Tuberous Sclerosis

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Background    Gross Pathology    Histopathology & Immunohistochemistry   Differential Diagnosis    Reference

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: tuberous sclerosis is a systemic disease with the brain as the most frequently affected organ. Clinically it is characterized by seizures, mental retardation and adenoma sebaceum. Pathologically, there is cortical tuber, subependymal nodules, and heterotopia in white matter of the brain. Subependymal giant cell astrocytoma (SEGA) is almost always associated with tuberous sclerosis. Review article- [Webb and Osborne, 1995]

Pathogenesis: the bizarre cells in the subependymal nodules may be pleuripotential and may represent a disruption of both migration and differentiation.

Clinical features:

• Diagnostic criteria: Tuberous sclerosis has been divided into definitive, provisional or suspicious category by clinical criteria [Roach ES et al., 1998], [Gomez MR, 1991].

• Clinical triad: seizures, mental retardation and adenoma sebaceum (facial angiofibroma). Only about 1/3 of the patients express the entire triad. The patients may also have behavioural problems such as hyperactivity.

• Seizures usually manifest in the first few months of life but adenoma sebacum will not appear until about 2 years of age and this will make the diagnosis difficult.

Organs involved:

Brain: The brain is the most frequently affected organ. Pathologic changes include cortical tuber, subependymal nodule, subependymal giant cell astrocytoma, heterotopia in white matter. These changes can be seen in fetus as early as 28 weeks of gestation. The spinal cord and peripheral nerve are rarely affected.

Skin (most common clinical manifestation):

• Hypomelanotic macule (occurs in 90% of patients), sometimes discovered at birth.

• Facial angiofibroma (adenoma sebacum) appears in between 2 and 5 years of age.

• Peri- or subuncal fibroma

• Shagreen patches (fibrous hamartomas of dorsal surfaces, rarely seen before puberty)

• Poliosis and leukotrichia.

Eye: retinal giant cell astrocytoma (occurs in 50% of patients), sometimes bilatera, and may present in children as leukoria. Other ocular features include hypopigmented iris spot, white eyelashes and hamartomata of eyelids and conjunctivae.

Kidney: angiolipoma (occurs in 40-80% of patients).

Heart and vessels: single or multiple cardiac rhabdomyomata (occurs in 25-50% of patients). Most of them are asymptomatic. Moyamoya phenomenon can be seen in tuberous sclerosis.

Bone: Skull may have multiple dipole bone islands. Cystic bone changes can also be seen.

Other organs: lung (lymphangiomyomatosis, may be a limited form), liver, adrenals, gonads, thyroid, teeth, and gums.

Prevalence: 1:6,000-10,000 in adult population [Hunt and Lindenbaum, 1984].

Genetics: autosomal dominant with very high penetrance. Occurrence of affected siblings with apparently unaffected parents is extremely rare [Michel et al., 1983]. TSC1 gene on chromosome 9q34 (gene product is hamartin) and TSC2 gene (gene product is tuberin) on chromosome 16p13.3 are involved. Sporadic cases were first thought of resulted from mutation but CT scans of asymptomatic family members revealed a significant numbers with abnormalities.

• Tuberin is expressed widely in normal organs but they are negative or very weakly expressed in hamartomas and subependymal giant cell astrocytomas.

• A third gene may also be present atchromosome 12q22-24.1, which is closely related to three enzymes including phenylalanine hydroxylase (12q2224).

GROSS PATHOLOGY: Head  

Cortical tubers greatly expand the gyri and blur the margin between gray and white matter. They may also be present in the depth of the sulci. Tubers are firmer on palpation. It may be easier to pick up tubers by palpation than by visual examination. Tubers are occasionally seen in the cerebellum. Calcification is common and can turn the tuber into a stony hard structure. The number of tubers varies and they can be scattered throughout the brain.

Subependymal hamartomas may occur in the 3rd and 4th ventricle and even the aqueduct but the most frequent site is the lateral ventruicles, particularly near the sulcus treminalis with their deep parts embedded in the caudate nucleus or thalamus. Obstruction of the foramen of Monro leading to hydrocephalus is common.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Cortical tubers:

• Cortical architecture: Normal cortical architecture is effaced by collections of large bizarre cells. These bizarre looking cells have amphophilic to slightly eosinophilic homogenous cytoplasm and well-defined cytoplasmic border. They also have stout processes, peripheral vacuolation, eccentric nuclei and prominent nucleoli. Multiple nuclei may be present.

• Immunostaining: The large bizarre cells usually express very little or no GFAP and neurofilament. However, these bizarre cells are positive for vimentin and nestin. Expression and tuberin has also been described.

• Gliosis: There may also be marked gliosis, particularly in the subpial zone where fibers are condensed into sheaf-like structures.

• Myelination: In older individuals myelin staining stops abruptly like a flat plate beneath the abnormal cortex, while the gyral core is depleted of myelin and gliotic.

Subependymal hamartomas:

• Nodules are covered by a thin ependyma and are composed elongated or markedly swollen glial cells and their processes, giant or multinucleated cells, and often marked calcium deposition. The swollen cells are not separated by brain tissue (they do not have an infiltrative pattern as those seen in gemistocytic astrocytoma). They typically have areas containing large pleomorphic cells and areas with spindle cells. Scattered clusters of neuroblasts may be seen in neonate cases. [Click here to see histology]

• Immunohistochemistry, it is not clear whether these bizarre cells are glial or neuronal origin. They may express both GFAP and NFP. Vimentin is usually very strongly expressed. In contrast to the bizarre cells associated with cortical tubers, the bizarre cells in the white matter and subependymal hamartomas express tuberin weakly or not at all.

DIFFERENTIAL DIAGNOSIS: Head  

SEGT from subependymal nodule: the histological distinction between these two entities are far from clear. Interestingly, the giant cells in both the hamartomas and SEGA are HMB-45 (-).  Hamartomas (such as lymphagiomyomatosis in lung) in other part of the body (in one case report) are HMB-45 (+). MIB-1 staining index in SEGA ranges from 0.1 to 3.8, mean=1.1 [Mod Pathol 1997 10:952] [Mod Pathol 1997 10:313] According to Lucy Rorke, these tumors are not astrocytomas and may have neuronal differentiation and should, therefore, be called subependymal giant cell tumor. According to one series, subependymoma giant cell tumor is the most frequently seen tumor of the lateral ventricles of children [Zuccaro G et al., 1999].

Arai Y, Ackerley CA, Becker LE. Loss of the TSC2 product tuberin in subependymal giant-cell tumors. Acta Neuropathol 1999 98:233-9.

Crino PB, Trojanowski JQ, Dichter MA, Eberwine J. Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci U S A 1996 93:14152-7

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Background    Gross Pathology    Histopathology & Immunohistochemistry   Differential Diagnosis    Reference