1. Case Study 65 Kenneth Clark, MD

2. 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.

3. Axial CT Scan

4. Answer Bilateral nodular calcifications of the frontal horns of the lateral ventricles.

5. Question 2 Following a massive retroperitoneal hemorrhage he died. A post mortem examination of the brain revealed several findings. Describe them.

7. 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.

8. ill-defined mass lesions involving the bilateral lateral ventricle floors multiple linear excrescences along the ependymal surface discrete foci of pale discoloration. The gray-white junction in these regions is mildly obscured

9. Question 3 These gross and radiologic features are pathognomonic for what disease?

10. Answer Tuberous Sclerosis Complex

11. 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 slidehere

12. 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. glassy eosinophilic cytoplasm Subependymal Giant Cell Astroctyoma (SEGA)

13. Question 5 Describe the histology of the cortical lesions (tubers). Are these neoplastic? Click here to view the slidehere

14. 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.ballooned cells Tubers are not neoplastic; they are developmental in origin.

15. Question 6 Are there any immunohistochemical stains that might help better appreciate the tuber lesions?

16. 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, SynaptophysinGFAPNeuNSynaptophysin

17. Question 7 What do these immunohistochemical stains tell you about the tuber lesion and likely say about the mental condition of the patient?

18. 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)

19. Question 8 How aggressive are subependymal giant cell astrocytomas (SEGA)?

20. 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.

21. Question 9 What is the cell of origin of the “balloon” cells seen in the cortical tubers?

22. 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.

23. Question 10 What are the genetics involved in TSC?

24. 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

25. Question 11 What are the other manifestation of TSC?

26. 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)

27. 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.