2021 NPB-09

This case was originally published in 2021. 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.

During prenatal ultrasound, a cardiac mass was identified in a 28-week-old fetus. MRI after delivery revealed multiple cardiac masses in the ventricular septum and right ventricle. Subsequent brain MRI showed T2/FLAIR hyperintensities in the subcortical white matter of bilateral cerebral hemispheres and multiple subependymal nodules (Image A). Dermatologic exam revealed hypomelanotic nodules and facial angiofibromas. Within a year of birth, the infant began having seizures. Epilepsy workup revealed a left anterior parietal seizure focus, and a resection of the T2 hyperintensity in that area was performed at two years of age.

Tissue Site
Brain, left parietal lobe

The whole slide image provided is an H&E-stained section of the brain from the left parietal lobe resection specimen.

The T2/FLAIR hyperintense lesion resected from this patient is a cortical tuber. Genetic testing was performed, and a pathogenic variant in the TSC1 gene was identified, consistent with a diagnosis of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that can affect multiple systems including the CNS, skin, heart, eyes, lungs, and kidneys, among others. The prevalence is 1:6,000 to10,000 live births, affecting one to two million people worldwide. TSC is caused by loss-of-function variants or deletions in one of two genes: TSC1 that encodes the protein hamartin, or TSC2 that encodes the protein tuberin. Within cells, these proteins form the tuberin-hamartin complex that normally functions as a negative regulator of the mTOR signaling pathway that leads to cell growth and proliferation. Genetic alterations in either TSC1 or TSC2 lead to disrupted function of this complex and cause the same disease phenotype. TSC is an autosomal dominant disease, but the majority of cases are due to de novo mutations. Mosaic mutations in the causative genes have also been identified, and accurate diagnosis can be further complicated by variable penetrance and clinical phenotypes. Most patients come to clinical attention in infancy or childhood, but rare cases may not present until adulthood.

Lesions associated with TSC include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) in the CNS. Dermatologic abnormalities include hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, and ungual fibromas. In addition, cardiac rhabdomyomas and renal angiomyolipomas are frequently encountered. Pulmonary involvement is seen in the form of lymphangioleiomyomatosis (typically occurring in females), and ocular involvement typically includes retinal hamartomas. Overall, hamartomatous lesions or low-grade neoplasms predominate in this disease complex. All the above-mentioned lesions are considered major diagnostic features, and a clinical diagnosis of TSC can be made with the identification of two major diagnostic features. A heterozygous pathogenic variant in TSC1 or TSC2 also provides definitive diagnosis.

Neuroimaging of CNS lesions is characteristic with cortical tubers displaying hypointensity on T1-weighted MRI and hyperintensity on T2/FLAIR. Subependymal nodules and subependymal giant cell astrocytomas are often calcified, allowing for easy visualization by CT, and some display post-contrast enhancement. MRI from our patient showed subcortical T2/FLAIR hyperintensity (Image A; top row, asterisks) as well as few subependymal nodules (Image A; bottom row, asterisks).

Gross examination of cortical tubers shows firm, ill-defined lesions with blurring of the gray-white junction. The involved gyri are often enlarged and irregular in shape. Cortical tubers are indistinguishable from lesions in sporadic focal cortical dysplasia type IIb. Subependymal nodules are also firm (often due to calcifications) and project into the ventricles. The majority are found along the lateral ventricles adjacent to the caudate or thalamic nuclei and are less often identified elsewhere in the ventricular system. Multiple subependymal nodules lining the ventricle have been termed “candle gutterings” due to their resemblance to wax dripping down a candle. SEGAs are also most often found in the lateral ventricle and/or near the foramen of Monro, and some have been proven, with serial imaging, to have arisen from subependymal nodules. However, they are larger in size and more likely to cause obstructive hydrocephalus.

Microscopic examination of cortical tubers reveals variable cellularity in the cortex and subcortical white matter with conspicuous disorganization (Image B and Image C). Balloon cells are easy to identify with their large size, abundant eosinophilic cytoplasm that is sometimes vacuolated, eccentric nuclei, and variably prominent nucleoli (Image D, Image E, Image F, and Image G). They can cluster together in an irregular fashion, as in our case, and are typically positive for GFAP and sometimes neuronal markers. Dysmorphic neurons that are enlarged with irregular ramified processes and Nissl substance are also commonly identified in tubers. Just as the gross appearance of cortical tubers can mimic sporadic cortical dysplasia, so can the microscopic appearance. The balloon cells in cortical tubers are identical to those seen in focal cortical dysplasia type IIb (International League Against Epilepsy (ILEA)). Consideration should be given to the possibility of TSC in a patient with multifocal cortical dysplasia type IIb (particularly when presenting at a very young age), even in the absence of family history due to the frequency of de novo mutations.

Microscopically, subependymal nodules are composed of enlarged and sometimes elongated or multinucleated glial cells in a fibrillar and vascular stroma with microcalcifications and overlying intact ependyma. SEGAs are well-circumscribed/solid World Health Organization (WHO) grade I neoplasms that show similar morphologic features to subependymal nodules, including large cells with both astrocytic and neuronal features. Sometimes the distinction between a subependymal nodule and SEGA can be difficult. SEGAs often display fascicular architecture and fibrillar background with calcifications and variable mitoses. Typically, there is no microvascular proliferation or necrosis. Tumor cells can express both glial and neuronal markers, and some have suggested TTF-1 positivity as a marker of SEGA. No consistent molecular alterations have been identified in SEGAs to date, other than biallelic inactivation of TSC1 or TSC2.

While treatment of the sequelae of TSC has been largely symptomatic in the past (surgical resection of epileptogenic foci or other low-grade neoplasms), new studies have shown SEGAs and renal angiomyolipomas can respond to treatment with mTOR inhibitors, specifically everolimus. This therapy is very promising because brain tumors and renal disease are the leading two causes of morbidity and mortality in TSC. In addition, mTOR inhibitors show promising results in the treatment of otherwise medication-refractory epilepsy.

• TSC is a rare, complicated, multisystem disease caused by autosomal dominant loss-of-function variants or deletions in the TSC1 or TSC2 genes.
• Disruption of the tuberin-hamartin complex in tuberous sclerosis leads to dysregulation of cell growth and proliferation via the mTOR cell signaling pathway.
• Common CNS manifestations of TSC include cortical tubers, subependymal nodules, and SEGAs.
• Cortical tubers are characterized microscopically by balloon cells and dysmorphic neurons and are indistinguishable from sporadic cortical dysplasia type IIb (ILAE).
• Subependymal nodules and SEGAs are similar histologically with large, atypical cells having mixed glial and neuronal differentiation.
• Treatment with mTOR inhibitors is very promising in tuberous sclerosis complex patients with SEGAs, medically refractory epilepsy, and renal angiomyolipomas.

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