Case Study 65
Kenneth Clark, MD
Question 1
• This is a 62-year-old man with a history of mild
mental retardation and bilateral renal
angiomyolipomas. A recent CT scan of the head
revealed distinct findings.
• Describe them.
Axial CT Scan
Answer
• Bilateral nodular calcifications of the frontal
horns of the lateral ventricles.
Question 2
• Following a massive retroperitoneal hemorrhage
he died. A post mortem examination of the brain
revealed several findings. Describe them.
Answer
• The ventricles appear mildly and asymmetrically
enlarged. There are ill-defined mass lesions
involving the bilateral lateral ventricle floors.
Both lesions are well-circumscribed and
encroach on the adjacent basal ganglia
structures. There are variegated tan-brown in
color with minute foci of hemorrhage and partial
calcification. In addition, the are multiple linear
excrescences along the ependymal surface that
are slightly firm on palpation; these measure 2
mm in width and up to 3 cm in length. The
cortical ribbon shows multiple discrete foci of
pale discoloration. The gray-white junction in
these regions is mildly obscured.
multiple linear excrescences
along the ependymal surface
ill-defined mass lesions involving
the bilateral lateral ventricle floors
discrete foci of pale discoloration.
The gray-white junction in these
regions is mildly obscured
Question 3
• These gross and radiologic features are
pathognomonic for what disease?
Answer
• Tuberous Sclerosis Complex
Question 4
• Describe the histology of the bilateral lesions of
the floor of the lateral ventricles. What is the
diagnosis?
• Click here to view the slide
Answer
• The mass lesions of the lateral ventricle floors
show neoplastic proliferations of ovoid cells with
glassy eosinophilic cytoplasm and large nuclei.
These cells are embedded within a dense gliotic
background with sclerotic hyalinized vessels and
extensive multifocal calcification.
• Subependymal Giant Cell Astroctyoma (SEGA)
Question 5
• Describe the histology of the cortical lesions
(tubers). Are these neoplastic?
• Click here to view the slide
Answer
• Sections of cortex show patchy effacement of
laminar architecture with several associated
features including marked pial fibrillary gliosis,
micro-calcifications, and numerous large, bizarre
and ballooned cells within the grey and deep
white matter. These balloon cells show
homogeneous glassy, bright eosinophilic
cytoplasm and often multi-nucleation. Very
atypical, enlarged neurons are also scattered
throughout.
• Tubers are not neoplastic; they are
developmental in origin.
Question 6
• Are there any immunohistochemical stains that
might help better appreciate the tuber lesions?
Answer
• GFAP (to highlight the gliosis)
• NeuN (to ascertain the degree of cortical
dysplasia and laminar effacement)
• Synaptophysin (to determine to the degree
of neuronal depletion and associated
synaptic loss
• Click to see GFAP, NeuN, Synaptophysin
Question 7
• What do these immunohistochemical
stains tell you about the tuber lesion and
likely say about the mental condition of the
patient?
Answer
• GFAP staining highlights the dense gliosis of the
cortical tuber lesions. NeuN staining highlights
the paucity of neurons and disruption of laminar
structure within the tuber lesions, and aberrant
NeuN staining in residual neurons likely
indicates neuronal dysplasia/dysfunction.
Synaptophysin also highlights the degree of
synaptic/neuronal depletion within the tuber.
• These explain the varying degrees of mental
retardation seen in patients with Tuberous
Sclerosis Complex (TSC)
Question 8
• How aggressive are subependymal giant
cell astrocytomas (SEGA)?
Answer
• SEGA is a benign, slow growing tumor (WHO
grade 1) that characteristically arises in the walls
of the lateral ventricles. They have no known
potential for malignant transformation. Clinically,
SEGAs occuring near the foramen of Monro can
result in obstructive hydrocephalus with resultant
symptoms related to increased intracranial
pressure.
Question 9
• What is the cell of origin of the “balloon”
cells seen in the cortical tubers?
Answer
• The cell of origin of the balloon cells is
unknown. Histologically they show both
glial and neuronal type features, however
immunohistochemical staining for glial
(GFAP) and neuronal (NeuN,
Synaptophysin) markers are completely
inconsistent and most often negative. It is
thought that the cell of origin is a mixed
glioneuronal progenitor cell.
Question 10
• What are the genetics involved in TSC?
Answer
• 60% of cases are sporadic, 40% inherited
• Autosomal Dominant with ~95% Penetrance
• Two Genes Idenfied
– TSC1 (9q34, 23 exons)  HAMARTIN
– TSC2 (16p13.3, 41 exons)  TUBERIN
• TSC1 mutations are generally less severe than
TSC2 mutations
• Tumor Suppressor Genes
• Two hits for disease manifestations
Question 11
• What are the other manifestation of TSC?
Answer
–
–
–
–
Angiomyolipomas (kidneys)
Pulmonary lymphangioleoimyomatosis
Cardiac rhabdomyomas
Skin Manifestations
• Facial Angiofibromas (adenoma sebaceum)
• Periungual Fibromas
• Hypomelanotic Macules
• Shagreen Patches (thick skin with dimpled orange
peel appearance)
References
• Louis D, Ohgaki H, Wiestler O, Cavanee W. WHO Classification of
Tumours of the Central Nervous System. IARC: Lyon 2007.
• Crino P, Aronica E, Baltuch G, and Nathanson K. Biallelic TSC
Gene Inactivation in Tuberous Sclerosis Complex. Neurology
(2010). 74:1716-1723.
• Grajkowska W, Kotulska K, Jurkiewicz E, and Matyja E. Brain
Lesions in Tuberous Sclerosis Complex (Review). Folia
Neuropathologica (2010). 48(3):139-149.
• Inoki K and Guan K. Tuberous Sclerosis Complex, Implication from
a Rare Genetic Disease to Common Cancer Treatment. Human
Molecular Genetics (2009). 18(1):R94-R100.
• Jones A, Deniells C, Snell R, Tachataki M, Idziaszcyk S, Krawczak
M, Sampson J, and Cheadle J. Molecular Genetic and Phenotypic
Analysis Reveals Differences Between TSC1 and TSC2 Associated
Familial and Sporadic Tuberous Sclerosis. Human Molecular
Genetics (1997). 6(12):2155-2161.
• Henske E, Wessner L, Golden J, et al. Loss of TSC2 in Both
Subependymal Giant Cell Astrocytomas and Angiomyolipomas
Supports a Two-Hit Model for the Pathogenesis of Tuberous
Sclerosis Tumors. Am J Pathol (1997). 151:1639–1647.