma: with heterogenous enhancement likely glioblastoma, while similar lesions without enhancement may be a lower-grade (WHO2,3) astrocytoma. Oligodendroglioma looks similar, but adds conglomerate calcifications. In contrast, largely fluid lesions with enhancement limited to a mural nodule are usually circumscribed gliomas—amenable to surgical extirpation. The most common extraaxial masses are meningioma and vestibular schwannoma. Schwannomas characteristically arise within the internal auditory canal, then spread into the cerebello-pontine angle cistern of the posterior fossa. Most meningiomas are supratentorial, around the cerebral hemisphere convexity.
KeywordsDifferential diagnosis Glioma Glioblastoma Primary CNS lymphoma tumefactive demyelination Meningioma Astrocytoma Metastasis Schwannoma Pilocytic Ganglioglioma Edema Contrast enhancement MRI CT
Distinguish intraaxial from extraaxial and intraventricular masses
Describe secondary effects: “volume effect” and perilesional vasogenic edema
Distinguish metastatic disease at gray–white junction from deeper infiltrating gliomas
Accurate image interpretation requires a knowledge base, understanding the patient’s clinical features, and experience. Radiology is often taught as an apprenticeship of pattern recognition. However, the best interpretations use pattern analysis instead of pattern recognition: progression of clinical course (acute-rapid, subacute-smoldering, chronic-prolonged); location of lesion (intra- vs. extraaxial); secondary effects (volume, edema, herniation); enhancement (solid, ring-like or leading edge, non-enhancing); blood-products; MR Spectroscopy (MRS); Diffusion-weighted Imaging (DWI and ADC values); response to treatment.
8.1.1 Time Course of Disease
Cerebrovascular events and traumatic lesions usually present acutely: skull impact and inertial trauma cause epidural, subdural, subarachnoid, and parenchymal hemorrhage; aneurysmal bleeding (“thunderclap headache”) into the subarachnoid space (SAH); deep hypertensive bleeds (basal ganglia and thalamus); acute neurologic deficit from ischemia-infarction (aphasia, paralysis, etc.). At the other end of the time spectrum, degenerative diseases and dementia may progress over months to years. In between, with symptom duration of weeks to months to years, are intracranial neoplasms. More rapid onset of symptoms occurs with high-grade glioma (glioblastoma) and metastatic disease.
Every image should be interpreted in the clinical context for each patient. When things are inconsistent, expand your differential diagnosis.
8.2 Intraaxial Vs. Extraaxial
8.3 Pattern Analysis
Radiology (also pathology and dermatology) are often taught using “pattern recognition.” This works well once you have accumulated—through experience—a built-in library of “patterns” that you may match with an unknown case. Another approach is a break down of the imaging features, analyze them separately, and then synthesize a differential diagnosis. Patterns of contrast enhancement may suggest more specific diagnoses: gyral gray-matter enhancement occurs with reperfusion after ischemia, post-ictal or seizures, and meningoencephalitis; ring enhancement implies “central necrosis”—but may be seen with an organized abscess as well as neoplasms .
8.4 Neoplastic Vs. Non-neoplastic Disease
Chronic destructive lesions cause a loss of brain volume or “negative volume effect,” with compensatory enlargement of ventricles and sulci. Adding cells (blood, pus, neoplasm) usually cause proportionate “positive volume effect” with compression of ventricles and effacement of sulci.
Tumefactive demyelination may be distinguished from a neoplasm by paucity of mass-effect; minimal/no perilesional edema; “open ring” enhancement; increased ADC; and low perfusion values.
8.5 Single Vs. Many Lesions
Multiple lesions have many possible causes—some neoplastic, others toxic, metabolic, inflammatory, or genetic.
8.6 Metastatic Disease
Solid tumors require angiogenesis to enlarge beyond a couple of millimeters. The bio-machinery to grow new vessels can remodel existing vessels and allow embolization of tumor cells. Once in circulation, the tumor emboli are distributed by blood flow: hematogenous dissemination. The brain requires about 20% of our cardiac output. It is a vast “filtration bed” where platelet thrombi, clots, and tumor emboli may lodge. The majority of these “particulates” will lodge in two places: in the subcortical gray–white junction, and in the penetrating vessels that supply the deep gray-matter (Fig. 8.4b, c)  Within the brain parenchyma, metastases are remarkably well localized, round solid or ring enhancing, often with a rim of reactive gliosis, and surrounded by perilesional vasogenic edema (Fig. 8.4d). Metastases from highly cellular primary tumors (such as small cell carcinoma) may show restricted diffusion. Survival after presentation with parenchymal brain metastasis may be as short as 6 months.
Metastatic lesions are usually peripheral cortical or subcortical, round, and well-demarcated with enhancement and perilesional vasogenic edema. At initial presentation with metastatic disease, 40–60% of patients will have a single or solitary (only brain) metastatic lesion.
8.7 Primary Neoplasms
8.7.1 Extraaxial Neoplasms
An important differential diagnosis of “en plaque” meningiomas are dural metastases in the appropriate clinical setting (e.g., in a patient with CA breast).
Meningiomas usually remain homogeneous, even when large. Vestibular schwannomas are distinguished by location at a nerve (e.g., arising within the internal auditory canal), and they often become heterogeneous as they grow and enlarge. Almost all extraaxial and non-glial neoplasms show contrast enhancement.
8.7.2 Intraaxial Neoplasms
The overwhelming majority of primary intraaxial neoplasms arise from the glia—or glial cell precursors.
After glial tumors, primary CNS lymphoma (PCNSL) represents an important intrinsic neoplasm.
Glial and mixed neoplasms
Diffusely infiltrating gliomas
Pilocytic astrocytoma Gr1
Astrocytoma IDH-wt Gr2
1 Glioblastoma IDH-wt Gr4
Subependymal giant-cell astrocytoma Gr1
Astrocytoma IDH-mut Gr2
2 Glioblastoma IDH-mut Gr4
Pleomorphic xanthoastrocytoma Gr2,3
Anaplastic Astro IDH-wt Gr3
Pilomyxoid astrocytoma Gr2
Anaplastic Astro IDH-mut Gr3
Choroid plexus neoplasms (papilloma, carcinoma, etc.) Gr1,2,3
Anaplastic oligodendroglioma Gr3
Cortical gray-matter signal changes with a large white-matter lesion suggest neoplastic infiltration—a differential feature favoring diffuse gliomas, not seen with metastasis nor tumefactive demyelination.
Gliomagenesis for diffuse gliomas follows several different pathways. Up to 80% of lower-grade (WHO Gr 2–3) diffuse glioma have a gain-of-function “priming mutation” in IDH (isocitrate dehydrogenase—90% IDH1 and 10% IDH2) that produces a 10,000-fold increase in dextro-2-hydroxygutarate (D2HG)—that can be used as a tumor marker on 3T MRS . Astrocytoma adds mutations in TP53 and ATRX. Oligodendrogliomas begin with the same IDH mutation, but add other mutations (TERT) and a codeletion of 1p19q, which is now the de facto standard marker . Glioblastoma (GBM) arises from a more complex series of mutations: 90% are IDH-wild type (primary GBM, usually older patients. However, about 10% of GBM are secondary, arising from a prior lower-grade lesion that has transformed. These are usually IDH-mutated and present in younger patients, often <40 years old.
Lower-grade diffuse gliomas (WHO Gr2,3) are deeply infiltrating masses without necrosis. They expand and non-destructively spread through the brain—often delaying the onset of a neurologic presentation. Diffuse lower-grade astrocytoma (WHO Gr 2,3) is usually homogeneous low attenuation on CT with water-like signal-intensity on MR. WHO Gr 2 astrocytomas do usually do not enhance, because they do not produce neovascularity. Instead, the tumor cells disperse and infiltrate into the surrounding brain and are supplied by normal pre-existing capillaries. Should enhancement appear on serial imaging of a known low-grade astrocytoma, it usually indicates transformation to a higher grade tumor.
IDH-mutant astrocytoma is usually in the frontal lobe, sharply demarcated, and often display the “T2-FLAIR mismatch” sign . IDH-wild type astrocytoma often has blurry margins—without the mismatch sign (Fig. 8.7e, f).
IDH-mutant gliomas have a much better prognosis than IDH-wild type. Virtually all (probably all) oligodendrogliomas have IDH mutations—and they enjoy the best prognosis of all diffuse gliomas. Next in survival is the IDH-mutant astrocytoma—about 70% of lower-grade WHO Gr 2,3 tumors. IDH-wild type astrocytoma (30% of WHO Gr 2,3) tends to have the same poor prognosis as IDH-wild glioblastomas. In some centers, they are monitored closely for progression and may then be treated like glioblastoma .
Pilocytic astrocytoma is most common in young patients (9–15 years of age) in the cerebellar hemispheres. Pleomorphic xanthoastrocytoma is present in children and mostly younger adults, typically in a superficial location of the cerebral hemispheres. Ganglioglioma usually present with seizures in young adults and most commonly located in the temporal lobe. Pilomyxoid astrocytoma is usually around the third ventricle (Fig. 8.9).
8.8 Primary CNS Lymphoma
Whereas the incidence of PCNL in immunocompromised patients has declined following the introduction of effective antiviral therapy, there has been a steady increase of PCNSL in immunocompetent patients.
PCNSL are mostly large B-cell lymphomas and commonly found in the periventricular regions or deep gray nuclei. Owing to their high cellularity, they demonstrate typically restricted diffusion. They enhance strongly with a homogenous enhancement pattern in immunocompetent patients and ring enhancement in the immunocompromised. On perfusion imaging, the rCBV is only minimally increased (much less than, e.g., in glioblastomas), as lymphoma grows angiocentrically and does not stimulate neoangiogenesis.
Glioblastomas are usually (90%) IDH-wild type with enhancement and necrosis. Diffuse lower-grade gliomas (WHO Gr2,3) overwhelmingly harbor IDH mutations and do not enhance. The T2-FLAIR mismatch sign indicates an IDH-mutant astrocytoma, distinguishing from oligodendroglioma and IDH-wild type astrocytoma. Dense calcifications suggest oligodendroglioma. Circumscribed gliomas usually show prominent contrast enhancement, a fluid component, and have BRAF mutations.
8.9 Concluding Remarks
There are multiple tools for triangulating a short differential diagnosis list, and it is important to use “pattern analysis” rather than simple “pattern recognition.” Key features include lesion location, relative “volume effect”; secondary vasogenic edema; homogeneity or heterogeneity of the lesion; and patterns of contrast enhancement (homogeneous, patchy, closed or open ring). Multiple lesions usually represent a systemic process: inflammatory; toxic; metabolic; genetic; or hematogenous dissemination. Extraaxial masses are non-glial, while intraaxial neoplasms may be metastatic from extra-CNS sources, or primary gliomas.
Take Home Messages
Lesions with vasogenic edema should also demonstrate contrast enhancement
Solitary deep lesions are more likely to be primary gliomas
Round nodular lesions at the gray–white junction are more likely to be metastatic
Diffuse gliomas affect the cortex, vasogenic edema does not
IDH-mutant diffuse astrocytoma shows T2-FLAIR mismatch sign
Extraaxial lesions are meningioma, schwannoma, and congenital cysts
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