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2012 — October Case of the Month

Posted October 16, 2012

CLINICAL SUMMARY: Brain  

CAP Foundation Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 4-year-old boy who appeared to be previously healthy presented with new-onset seizure. On admission, his physical examination was unremarkable except for small papules on the forehead and bilateral nasal labial folds. A MRI study was performed and showed multifocal regions of high signal intensity in the cerebral cortex located in the right and left frontal lobes, left parietal lobe, and right occipital lobe. Electroencephalogram (EEG) studies localized seizure activity to the left frontal and parietal lobe lesions. The patient underwent gross total excision of the right frontal and parietal lobe lesions. Two resection specimens measuring 3.3 x 2.6 x 1.8 cm and 3.2 x 1.8 x 0.9 cm were received. Upon inspection, both specimens were firm to palpation. On sectioning, the cortex appeared to be expanded in both specimens with a blurring of the gray-white interface.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 31, and is cortical tuber associated with tuberous sclerosis.

Criteria for Diagnosis and Comments:
The diagnosis for this case is cortical tuber associated with tuberous sclerosis. Histological sections of cortical tubers can show variable features. Common to all tubers is a disorganized cortical architectural pattern or cortical dysplasia (malformation of cortical development). This usually consists of an altered cortical architecture, including abnormal cortical layering, an abnormal orientation or positioning of neurons within the cortex, occasional dysmorphic neurons, and large ballooned cells. The ballooned cells are characterized by abundant eosinophilic cytoplasm with eccentrically placed round to oval nuclei. The cortex usually demonstrates marked reactive gliosis, most pronounced under the cortical surface (subpial gliosis) and around blood vessels in the superficial cortex. Dystrophic calcification is variably present.

Immunohistochemistry can be useful in the evaluation of the various cellular components of the tuber. Immunostaining for GFAP or S100 protein is useful in highlighting reactive astrocytes. A subset of the large ballooned cells may also demonstrate weak immunoreactivity with these glial antibodies. Positive immunostaining of the balloon cells with neuronal markers including synaptophysin and neurofilament may also be observed, indicating somewhat aberrant, bimodal differentiation.

Morphologically, the findings in the cortical tuber overlap considerably with other forms of cortical dysplasia; tubers are considered a form of cortical dysplasia in the setting of tuberous sclerosis complex. A major clue to the diagnosis of tuberous sclerosis in this patient is the finding of cutaneous facial stigmata and the multiplicity and bilaterality in the brain of the cortical dysplastic lesions. In cortical dysplasia unassociated with tuberous sclerosis, the tissue that is dysplastic may involve a large portion of brain tissue, but usually does not occur as multiple, discrete foci of dysplasia (i.e. multifocal tubers).

The other major differential diagnostic consideration for the pathologist is to distinguish a tuber from several types of low grade neoplasms. Subependymal giant cell astrocytoma (SEGA) is another tuberous sclerosis-associated lesion that is a somewhat akin to a hamartoma, but is, almost by definition, restricted to the region of the foramen of Monro. Histologically, SEGA is comprised of a population of large astrocytic cells with abundant eosinophilic cytoplasm which can resemble the balloon cells encountered in the cortical tuber. In the SEGA, however, the giant astrocytes are often more numerous, focally confluent, and usually intermixed with a second population of atypical astrocytic cells marked by a high nuclear to cytoplasmic ratio. Also, in contrast to the balloon cells tubers, these large astrocytes frequently demonstrate diffuse and strong immunoreactivity for GFAP and S100 protein.

Distinction of the cortical tuber from ganglioglioma is also another diagnostic consideration. Gangliogliomas are often associated with patients who similarly present with medically-intractable epilepsy. In contrast to tubers, which are often multifocal, gangliogliomas are uni-focal masses, most commonly arising in the temporal lobe region. What sets ganglioglioma apart from a cortical tuber is the presence of both an atypical ganglion cell as well as an atypical gliomatous component. Although occasional dysmorphic-appearing ganglionic cells may be observed in a cortical tuber, these are a more conspicuous feature in a ganglioglioma. Most distinctive of ganglioglioma, however, is the presence of a true neoplastic, glioma component that usually resembles a low grade astrocytoma, pilocytic-type astrocytoma, or sometimes low grade oligodendroglioma. Although gliosis in a cortical tuber may be focally prominent, reactive astrocytes generally lack the atypia or the increased cell density that marks the glioma component of the ganglioglioma.

In instances of cortical tubers which have a relative paucity of balloon cells, the lesion may resemble a low grade diffuse, fibrillary astrocytoma. The presence of balloon cells is generally not a feature of a fibrillary astrocytoma so the finding of balloon cells should be serve as a “red flag” against the diagnosis of a diffuse astrocytoma. Fibrillary astrocytoma is also marked by a population of clearly malignant cells with high nuclear cytoplasmic ratio, nuclear irregularities, and nuclear hyperchromasia. Rare mitotic figures may also be observed, which would be distinctly unusual in a cortical tuber.

Conversely, in examples of tubers which are balloon cell-rich, the lesion may resemble a gemistocytic astrocytoma. Gemistocytic astrocytoma is also marked by a population of large cells with abundant eosinophilic cytoplasm that are strongly GFAP and S100 protein positive and do not stain with neuronal-related antibodies. Gemistocytic astrocytoma will also have an admixed subpopulation of atypical astrocytic cells with high nuclear to cytoplasmic ratio and morphology resembling tumor cells seen in the diffuse, fibrillary astrocytomas.

The diagnosis of patients with tuberous sclerosis complex is usually made based on the presence of specific criteria identifiable on physical examination or imaging studies. Central nervous system pathology including cortical tubers along with subependymal giant cell astrocytomas and subependymal nodules represent major criteria for diagnosis of tuberous sclerosis. The vast majority of patients, approximately 80 to 85%, usually have experienced seizures during their clinical course. In addition to the CNS pathology, patients with tuberous sclerosis complex may develop lesions in a wide variety of other organ systems including the skin, eye, heart, kidney, gastrointestinal tract, teeth, and bone.

On imaging studies, cortical tubers are difficult to detect on CT imaging unless calcified. On MRI studies, low T1 signal is found in subcortical region of some tubers and increased gyral intensity on T2-weighted images. There has been some correlation of severity of cerebral impairment in tuberous sclerosis complex patients with number of tubers utilizing MRI studies.

In the last two decades, there has been considerable advancement in our understanding of the genetics of the tuberous sclerosis (TS) complex. The complex is an autosomal dominant disorder with a high spontaneous mutation rate. Sporadic cases account for approximately two-thirds of patients afflicted with TS complex. Genetic linkage studies have identified different subsets based on the involvement of two distinct genetic loci: one on chromosome 9q34 (TSC1) and the other on chromosome 16p13 (TSC2). The TSC2 gene encodes for tuberin. Mutations within the TSC2 gene appear to be distributed throughout the gene and are generally more common than the TSC1 mutations in sporadic tuberous sclerosis complex patients. The TSC1 gene protein product is hamartin. Many of the TSC1 mutations cause premature protein truncation.

Antibodies directed at hamartin and tuberin exist and have been noted on immunohistochemical studies to localize within tubers. Give the diversity of lesions observed in the TS complex, it would seem that gene products of TSC1 and TSC2 have different effects on the growth and differentiation of cells, as well as on cell function in multiple organ systems.

The treatment of TS complex patients is often directed at complications related to various pathologies found in that individual. Anti-epileptogenetic medications are used to control seizure activity. Intractable seizures related to a particular tuber may prompt neurosurgical resection of the lesion, usually with good postoperative results.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which disorder is marked by architectural disorganization of the cortex outside the setting of tuberous sclerosis complex? A. Cortical dysplasia (malformation of cortical development)
B. Cortical tuber associated with tuberous sclerosis
C. Diffuse, fibrillary astrocytoma
D. Ganglioglioma
E. Gemistocytic astrocytoma
F. Subependymal giant cell astrocytoma
2. Which lesion represents a hamartomatous, intraventricular mass in patients with tuberous sclerosis complex? A. Cortical dysplasia (malformation of cortical development)
B. Cortical tuber associated with tuberous sclerosis
C. Diffuse, fibrillary astrocytoma
D. Ganglioglioma
E. Gemistocytic astrocytoma
F. Subependymal giant cell astrocytoma
3. Which lesion is marked by an atypical neuronal cell component admixed with areas resembling pilocytic astrocytoma? A. Cortical dysplasia (malformation of cortical development)
B. Cortical tuber associated with tuberous sclerosis
C. Diffuse, fibrillary astrocytoma
D. Ganglioglioma
E. Gemistocytic astrocytoma
F. Subependymal giant cell astrocytoma

References

  1. Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ. Molecular genetic advances in tuberous sclerosis. Hum Genet. 2000;107:97-114.
  2. Franz DN. Diagnosis and management of tuberous sclerosis complex. Semin Pediatr Neurol. 1998;5:253-268.
  3. Goodman M, Lamm SH, Engel A, et al. Cortical tuber count: A biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol. 1997;12:85-90.
  4. Hyman MH, Whittemore VH. National Institute of Health consensus conference: Tuberous sclerosis complex. Arch Neurol. 2000;57:662-665.
  5. Johnson MW, Emelin JK, Park SH, Vinters HV. Co-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain Pathol. 1999;9:45-54.
  6. Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol. 2000;15:652-659.
  7. Nixon JR, Houser OW, Gomez MR, Okazaki H. Cerebral tuberous sclerosis: MRI imaging. Radiology. 1989;170(pt 1):869-873.
  8. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: Revised clinical diagnosis criteria. J Child Neurol. 1998;13:624-628.
  9. Sampson JR, Harris PC. The molecular genetics of tuberous sclerosis. Hum Mol Genet. 1994;3:1477-1480.
  10. Short MP, Richardson Jr EP, Haines JL, Kwiatkowski DJ. Clinical, neuropathological and genetic aspects of the tuberous sclerosis complex. Brain Pathol. 1995;5:173-179.
  11. Sparagana SP, Roach ES. Tuberous sclerosis complex. Curr Opin Neurol. 2000;13:115-119.
  12. Weiner DM, Ewalt DH, Roach ES, Hensle TW. The tuberous sclerosis complex: A comprehensive review. J Am Coll Surg. 1998;187:548-561.

Author:
2009
Richard A. Prayson, MD FCAP
Neuropathology Committee
The Cleveland Clinic Foundation
Cleveland, OH