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Subependymal giant cell astrocytoma with atypical clinical and pathological features: a diagnostic pitfall


Subependymálny obrovskobunkový astrocytóm s atypickými klinickými a patologickými črtami: diagnostická pasca

Subependymálny obrovskobunkový astrocytóm (SEGA) je benígny pomaly rastúci tumor asociovaný so syndrómom tuberóznej sklerózy. Vyskytuje sa takmer výlučne v oblasti foramen Monro. Šírene do parenchýmu hemisféry a znepokojujúce histologické črty ako sú nekrózy, mitózy, mikrovaskulárna proliferácia a pleomorfia sú nezvyčajné, ale vzácne môžu byť prítomné. Prezentujeme prípad SEGA u pacienta, u ktrorého zatiaľ nie sú prítomné ďalšie známky syndrómu tuberóznej sklerózy, s atypickým radiologickým nálezom a mikroskopicky prítomnými nekrózami. Tieto znepokojujúce črty iniciálne viedli k nesprávnej diagnóze glioblastómu. Je diskutovaná diferenciálna diagnóza SEGA.

Kľúčové slová:
subependymálny obrovskobunkový astrocytóm – atypický – nekróza


Authors: Marián Švajdler jr. 1;  Ladislav Deák 2;  Boris Rychlý 3;  Peter Talarčík 3;  Lucia Fröhlichová 1
Authors place of work: Department of pathology, L. Pasteur’s University Hospital, Košice, Slovakia 1;  Department of pediatric oncology and haematology, Children’s University Hospital, Košice, Slovakia 2;  Cytopathos s. r. o., Bratislava, Slovakia 3
Published in the journal: Čes.-slov. Patol., 49, 2013, No. 2, p. 76-79
Category: Původní práce

Summary

Subependymal giant cell astrocytoma (SEGA) is benign, slowly growing tumor linked to the tuberous sclerosis complex. It almost always occurs near the foramen of Monro. Parenchymal extension and worrisome histological features, such as necrosis, mitoses, microvascular proliferation and pleomorphism are unusual in these tumors, but can occur rarely. A case of SEGA is presented, in a patient with no signs of tuberous sclerosis so far, with atypical imaging findings and areas of necrosis found microscopically. These worrisome features initially led to the false diagnosis of glioblastoma. The differential diagnosis of SEGA is discussed.

Keywords:
subependymal giant cell astrocytoma – atypical – necrosis


Subependymal giant cell astrocytoma (SEGA) is benign, WHO grade 1, slowly growing tumor linked to the tuberous sclerosis complex (TSC), which forms an expansive mass in the wall of the lateral or third ventricle, almost always near the foramen of Monro (1–3). Parenchymal extension and worrisome histological features, such as necrosis, mitoses, microvascular proliferation or pleomorphism, are unusual in these tumors, but can occur (4). We present an unusual case of SEGA in a patient with no signs of TSC so far, which formed a large solid and cystic parenchymal mass, with a shift of the midline structures and microscopically showed areas of necrosis. These worrisome features led to the false diagnosis of glioblastoma.

CASE REPORT

1.5-year-old girl was admitted to the hospital in June 2008 because of walking difficulties and febrility. At admission, signs of intracranial hypertension were found. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large expansive tumor in the left fronto-parieto-temporal region, with a shift of the midline structures and hydrocephalus. Gadolinium enhanced MRI showed non-homogenous, predominantly peripheral (“ring”) contrast enhancement of the tumor (Fig. 1). Partial resection of the tumor was performed (Fig. 2).

Fig. 1. Preoperative CT imaging showed large expansive fronto-parieto-temporal lesion with shift of the midline structures and hydrocephalus. Intratumoral calcification could be seen. Although the tumor was subependymal and near the foramen of Monro, such extensive involvement of the hemisphere was unusual for SEGA (A, B). T1 MRI with gadolinium showed non-homogenous, predominantly peripheral (“ring”) contrast enhancement of the tumor (C, D).
Fig. 1. Preoperative CT imaging showed large expansive fronto-parieto-temporal lesion with shift of the midline structures and hydrocephalus. Intratumoral calcification could be seen. Although the tumor was subependymal and near the foramen of Monro, such extensive involvement of the hemisphere was unusual for SEGA (A, B). T1 MRI with gadolinium showed non-homogenous, predominantly peripheral (“ring”) contrast enhancement of the tumor (C, D).

Fig. 2. Postoperative CT showing the result of partial resection of the tumor.
Fig. 2. Postoperative CT showing the result of partial resection of the tumor.

Microscopically, the tumor was composed of large gemistocyte-like cells with prominent excentric nuclei, some with prominent nucleoli. Binucleated cells resembling dysplastic ganglion cells could also be seen. The cytoplasm was fibrillary to glassy and the growth of the tumor was solid and expansive. Mitoses were hard to find and microvascular proliferation was not present. However, large areas of geographic necrosis without pseudopalisading were found (Fig. 3).

Fig. 3. Expansive growth of the tumor. Note sharp interface with normal parenchyma (A). Gemistocyte-like cells with prominent excentric nuclei and prominent nucleoli, some binucleated cells are also present (B, C). Geographic infarct-like necrosis without pseudopalisading (D). Hematoxylin-eosin, original magnification 100x (A), 200x (B), 400x (C) and 100x (D).
Fig. 3. Expansive growth of the tumor. Note sharp interface with normal parenchyma (A). Gemistocyte-like cells with prominent excentric nuclei and prominent nucleoli, some binucleated cells are also present (B, C). Geographic infarct-like necrosis without pseudopalisading (D). Hematoxylin-eosin, original magnification 100x (A), 200x (B), 400x (C) and 100x (D).

By immunohistochemistry, most of the neoplastic cells were GFAP positive (clone 6F2, DiagnosticBioSystems), with patchy neurofilament protein expression (clone 2F11, DiagnosticBioSystems) (Fig. 4). Neural filaments were not stained in the background, confirming the non-infiltrative growth pattern. The Ki-67 labeling index (clone MIB-1, DAKO) was very low, approximately 1 %. P53 (clone DO-7, Neomarkers) focally and faintly stained some of the nuclei (< 2 %, not shown).

Fig. 4. GFAP expression (A) and patchy neurofilament protein expression (B) by the neoplastic cells. Immunohistochemistry, original magnification 400x (A) and 200x (B).
Fig. 4. GFAP expression (A) and patchy neurofilament protein expression (B) by the neoplastic cells. Immunohistochemistry, original magnification 400x (A) and 200x (B).

At the time of sign-out, no further clinical data, including the results of imaging were available to the pathologist. Despite the presence of necrosis, the case was signed-out as SEGA, WHO grade 1.

After the sign-out, clinicians asked for a second look opinion, because of atypical and worrisome imaging characteristics of the tumor and the presence of the necrosis, not quite consistent with SEGA. A second look was done at a prominent international academic institution. Two neuropathology experts agreed on the diagnosis of glioblastoma, WHO grade 4, despite lack of mitoses and very low proliferation index (the Ki-67 immunohistochemistry was repeated at that institution).

In August 2008, a second partial resection was done and chemotherapy was initiated (POG protocol 9233/34). After initial clinical response, residual tumor size remained stable from the 11th month after beginning chemotherapy. In January 2010 chemotherapy was finished and in March 2010 gross total resection of the residual tumor was performed at another hospital (Fig. 5). Pathological diagnosis at that institution was SEGA again, and planned radiotherapy was canceled. Histomorphology of the resected tumor after the chemotherapy was identical with the previous biopsies. At the time of writing this report (November 2012), i.e. more than four years after initial diagnosis, the patient is in very good clinical condition, with no evidence of the disease. So far, no signs of TSC are evident in the patient. Despite that, we have changed the final diagnosis back to SEGA. Results of the molecular genetics are pending.

Fig. 5. T1 MRI with gadolinium enhancement after gross total resection.
Fig. 5. T1 MRI with gadolinium enhancement after gross total resection.

DISCUSSION

SEGA is one of the major criteria for the diagnosis of TSC (1–3). In most patients with SEGA, the diagnosis of TSC has already been established, but in some cases it seems to be sporadic or precede other signs of the syndrome (5–8). Whether these cases are truly sporadic or represent forme fruste of TSC remains a controversial and unsolved issue at this time. Testing for the mutation of TSC1 and TSC2 genes may be helpful, when a patient does not fulfill criteria for the definite diagnosis. SEGA occurs during the first two decades of life (mean age is 13 years), but rare infant and even congenital cases have been described (4, 9, 10). Patients usually show symptoms of increased intracranial pressure or a worsening of epilepsy.

By imaging, SEGAs are well circumscribed, hyperdense relative to the cortex by CT, with frequent calcifications, mixed intensities on T1 and T2-weighted MRI images and contrast enhancement on both CT and MRI (11). A spontaneous hemorrhage can occur rarely (5). Although the location near the foramen of Monro is characteristic, extraventricular examples have been reported (12,13).

Microscopically, SEGA shows a non-infiltrating growth pattern and is composed of large polygonal gemistocyte-like cells with eosinophilic and sometimes glassy cytoplasm, excentric nuclei and prominent nucleoli. Bi- and multinucleation is quite common and some tumor cells strongly resemble normal and dysplastic ganglion cells. A streaming spindle cell pattern and perivascular pseudorossetes reminiscent of an ependymoma can also be present. Focal inflammatory infiltrates composed of T-cells and mastocytes are common (2,8).

Immunohistochemically, tumor cells are variably GFAP and S100 positive, and they can consistently but focally also express neuronal markers (neurofilament protein, class III beta-tubulin, synaptophysin, Neu-N). The Ki-67 labeling index is very low and focal P53 immunopositivity (mean labeling index 2.4 %) was described in 60 % of cases in one study (8,14–16).

In some of the tumors nuclear pleomorphism, mitoses, necroses, microvascular proliferation and increased Ki-67 labeling can be found (2,4,8,17). There is a very unusual case report of a 17-year-old male patient with TSC and spinal cord metastasis of SEGA (18). Traditionally, these “high grade” features are declared not to impact the diagnosis or prognosis. However, some of these“atypical” SEGAs are larger and are symptomatic in younger children, indicating more rapid growth and the possibility of a more aggressive course than usual SEGAs (4). However, more studies on this topic are needed.

Gemistocytic astrocytoma (GA), with high propensity to progress to glioblastoma (although this still remains controversial), is clearly the most important differential diagnosis, as demonstrated in our case. GA is defined as a diffuse astrocytoma variant, characterized by the presence of an arbitrary set fraction of at least 20 % of gemistocytic astrocytes in a diffuse infiltrating astrocytoma (19,20). Highly cellular regions of GA, composed of gemistocytes with plump, glassy cytoplasm and entrapped neurons can resemble SEGA. Binucleated cells and lymphocytic infiltrates are also common. However, an admixture of smaller, atypical, non-gemistocytic neoplastic astrocytes is typical for GA. GFAP often stains the periphery of the cytoplasm of gemistocytes in GA and neurofilament protein will highlight entrapped neural processes in the background. Staining for neuronal markers in the neoplastic cells is not expected in GA. P53 gene mutations and more diffuse immunohistochemical P53 expression are typical of GA (19-21). Cytologic features of SEGA in smear preparations are described as highly characteristic, and also can help to separate it from GA (22), although, in our opinion, in a case of an “atypical” SEGA, smear cytology probably will not clearly distinguish these two tumors.

In conclusion, in some cases SEGA and high grade GA or glioblastoma are lookalikes, and even experts in neuropathology can misdiagnose them. Low mitotic count and Ki-67 labeling index, expansive growth pattern (without entrapped neurofilaments) and absence of atypical small cells are probably the best discriminating features. P53 immunohistochemistry and/or genetics can help in difficult cases. Unusual imaging and microscopic features rarely occur in SEGAs, but careful histological and immunohistochemical examination should lead to the correct diagnosis. Whether these “atypical” SEGAs do show a more aggressive course still remains in question.

Correspondence address:

Marián Švajdler jr., M.D.

Department of Pathology, L. Pasteur’s University Hospital

Trieda SNP 1, 041 90 Košice, Slovakia

Tel/Fax: +421 55 640 2945

e-mail: svajdler@yahoo.com


Zdroje

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2. Lopes MBS, Wiestler OD, Stemmer-Rachaminov AO, Sharma MC. Tuberous sclerosis complex and subependymal giant cell astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee K, eds. World health organisation classification of tumors. WHO classification of tumors of the central nervous system (4th ed). Lyon, IARC; 2007: 218-221.

3. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006; 355(13): 1345-1356.

4. Grajkowska W, Kotulska K, Jurkiewicz E, et al. Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathol 2011; 49(1): 39-46.

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6. Ichikawa T, Wakisaka A, Daido S, et al. A case of solitary subependymal giant cell astrocytoma: two somatic hits of TSC2 in the tumor, without evidence of somatic mosaicism. J Mol Diagn 2005; 7(4): 544-549.

7. Takei H, Adesina AM, Powell SZ. Solitary subependymal giant cell astrocytoma incidentally found at autopsy in an elderly woman without tuberous sclerosis complex. Neuropathology 2009; 29(2): 181-186.

8. Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C. Subependymal giant cell astrocytoma—a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol Oncol Res 2004; 10(4): 219-224.

9. Raju GP, Urion DK, Sahin M. Neonatal subependymal giant cell astrocytoma: new case and review of literature. Pediatr Neurol 2007; 36(2): 128-131.

10. Pizer B. Congenital subependymal giant cell astrocytoma diagnosed on fetal MRI. Arch Dis Child 2006; 91(6): 520.

11. Christoforidis GA, Drevelegas A, Bourekas EC, Karkavelas G. Low-grade gliomas. In: Drevelegas A, ed. Imaging of Brain Tumors with Histological Correlations, 2nd ed. Berlin-Heidelberg, Springer-Verlag; 2011: 73-156.

12. Bollo RJ, Berliner JL, Fischer I, et al. Extraventricular subependymal giant cell tumor in a child with tuberous sclerosis complex. J Neurosurg Pediatr 2009; 4(1): 85-90.

13. Isik U, Dincer A, Sav A, Ozek MM. Basal ganglia location of subependymal giant cell astrocytomas in two infants. Pediatr Neurol 2010; 42(2): 157-159.

14. Lopes MB, Altermatt HJ, Scheithauer BW, Shepherd CW, VandenBerg SR. Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol 1996; 91(4): 368-375.

15. Buccoliero AM, Franchi A, Castiglione F, et al. Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study. Neuropathology 2009; 29(1): 25-30.

16. Sharma M, Ralte A, Arora R, Santosh V, Shankar SK, Sarkar C. Subependymal giant cell astrocytoma: a clinicopathological study of 23 cases with special emphasis on proliferative markers and expression of p53 and retinoblastoma gene proteins. Pathology 2004; 36(2): 139-144.

17. Chow CW, Klug GL, Lewis EA. Subependymal giant-cell astrocytoma in children. An unusual discrepancy between histological and clinical features. J Neurosurg 1988; 68(6): 880-883.

18. Telfeian AE, Judkins A, Younkin D, Pollock AN, Crino P. Subependymal giant cell astrocytoma with cranial and spinal metastases in a patient with tuberous sclerosis. Case report. J Neurosurg 2004; 100(5, Suppl Pediatrics): 498-500.

19. Tihan T, Vohra P, Berger MS, Keles GE. Definition and diagnostic implications of gemistocytic astrocytomas: a pathological perspective. J Neurooncol 2006; 76(2): 175-183.

20. von Deimling A, Burger PC, Nakazato Y, Ohgaki H, Kleihues P. Diffuse astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee K, eds. World health organisation classification of tumors. WHO classification of tumors of the central nervous system (4th ed). Lyon, IARC; 2007: 25-29.

21. Avninder S, Sharma MC, Deb P, et al. Gemistocytic astrocytomas: histomorphology, proliferative potential and genetic alterations—a study of 32 cases. J Neurooncol 2006; 78(2): 123-127.

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Štítky
Patologie Soudní lékařství Toxikologie

Článek vyšel v časopise

Česko-slovenská patologie

Číslo 2

2013 Číslo 2

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