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Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas
Journal of Cancer Research and Practice xxx (2017) 1e4
Contents lists available at ScienceDirect
Journal of Cancer Research and Practice journal homepage: http://www.journals.elsevier.com/journal-of-cancerresearch-and-practice
Case Report
Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas Shehla Iftikhar a, Iftikhar Ahmad a, *, Imran Masoud Qasmi b, Khushnaseeb Ahmad a, Hina Manzoor a a b
Center for Nuclear Medicine and Radiotherapy (CENAR), Quetta, Pakistan Combined Military Hospital, Quetta, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 February 2017 Received in revised form 9 May 2017 Accepted 17 May 2017 Available online xxx
Tuberous sclerosis complex (TSC) is a rare autosomal disorder that typically affects children. The manifestations of TSC include development of benign lesions in various organs, primarily in the brain, skin, kidneys, heart, and lungs. TSC management often involves multidisciplinary specialties. Herein, we present a case of a 5-year-old male patient who presented with a headache, vomiting and fever. Radiological assessment demonstrated a lobulated enhancing tumor in the right lateral ventricle near the foramen of Monro for which he underwent craniotomy (total tumor resection), which turned out to be subependymal giant cell astrocytomas upon histopathological examination. A follow-up MRI after 10 months showed cortical dysplasias, with tiny subependymal nodules. Dermatology examination revealed hypomelanotic macules, angiofibromas and shagreen patch. At his one-year follow-up, the patient exhibited normal mental and physical growth. Therefore, calling attention to TSC diagnosis and management depending upon the particular presentation may improve the quality of life of TSC patients. © 2017 The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Tuberous sclerosis complex Subependymal giant cell astrocytoma Angiofibromas Hamartoma
1. Introduction Tuberous sclerosis complex (TSC) is a rare autosomal dominant syndrome caused by mutations or defects in either of two genes: TSC-1, located on chromosome 9 (9q34), and TSC-2, located on chromosome 16 (16p 13.3). The complex caused by each of these two genes appears to be phenotypically identical.1 TSC is typically characterized by the array of benign growths at several body parts. Specifically, it may affect organs like the brain, heart, eyes, skin, lungs, kidneys, and teeth.2 Subsequently, significant health complications such as seizures, intellectual disability, developmental delay, behavior change, and autism may be observed in individuals presenting with TSC.3 The brain lesions that usually arise in TSC include subependymal giant cell astrocytoma (SEGA), migrational anomalies, subependymal nodules, cortical dysplasias and hamartomas of the cerebral and cerebellar cortex.4 However, it has been suspected that only SEGAs are likely to enlarge (although histologically benign),
* Corresponding author. Center for Nuclear Medicine and Radiotherapy (CENAR), Quetta, Pakistan. E-mail address: [email protected] (I. Ahmad). Peer review under responsibility of The Chinese Oncology Society.
and capable of causing progressive neurologic dysfunction/symptoms. SEGAs typically evolve from subependymal nodules located in the anterior lateral ventricles. The incidence of SEGA tumors occur in 6e14% of cases involving tuberous sclerosis.5 Total surgical resection or medical therapy based on mammalian target of rapamycin (mTOR) inhibitors is the treatment of choice for most patients with SEGA. Enlargement and local invasion of the tumor may complicate the desired treatment outcomes.6 Consequently, early recognition of SEGA facilitates improved prognosis. Herein, we have presented a case of TSC accompanied by SEGA, among six major TSC features, in a young child (age ¼ 5 years) and herein share our treatment experience. 2. Case report A 5-year-old male child presented with headache, vomiting and fever of one month's duration. The patient had a history of several episodes of fits during his first year of life. A subsequent brain magnetic resonance (MR) study revealed avidly enhancing mass lesion in the right lateral ventricle near the foramen of Monro, causing mild bilateral venriculomegaly signifying moderate hydrocephalous (Fig. 1A). The tumor was located just above the interventricular foramen of Monro. Total surgical resection of the
http://dx.doi.org/10.1016/j.jcrpr.2017.05.002 2311-3006/© 2017 The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
2
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
Fig. 1. MR images of the brain; (A) pre-surgery MR images showing lobulated avidly enhancing signal intensity lesion in right ventricle and moderate dilation of bilateral lateral ventricles which signify moderate hydrocephalous, and (B, C) post-surgery MR images showing no residual/recurrent tumor in the right ventricle. A small CSF signal intensity area is noted along the right frontal horn likely post-surgical changes.
mass was performed by way of right frontal craniotomy, and cerebral spinal fluid (CSF) diversion (i.e., shunt) was not considered necessary. Post-surgical MR imaging (Fig. 1B and C) showed no residual tumor. The patient's complaints were resolved and performance status improved to ECOG zero. Histopathology revealed sheets of gemistiocytes, ganglion-like
cells and spindle-shaped astrocytes; perivascular pseudo-rosettes were also seen. Immunohistochemistry staining patterning was as follows: Ki-67 was low, GFAP and EMA were positive. All of these findings were suggestive of SEGA (WHO grade I) of the right ventricle. Follow-up MR imaging after six months demonstrated
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
abnormal hyperintensegyral thickening, focal deep white matter, abnormal signal intensity lesions and non-enhancing small subependymal nodule in body of right lateral ventricle (Fig. 2). Such findings suggested cortical tubers, band heterotopias and subependymal hamartoma, supporting the suspicion towards TSC. Dermatological examination revealed cutaneous angiofibromas of the face, shagreen patches on the forehead and lateral neck, 3e4 hypo-pigmented patches on the trunk and legs (Fig. 3). Ultrasound of the patient's abdomen was unremarkable, and no renal abnormality was noted. Additionally, ophthalmological, cardiac, dental and chest examinations (on x-rays), and family history were all unremarkable.
3. Discussion Clinical symptoms of tuberous sclerosis typically manifest at an early age, typically before 10 years of age. However, it is exceedingly rare in neonates and uncommon in adults. Recently, the diagnostic criteria for TSC have been established.4 Specifically, eleven major and six minor features have been attributed to TCS, which are described in Table 1. However, the definite TSC diagnosis is confirmed with the expression of two major or one major and two minor features. Furthermore, the presence of one major and one minor feature is termed as a “probable” TSC diagnosis, while the “possible” TSC diagnosis manifests one major or two minor features. That said, expression of two major or one major with two (or more than two) minor features confirms TCS diagnosis. In our patient, however, it was interesting to note that 6 major criteria were present, making it a very conspicuous presentation of TSC. In our case, three out of four major skin features (i.e., hypomelanotic macules, angiofibromas, shagreen patch; Fig. 2) and all three major brain features (i.e., cortical dysplasia, subependymal nodule, and SEGA) were observed. However, major criteria features of TSC related to the eyes (i.e., multiple retinal hamartomas), heart (i.e., cardiac rhabdomyoma), lungs (i.e., lymphangioleiomyomatosis; LAM) and kidneys (i.e., angiomyolipomas) were not observed. Also, no minor features of TSC were expressed by the patient. Optimal therapeutic options typically vary from case to case in the management of TSC. For instance, TSC associated skin lesions have been treated by surgical excision (including dermabrasion, vascular lasers, ablative lasers and physically destructive techniques such as shave excision and electrodessication) and mammalian target of rapamycin (mTOR) inhibitors for SEGA.7e10 It has been recommended that detailed dermatologic inspection of the skin lesions should be performed periodically for rapidly changing, disfiguring, or symptomatic lesions towards the implementation of any specific mode of therapy.11 Moreover, early intervention has been recommended for bleeding, potentially
3
disfiguring or symptomatic (i.e., problematic or negatively affecting function) skin lesions.11 Some manifestations of TSC, like SEGA, usually appear in childhood, as seen in our patient; however, these manifestations are likely to diminish in adulthood, without causing new problems. Nevertheless, patients who presented with SEGA in childhood should be radiologically monitored for lifetime duration to monitor for possible growth; alternatively, continued monitoring is not required for patients who have not demonstrated SEGA by the age of 25.10 Moreover, surgical resection or medical therapy, depending on whether SEGA is symptomatic or asymptomatic, can in fact be effective.9 It has been recommended that the choice of therapeutic modality should take crucial factors such as risk of complications, expected length and cost of treatment, into considerations.6 In our patient, total resection of the SEGA was performed due to ventricle enlargement. Surgical resection also appears beneficial for releasing elevated intracranial pressure caused by ventricular obstruction. The tumor in our patient was located near the foramen of Monro, probably blocking the CSF traffic and subsequently increasing the intra-cranial pressure. This speculation was supported by the observation that symptoms such as headache were relieved after tumor resection. MRI assessment of a patient has crucial practical consequences to most optimally plan surgical resection in TSC. The epileptogenic zone in TSC patients has been identified with MRI alone, with high sensitivity and specificity.12 In particular, typical changes of TSC such as tubers, cystic changes, and calcifications were identified. Further, abnormalities caused by focal cortical dysplasia such as increased cortical thickness, transmantle change, abnormal gyration, gray/white matter junction blurring were also identified on MR imaging.12,13 Moreover, TSC associated tubers have been classified in three types, based on the MRI signal intensity, which are also correlated to genetics and clinical manifestations.14 In addition to MRI, ultrasound and CT also play critical roles in the diagnostic workup (e.g., renal, cardiac, hepatic and splenic manifestations) of TSC.15
4. Conclusion TSC is a rare autosomal dominant neurocutaneous disorder which provokes the development of several benign tumors. TSC typically affects the brain, skin, retina, lungs and kidneys. In this study, we presented a case of TSC where the disease manifestations were observed in both the brain and skin. TSC-associated SEGA was treated with complete surgical resection. Specifically, three major manifestations of both brain (i.e., cortical dysplasia, subependymal nodules, SEGA) and skin (i.e., hypomelanotic macules, angiofibromas, shagreen patch) were observed. The patient was treated
Fig. 2. Follow-up (six months) MR images showing FLAIR-dependent hyperintense signals in the bilateral fronto-parietal regions signifying cortical tubers with associated abnormal gyral thickening (square box) and radial band (encircled). A small sub-ependymal nodule (hamartoma) may also be noted (arrow).
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
4
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
Fig. 3. Dermatology manifestation of TSC; (A) showing multiple small facial angiofibromas, (B) hypomelanotic macule on the lower back, (C, D) shagreen patches on forehead and lateral neck.
References
Table 1 Diagnostic criteria for tuberous sclerosis complex.4 Major features
Minor features
Hypomelanotic macules (with 3, at least 5-mm diameter) Angiofibromas (3) Ungual fibromas (2) Shagreen patch Multiple retinal hamartomas Cortical dysplasias Subependymal nodules Subependymal giant cell astrocytoma Cardiac rhabdomyoma Lymphangioleiomyomatosis Angiomyolipomas (2)
“Confetti” skin lesions Dental enamel pits (>3) Intraoral fibromas (2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas
with total surgical resection for the brain tumor. Subsequently, the systemic symptoms (e.g., headache) were relieved and performance status improved at the time of one-year follow-up. The patient has normal mental and physical growth.
Conflict of interest None.
Acknowledgements The authors are thankful to Dr. Fazalur Rehman Panezai of BMC and Mushtaq Ahmad, Dr. Ali Yousaf, Dr. Nazia Dildar, Dr. Umer Aamir and Dr. Uzma Bashir of the Combined Military Hospital, Quetta, Pakistan for their expertise and opinions regarding neurology, radiology and dermatology findings.
1. Au KS, Williams AT, Gambello MJ, Northrup H. Molecular genetic basis of tuberous sclerosis complex; from bench to bedside. J Child Neurol. 2004;19: 699e799. 2. Romanelli P, Verdecchia M, Rodas R, Seri S, Curatolo P. Epilepsy surgery for tuberous sclerosis. Pediatr Neurol. 2004;31:239e247. 3. Syed KN. Tuberous sclerosis. J Pak Med Assoc. 2010;60:683e685. 4. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:243e254. 5. Haque S. Tuberous sclerosis complex: a case report. Chattagram Maa-O-Shishu Hosp Med Coll J. 2014;13:89e92. 6. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:255e265. 7. Papadavid E, Markey A, Bellaney G, Walker NP. Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis. Br J Dermatol. 2002;147:337e342. 8. Birca A, Mercier C, Major P. Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex. J Neurosurg Pediatr. 2010;6:381e384. 9. Kotulska K, Borkowska J, Roszkowski M, et al. Surgical treatment of subependymal giant cell astrocytoma in tuberous sclerosis complex patients. Pediatr Neurol. 2014;50:307e312. 10. Roth J, Roach ES, Bartels U, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the international tuberous sclerosis complex consensus conference 2012. Pediatr Neurol. 2013;49: 439e444. 11. Teng JC, Cowen EW, Wataya-Kaneda M, et al. Dermatologic and dental aspects of the 2012 international tuberous sclerosis complex consensus statements. JAMA Dermatol. 2014;150:1095e1101. 12. Jahodova A, Krsek P, Kyncl M, et al. Distinctive MRI features of the epileptogenic zone in children with tuberous sclerosis. Eur J Radiol. 2014;83:703e709. 13. House PM, Holst B, Lindenau M, et al. Morphometric MRI analysis enhances visualization of cortical tubers in tuberous sclerosis. Epilepsy Res. 2015;117: 29e34. 14. Gallagher A, Grant EP, Mada N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol. 2011;257:1373e1381. 15. Manoukian SB, Kowal DJ. Comprehensive imaging manifestations of tuberous sclerosis. Am J Roentgenol. 2015;204:933e943.
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
Contents lists available at ScienceDirect
Journal of Cancer Research and Practice journal homepage: http://www.journals.elsevier.com/journal-of-cancerresearch-and-practice
Case Report
Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas Shehla Iftikhar a, Iftikhar Ahmad a, *, Imran Masoud Qasmi b, Khushnaseeb Ahmad a, Hina Manzoor a a b
Center for Nuclear Medicine and Radiotherapy (CENAR), Quetta, Pakistan Combined Military Hospital, Quetta, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 February 2017 Received in revised form 9 May 2017 Accepted 17 May 2017 Available online xxx
Tuberous sclerosis complex (TSC) is a rare autosomal disorder that typically affects children. The manifestations of TSC include development of benign lesions in various organs, primarily in the brain, skin, kidneys, heart, and lungs. TSC management often involves multidisciplinary specialties. Herein, we present a case of a 5-year-old male patient who presented with a headache, vomiting and fever. Radiological assessment demonstrated a lobulated enhancing tumor in the right lateral ventricle near the foramen of Monro for which he underwent craniotomy (total tumor resection), which turned out to be subependymal giant cell astrocytomas upon histopathological examination. A follow-up MRI after 10 months showed cortical dysplasias, with tiny subependymal nodules. Dermatology examination revealed hypomelanotic macules, angiofibromas and shagreen patch. At his one-year follow-up, the patient exhibited normal mental and physical growth. Therefore, calling attention to TSC diagnosis and management depending upon the particular presentation may improve the quality of life of TSC patients. © 2017 The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Tuberous sclerosis complex Subependymal giant cell astrocytoma Angiofibromas Hamartoma
1. Introduction Tuberous sclerosis complex (TSC) is a rare autosomal dominant syndrome caused by mutations or defects in either of two genes: TSC-1, located on chromosome 9 (9q34), and TSC-2, located on chromosome 16 (16p 13.3). The complex caused by each of these two genes appears to be phenotypically identical.1 TSC is typically characterized by the array of benign growths at several body parts. Specifically, it may affect organs like the brain, heart, eyes, skin, lungs, kidneys, and teeth.2 Subsequently, significant health complications such as seizures, intellectual disability, developmental delay, behavior change, and autism may be observed in individuals presenting with TSC.3 The brain lesions that usually arise in TSC include subependymal giant cell astrocytoma (SEGA), migrational anomalies, subependymal nodules, cortical dysplasias and hamartomas of the cerebral and cerebellar cortex.4 However, it has been suspected that only SEGAs are likely to enlarge (although histologically benign),
* Corresponding author. Center for Nuclear Medicine and Radiotherapy (CENAR), Quetta, Pakistan. E-mail address: [email protected] (I. Ahmad). Peer review under responsibility of The Chinese Oncology Society.
and capable of causing progressive neurologic dysfunction/symptoms. SEGAs typically evolve from subependymal nodules located in the anterior lateral ventricles. The incidence of SEGA tumors occur in 6e14% of cases involving tuberous sclerosis.5 Total surgical resection or medical therapy based on mammalian target of rapamycin (mTOR) inhibitors is the treatment of choice for most patients with SEGA. Enlargement and local invasion of the tumor may complicate the desired treatment outcomes.6 Consequently, early recognition of SEGA facilitates improved prognosis. Herein, we have presented a case of TSC accompanied by SEGA, among six major TSC features, in a young child (age ¼ 5 years) and herein share our treatment experience. 2. Case report A 5-year-old male child presented with headache, vomiting and fever of one month's duration. The patient had a history of several episodes of fits during his first year of life. A subsequent brain magnetic resonance (MR) study revealed avidly enhancing mass lesion in the right lateral ventricle near the foramen of Monro, causing mild bilateral venriculomegaly signifying moderate hydrocephalous (Fig. 1A). The tumor was located just above the interventricular foramen of Monro. Total surgical resection of the
http://dx.doi.org/10.1016/j.jcrpr.2017.05.002 2311-3006/© 2017 The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
2
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
Fig. 1. MR images of the brain; (A) pre-surgery MR images showing lobulated avidly enhancing signal intensity lesion in right ventricle and moderate dilation of bilateral lateral ventricles which signify moderate hydrocephalous, and (B, C) post-surgery MR images showing no residual/recurrent tumor in the right ventricle. A small CSF signal intensity area is noted along the right frontal horn likely post-surgical changes.
mass was performed by way of right frontal craniotomy, and cerebral spinal fluid (CSF) diversion (i.e., shunt) was not considered necessary. Post-surgical MR imaging (Fig. 1B and C) showed no residual tumor. The patient's complaints were resolved and performance status improved to ECOG zero. Histopathology revealed sheets of gemistiocytes, ganglion-like
cells and spindle-shaped astrocytes; perivascular pseudo-rosettes were also seen. Immunohistochemistry staining patterning was as follows: Ki-67 was low, GFAP and EMA were positive. All of these findings were suggestive of SEGA (WHO grade I) of the right ventricle. Follow-up MR imaging after six months demonstrated
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
abnormal hyperintensegyral thickening, focal deep white matter, abnormal signal intensity lesions and non-enhancing small subependymal nodule in body of right lateral ventricle (Fig. 2). Such findings suggested cortical tubers, band heterotopias and subependymal hamartoma, supporting the suspicion towards TSC. Dermatological examination revealed cutaneous angiofibromas of the face, shagreen patches on the forehead and lateral neck, 3e4 hypo-pigmented patches on the trunk and legs (Fig. 3). Ultrasound of the patient's abdomen was unremarkable, and no renal abnormality was noted. Additionally, ophthalmological, cardiac, dental and chest examinations (on x-rays), and family history were all unremarkable.
3. Discussion Clinical symptoms of tuberous sclerosis typically manifest at an early age, typically before 10 years of age. However, it is exceedingly rare in neonates and uncommon in adults. Recently, the diagnostic criteria for TSC have been established.4 Specifically, eleven major and six minor features have been attributed to TCS, which are described in Table 1. However, the definite TSC diagnosis is confirmed with the expression of two major or one major and two minor features. Furthermore, the presence of one major and one minor feature is termed as a “probable” TSC diagnosis, while the “possible” TSC diagnosis manifests one major or two minor features. That said, expression of two major or one major with two (or more than two) minor features confirms TCS diagnosis. In our patient, however, it was interesting to note that 6 major criteria were present, making it a very conspicuous presentation of TSC. In our case, three out of four major skin features (i.e., hypomelanotic macules, angiofibromas, shagreen patch; Fig. 2) and all three major brain features (i.e., cortical dysplasia, subependymal nodule, and SEGA) were observed. However, major criteria features of TSC related to the eyes (i.e., multiple retinal hamartomas), heart (i.e., cardiac rhabdomyoma), lungs (i.e., lymphangioleiomyomatosis; LAM) and kidneys (i.e., angiomyolipomas) were not observed. Also, no minor features of TSC were expressed by the patient. Optimal therapeutic options typically vary from case to case in the management of TSC. For instance, TSC associated skin lesions have been treated by surgical excision (including dermabrasion, vascular lasers, ablative lasers and physically destructive techniques such as shave excision and electrodessication) and mammalian target of rapamycin (mTOR) inhibitors for SEGA.7e10 It has been recommended that detailed dermatologic inspection of the skin lesions should be performed periodically for rapidly changing, disfiguring, or symptomatic lesions towards the implementation of any specific mode of therapy.11 Moreover, early intervention has been recommended for bleeding, potentially
3
disfiguring or symptomatic (i.e., problematic or negatively affecting function) skin lesions.11 Some manifestations of TSC, like SEGA, usually appear in childhood, as seen in our patient; however, these manifestations are likely to diminish in adulthood, without causing new problems. Nevertheless, patients who presented with SEGA in childhood should be radiologically monitored for lifetime duration to monitor for possible growth; alternatively, continued monitoring is not required for patients who have not demonstrated SEGA by the age of 25.10 Moreover, surgical resection or medical therapy, depending on whether SEGA is symptomatic or asymptomatic, can in fact be effective.9 It has been recommended that the choice of therapeutic modality should take crucial factors such as risk of complications, expected length and cost of treatment, into considerations.6 In our patient, total resection of the SEGA was performed due to ventricle enlargement. Surgical resection also appears beneficial for releasing elevated intracranial pressure caused by ventricular obstruction. The tumor in our patient was located near the foramen of Monro, probably blocking the CSF traffic and subsequently increasing the intra-cranial pressure. This speculation was supported by the observation that symptoms such as headache were relieved after tumor resection. MRI assessment of a patient has crucial practical consequences to most optimally plan surgical resection in TSC. The epileptogenic zone in TSC patients has been identified with MRI alone, with high sensitivity and specificity.12 In particular, typical changes of TSC such as tubers, cystic changes, and calcifications were identified. Further, abnormalities caused by focal cortical dysplasia such as increased cortical thickness, transmantle change, abnormal gyration, gray/white matter junction blurring were also identified on MR imaging.12,13 Moreover, TSC associated tubers have been classified in three types, based on the MRI signal intensity, which are also correlated to genetics and clinical manifestations.14 In addition to MRI, ultrasound and CT also play critical roles in the diagnostic workup (e.g., renal, cardiac, hepatic and splenic manifestations) of TSC.15
4. Conclusion TSC is a rare autosomal dominant neurocutaneous disorder which provokes the development of several benign tumors. TSC typically affects the brain, skin, retina, lungs and kidneys. In this study, we presented a case of TSC where the disease manifestations were observed in both the brain and skin. TSC-associated SEGA was treated with complete surgical resection. Specifically, three major manifestations of both brain (i.e., cortical dysplasia, subependymal nodules, SEGA) and skin (i.e., hypomelanotic macules, angiofibromas, shagreen patch) were observed. The patient was treated
Fig. 2. Follow-up (six months) MR images showing FLAIR-dependent hyperintense signals in the bilateral fronto-parietal regions signifying cortical tubers with associated abnormal gyral thickening (square box) and radial band (encircled). A small sub-ependymal nodule (hamartoma) may also be noted (arrow).
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002
4
S. Iftikhar et al. / Journal of Cancer Research and Practice xxx (2017) 1e4
Fig. 3. Dermatology manifestation of TSC; (A) showing multiple small facial angiofibromas, (B) hypomelanotic macule on the lower back, (C, D) shagreen patches on forehead and lateral neck.
References
Table 1 Diagnostic criteria for tuberous sclerosis complex.4 Major features
Minor features
Hypomelanotic macules (with 3, at least 5-mm diameter) Angiofibromas (3) Ungual fibromas (2) Shagreen patch Multiple retinal hamartomas Cortical dysplasias Subependymal nodules Subependymal giant cell astrocytoma Cardiac rhabdomyoma Lymphangioleiomyomatosis Angiomyolipomas (2)
“Confetti” skin lesions Dental enamel pits (>3) Intraoral fibromas (2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas
with total surgical resection for the brain tumor. Subsequently, the systemic symptoms (e.g., headache) were relieved and performance status improved at the time of one-year follow-up. The patient has normal mental and physical growth.
Conflict of interest None.
Acknowledgements The authors are thankful to Dr. Fazalur Rehman Panezai of BMC and Mushtaq Ahmad, Dr. Ali Yousaf, Dr. Nazia Dildar, Dr. Umer Aamir and Dr. Uzma Bashir of the Combined Military Hospital, Quetta, Pakistan for their expertise and opinions regarding neurology, radiology and dermatology findings.
1. Au KS, Williams AT, Gambello MJ, Northrup H. Molecular genetic basis of tuberous sclerosis complex; from bench to bedside. J Child Neurol. 2004;19: 699e799. 2. Romanelli P, Verdecchia M, Rodas R, Seri S, Curatolo P. Epilepsy surgery for tuberous sclerosis. Pediatr Neurol. 2004;31:239e247. 3. Syed KN. Tuberous sclerosis. J Pak Med Assoc. 2010;60:683e685. 4. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:243e254. 5. Haque S. Tuberous sclerosis complex: a case report. Chattagram Maa-O-Shishu Hosp Med Coll J. 2014;13:89e92. 6. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:255e265. 7. Papadavid E, Markey A, Bellaney G, Walker NP. Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis. Br J Dermatol. 2002;147:337e342. 8. Birca A, Mercier C, Major P. Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex. J Neurosurg Pediatr. 2010;6:381e384. 9. Kotulska K, Borkowska J, Roszkowski M, et al. Surgical treatment of subependymal giant cell astrocytoma in tuberous sclerosis complex patients. Pediatr Neurol. 2014;50:307e312. 10. Roth J, Roach ES, Bartels U, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the international tuberous sclerosis complex consensus conference 2012. Pediatr Neurol. 2013;49: 439e444. 11. Teng JC, Cowen EW, Wataya-Kaneda M, et al. Dermatologic and dental aspects of the 2012 international tuberous sclerosis complex consensus statements. JAMA Dermatol. 2014;150:1095e1101. 12. Jahodova A, Krsek P, Kyncl M, et al. Distinctive MRI features of the epileptogenic zone in children with tuberous sclerosis. Eur J Radiol. 2014;83:703e709. 13. House PM, Holst B, Lindenau M, et al. Morphometric MRI analysis enhances visualization of cortical tubers in tuberous sclerosis. Epilepsy Res. 2015;117: 29e34. 14. Gallagher A, Grant EP, Mada N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol. 2011;257:1373e1381. 15. Manoukian SB, Kowal DJ. Comprehensive imaging manifestations of tuberous sclerosis. Am J Roentgenol. 2015;204:933e943.
Please cite this article in press as: Iftikhar S, et al., Tuberous sclerosis complex with sub-ependymal giant cell astrocytomas, Journal of Cancer Research and Practice (2017), http://dx.doi.org/10.1016/j.jcrpr.2017.05.002