case report J Neurosurg 122:773–777, 2015

Intracranial desmoplastic small round cell tumor presenting as a suprasellar mass Sravan K. Thondam, MRCP,1 Daniel du Plessis, FRCPath,2 Daniel J. Cuthbertson, PhD,1 Kumar S. V. Das, FRCR,3 Mohsen Javadpour, FRCS(SN),3 Ian A. MacFarlane, FRCP,1 James Leggate, FRCS,2 Brian Haylock, FRCR,4 and Christina Daousi, FRCP1 Department of Endocrinology, University Hospital Aintree, Liverpool; 2Neuropathology Unit and Clinical Neurosciences Center, Salford Royal Hospital, Salford, Greater Manchester; 3Walton Center for Neurology & Neurosurgery, Liverpool; and 4 Clatterbridge Cancer Center, Liverpool, United Kingdom 1

Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive neoplasms that typically arise from abdominal and pelvic peritoneum in young adults. Other primary sites are uncommon, and an intracranial origin is exceptionally rare. Here the authors report the first case of a DSRCT presenting as a primary suprasellar tumor causing panhypopituitarism and severe bitemporal hemianopia in a young man. Macroscopic debulking of the tumor was undertaken, and histology revealed features of DSRCT. Reverse transcription polymerase chain reaction confirmed the presence of Ewing’s sarcoma–Wilms tumor 1 (EWS-WT1) gene rearrangement specific to DSRCT. Postoperative whole-body imaging showed no primary malignancy elsewhere. The tumor recurred 4 months after surgery, and this was followed by cervical and mediastinal lymph node metastases. The patient died 20 months after initial presentation of rapidly progressive disease. DSRCTs should be included in the differential diagnosis of an unusual suprasellar mass in young adults. Early diagnosis is essential, and once the tumor is identified histologically, gross-total resection and radical postoperative treatment involving radiotherapy, chemotherapy, and close surveillance are required because of the lesion’s potential for rapidly progressive malignancy. http://thejns.org/doi/abs/10.3171/2014.10.JNS132490

Key Words  desmoplastic small round cell tumor; suprasellar mass; EWS-WT1 gene fusion; intracranial malignant tumor; oncology

D

small round cell tumors (DSRCTs) are rare primitive neoplasms that have an aggres­ sive clinical course. Despite multiple modalities of treatment, these tumors remain incurable and have poor long-term survival rates. They were first described in 1989 by Gerald and Rosai.3 These tumors are more common in males and usually present in adolescence or early adult­ hood. There are no reliable biomarkers or specific radio­ logical signs for their diagnosis; however, recent advances in molecular biology and immunohistochemistry allow re­ liable diagnosis through examination of a biopsy specimen in most cases. Cytogenetic analysis in DSRCTs has shown a specific chromosomal abnormality, t(11;22)(p13;q12), as a result of gene translocation and rearrangement of the esmoplastic

genes for Ewing’s sarcoma (EWS) and Wilms tumor 1 (WT1). The gene fusion of EWS-WT1 is described to be specific to DSRCTs.4 DSRCTs typically arise from abdominal and pelvic peritoneum and spread over serosal surfaces, leaving mul­ tiple small peritoneal implants. There have been a small number of reports of DSRCTs affecting other organs, such as lymph nodes, ovaries, kidneys, pancreas, tunica vaginal­ is, testis, liver, and pleura. Such tumors arising within the cranium are extremely rare. Three definite and two pos­ sible cases of intracranial DSRCTs (one tentorial, one cer­ ebellopontine angle, one temporal lobe, and two cerebel­ lar tumors) have been previously reported.1,7,10,11 Here we report the first case of intracranial DSRCT presenting as

Abbreviations  DSRCT = desmoplastic small round cell tumor; EMA = epithelial membrane antigen; EWS = Ewing’s sarcoma; FISH = fluorescent in situ hybridization; PLAP = placental alkaline phosphatase; RT-PCR = reverse transcription polymerase chain reaction; WT1 = Wilms tumor 1. Submitted  November 12, 2013.  Accepted  October 16, 2014. include when citing  Published online December 5, 2014; DOI: 10.3171/2014.10.JNS132490. Disclosure  The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. ©AANS, 2015

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a suprasellar mass. The tumor caused panhypopituitarism and visual field defects as a result of optic chiasm com­ pression in a young man and had a fatal outcome because of progressive disease.

Case Report

History and Examination

A 27-year-old man was referred to the endocrinology clinic with a history of excessive tiredness, lethargy, and loss of libido. He had a medical history of depression and had been treated with fluoxetine. His secondary sexual characteristics were normal, but he had a reduced testicu­ lar volume (12 ml) bilaterally. There were no clinical fea­ tures to suggest the presence of acromegaly or Cushing’s disease. His visual fields were full to confrontation, and no neurological deficits were identified during clinical ex­ amination on his initial visit. Blood tests revealed panhy­ popituitarism with the following parameters: testosterone < 0.4 nmol/L (normal range 8.5–29 nmol/L), undetectable luteinizing hormone and follicle-stimulating hormone, random cortisol 14 nmol/L, thyroid-stimulating hormone < 0.01 mIU/L (normal range 0.4–4.5 mIU/L), free T4 9.3 pmol/L (normal range 10–23 pmol/L), insulin-like growth factor–I 11 nmol/L (age and sex-adjusted normal range 15–47 nmol/L), random growth hormone 0.2 μg/L, and prolactin 835 mIU/L (normal < 350 mIU/L). The patient’s treatment regimen began with replacement doses of hy­ drocortisone followed by levothyroxine. Gadolinium-en­ hanced MRI showed a large suprasellar heterogeneously enhancing mass extending upward into the third ventricle, compressing the optic chiasm, and downward to the pi­ tuitary fossa (Fig. 1A). No abnormality was detected in the rest of the brain. The patient was referred for urgent neurosurgical and ophthalmic assessments, but he failed to attend these appointments as well as further endocrine follow-up appointments. Operation

A year later, the patient presented to the emergency de­ partment with worsening frontal headaches, drowsiness, and bitemporal hemianopia. Repeat MRI demonstrated a significant increase in the size of the suprasellar tumor (Fig. 1B). He was admitted to the neurosurgical unit, un­ derwent a right frontoparietal craniotomy, and had neartotal removal of the tumor (Fig. 1C). He developed central diabetes insipidus postsurgery and began treatment with desmopressin while continuing with hydrocortisone and levothyroxine replacement therapy. Pathology Findings

Histological examination revealed a tumor consisting of nests and cords of fairly uniform tumor cells charac­ terized by hyperchromatic nuclei and indistinct cytoplasm distributed in a desmoplastic stroma (Fig. 2A). Some tu­ mor cell nests appeared obliterated by dystrophic calci­ fication. Mitotic activity and necrosis were discernible in the cell nests. Immunohistochemical staining revealed strong diffuse immunopositivity for cytokeratin CAM 5.2, vimentin, and desmin (Fig. 2B). Desmin (Fig. 2B) and placental alkaline phosphatase (PLAP) (Fig. 2C) stain­ 774

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Fig. 1. A: Pituitary Gd-enhanced MR image showing a large heterogeneously enhancing suprasellar mass extending toward the third ventricle and downward into the pituitary fossa.  B: MR image obtained 1 year after the initial presentation showing the grossly enlarged suprasellar tumor compressing the optic chiasm.  C: Postoperative MR image revealing good surgical debulking of the tumor and a small residual tumor left adjacent to the thalamic region.  D: MR image obtained 4 months after surgery showing rapid expansion of the suprasellar tumor remnant measuring 4.5 cm in coronal and 3.5 cm in anteroposterior dimensions.

ing demonstrated strong paranuclear dot to curvilinear positivity in a significant proportion of tumor cells. A subset of tumor cells that was dispersed through the nests also showed positivity for neurofilament protein and fo­ cal weak staining with neuron-specific enolase (Fig. 2D). Strong but patchy positivity was seen with epithelial mem­ brane antigen (EMA), with focal positivity for CK7 and CK20. The tumor cells were negative for chromogranin, synaptophysin, CD56, CD99, S100, and WT-1 (aminoterminal antibody used). Fluorescent in situ hybridization (FISH) analysis using the EWSR1 gene probe (Vysis LSI EWSR1 Dual Color Break Apart Probe, Abbott Molecu­ lar) demonstrated EWSR1 gene arrangement in multiple tissue areas. Reverse transcription polymerase chain reac­ tion (RT-PCR) analysis with DNA sequencing of the PCR product confirmed an EWS exon 8/WT1 exon 8 transloca­ tion and EWS-WT1 transcript corroborating the diagnosis of DSRCT. Thus, the cytoarchitectural features, immuno­ phenotype, and genotype were consistent with a diagnosis of DSRCT. Radiology Findings

Immediate postoperative CT scans of the thorax, ab­ domen, and pelvis showed no evidence of a primary ma­ lignancy elsewhere, supporting that the DSRCT in the suprasellar region represented a primary CNS tumor and not a metastatic deposit. An MRI scan obtained 4 months after craniotomy revealed rapid expansion of the suprasel­

Suprasellar desmoplastic small round cell tumor

Fig. 2. A: Nests of tumor cells with hyperchromatic nuclei and indistinct cytoplasm surrounded by desmoplastic stroma. H & E stain, original magnification ×100.  B: Paranuclear dot and curvilinear desmin immunopositivity of tumor cells. Desmin, original magnification ×630.  C: Distinctive paranuclear curvilinear and dot positivity for PLAP. Original magnification ×400.  D: Subset of tumor cells showing neurofilament immunostaining. Original magnification ×200. Figure is available in color online only.

lar tumor remnant measuring 4.5 × 3.5 cm (Fig. 1D). The patient started receiving fractionated conformal radiother­ apy, but treatment was discontinued after 1 week because of general deterioration in his condition. A repeat CT scan of the thorax, abdomen, and pelvis showed extensive met­ astatic disease involving mediastinal, subcarinal, and hilar lymph nodes, causing occlusion of the right main bron­ chus and right pulmonary infiltrates. No intraabdominal masses or lymph nodes were identified, and the appear­ ances of the liver, spleen, and adrenal glands were normal. The histological results of a fine-needle aspirate obtained from a cervical lymph node were once again consistent with DSRCT. Palliative chemotherapy was considered; however, the patient’s clinical condition deteriorated rap­ idly and he died 20 months after his initial presentation.

Discussion

An intracranial DSRCT presenting as a suprasellar mass poses a major challenge in diagnosis and manage­ ment. A tissue biopsy is essential to differentiate this lesion from other suprasellar tumors, such as invasive pituitary adenomas, craniopharyngiomas, gliomas, meningiomas, and metastases. Although the majority of DSRCTs have characteristic histological features, a significant propor­ tion can exhibit a wide range of morphological features.8 The main differential diagnoses for these tumors pre­ senting in the CNS based on histological findings should include medulloblastomas, atypical teratoid/rhabdoid tu­ mors, and primitive neuroectodermal tumors.7 Immuno­ cytochemistry and molecular genetics help to distinguish DSRCTs reliably from other tumors. Cytogenetic analysis in DSRCTs has shown a specific chromosomal abnormality, t(11;22)(p13;q12), as a result of gene translocation and rearrangement of the genes for

EWS and WT1.4 This can be demonstrated by RT-PCR or by FISH. The authors of a large series of DSRCTs re­ ported a significant variation in clinical features, cytology, and immunoreactivity, but the gene fusion EWS-WT1 was consistently distinctive to this tumor.2 Histological ex­ amination, immunocytochemistry, and genotyping in our case demonstrated features typical of a DSRCT, which are quite distinct from the other tumors mentioned above. The rare occurrence of these tumors makes the study of different treatment modalities and their impact on sur­ vival very difficult. Kushner et al.5 showed that intense al­ kylator-based therapy with the P6 protocol (cyclophospha­ mide, doxorubicin, vincristine, ifosfamide, and etoposide) improved remission rates in patients with intraabdominal or pelvic DSRCTs. In that study, 7 of 12 patients achieved a short-term remission, and 4 had complete remission for over 1 year. Quaglia and Brennan9 studied 40 patients, 27 of whom had intraabdominal tumors. Overall survival at 3 years from diagnosis was 29%, and induction chemothera­ py with P6 protocol and gross-total resection of the tumor were associated with improved survival. Lal et al.6 showed that multimodality treatment improved the survival rate in a study of 66 patients with predominantly intraabdominal tumors. The 3-year survival rate was 55% in patients re­ ceiving induction chemotherapy (P6 protocol) combined with surgical debulking and radiotherapy. Systematic review of the literature yielded only 5 cases of intracranial DSRCTs. Evaluation of presenting symp­ toms, pathological findings, management, and outcome of these limited cases shows the aggressive nature of these tumors despite multiple modalities of treatment (Table 1). Tison et al.10 reported on a 24-year-old man with poste­ rior cranial fossa tumor adherent to the tentorium. This patient underwent a partial excision of the tumor and re­ ceived 3 cycles of chemotherapy (PCNU cisplatin and V16) combined with radiotherapy and was receiving intra­ cranial methotrexate at the time the study was published. There are no details published on long-term survival for this patient. Neder et al.7 reported on 2 cases of DSRCT. The first patient was a 37-year-old man with a cerebel­ lopontine angle tumor. He underwent subtotal resection and stereotactic irradiation but the disease progressed to spinal metastases 6 months later. He died 2 years after diagnosis despite receiving whole-brain and whole-spine radiotherapy and chemotherapy. The second patient was a 39-year-old man, with multiple lesions in the left cerebel­ lar hemisphere and spinal leptomeninges, who presented with cauda equina syndrome. He underwent surgical de­ compression of the spinal cord and conus medullaris fol­ lowed by radiotherapy and 3 courses of chemotherapy. He developed further posterior fossa and spinal axis lesions 27 months after diagnosis. Yachnis et al.11 described a possible DSRCT in a 9-month-old girl with an aggressive posterior cranial fossa tumor requiring the placement of a ventriculoperitoneal shunt for obstructive hydrocephalus. She required a sec­ ond craniotomy for tumor debulking surgery 18 months later despite intensive chemotherapy. Long-term survival details of this patient are not available. Bouchireb et al.1 described a 6-year-old girl with a right temporal lobe tu­ mor in whom histological and immunochemistry findings J Neurosurg  Volume 122 • April 2015

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Age, Sex

Clinical Features on Initial Presentation MRI Findings

Histology, Immunocytochemistry, & Cytogenetics

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9 mos, F

Projectile vomiting & increased head circumference

Enhancing rt cerebellar mass compressing & displacing brainstem Marked obstructive hydrocephalus

chemo = chemotherapy; CPA = cerebellopontine angle.

Yachnis et al., 1992

Demarcated nests of tumor cells separated by mesenchymal stroma Nest cell positive for GFAP, cyto­ keratin, & vimentin Negative for desmin immunoreactivity Tison et al., 24 yrs, M Headache, vomit- Posterior cranial fossa tumor Nests of small uniform round & oval tumor cells separated by 1996 ing, vertigo, & (3 × 4 × 3.5 cm) adherent desmoplastic stroma impaired hearing to tentorium & petrous part of temporal bone, displac- Strong immunoreactivity for keratin, vimentin, desmin, & EMA ing lt cerebellar hemiSouthern blot for genomic DNA sphere extraction, PCR analysis of EWS-WT1 fusion gene Well-demarcated heterogeSmall malignant cells w/ hyperBouchireb et 6 yrs, F 3-wk history of al., 2008 headaches, neously enhancing mass in chromatic nuclei & eosinocomplex partial rt temporal lobe philic cytoplasm embedded in fibromyxoid stroma seizures, & Positive staining for vimentin, dysphasia desmin, & synaptophysin EWS-WT1 translocation by FISH Neder et al., 37 yrs, M 5-mo history of lt- Heterogeneously enhancing Intracranial & spinal biopsies: 2009 side hearing mass in lt CPA w/ mild round to oval hyperchromatic loss & tinnitus mass effect nuclei w/ inconspicuous nucleoli in addition to desmoplastic stroma Positive staining for EMA, CAM 5.2, desmin, & nuclear INI-1 EWS-WT1 translocation by RTPCR & FISH 39 yrs, M 4-mo history of gait Multiple enhancing lesions in Laminectomy samples: tumor imbalance & lt cerebellar hemisphere & cells w/ oval to irregular nuclei bilat lower limb metastasis in spinal leptow/ coarse chromatin & scanty weakness; later meningeal space cytoplasm; positive staining for developed EMA, CAM 5.2, desmin, & urinary & fecal nuclear INI-1; EWS-WT1 incontinence translocation by RT-PCR

Authors & Year

TABLE 1. Literature review of reported cases of intracranial DSRCTs

Alive & disease free after 18 mos of followup

None at time of publication

Metastasis to spinal lep­to­ meningeal space at presentation

Decompression of spinal cord & conus medullaris followed by radiotherapy Laminectomy of T12–L5 showed cauda equina nerve roots studded w/ gray tumor nodules Three courses of chemo (cisplatin, etoposide, & Holoxan)

Increase in posterior fossa tumor; further spread in spinal axis after 27 mos of follow-up

Spinal leptome­ Initial subtotal resection of CPA mass & Died 2 yrs after ninges 6 mos stereotactic radiation to tumor bed diagnosis w/ after diagno­ Debulking of intradural spinal nodules & progressive sis spinal radiation (4500 rad); radiosurgery disease to CPA (100 rad) & whole brain (3600 rad) Chemo (carboplatin temozolomide)

Complete excision of tumor Seven courses of chemo w/ P6 protocol (cyclophosphamide, doxorubicin, vin­ cristine, ifosfamide, & etoposide); focal conformal radiotherapy to tumor bed at 54 Gy

Partial excision of tumor Alive & no clini­cal Three cycles of chemo consisting of PCNU signs of re­ cisplatin & V16; intracranial methotrexlapse at time of ate every 40 days; radiotherapy publication

None at time of publication

Alive at time of publication

Outcome

Ventriculoperitoneal shunt Chemo w/ cisplatin, cyclophosphamide, vincristine, & high-dose methotrexate Second craniotomy for debulking surgery 1.5 yrs after original presentation

Treatment

None at time of publication

Site of Metastasis

S. K. Thondam et al.

Suprasellar desmoplastic small round cell tumor

were not diagnostic of DSRCT but had the characteristic EWS-WT1 translocation. This patient underwent excision of the mass followed by P6 protocol chemotherapy5 and focal conformal irradiation of tumor bed at 54 Gy. She was reported to be free of the disease 18 months after di­ agnosis. In summary, we have described the first case of an in­ tracranial DSRCT presenting as a suprasellar mass, caus­ ing panhypopituitarism and bitemporal hemianopia in a young man who died of progressive disease. Despite mul­ timodality treatment, the aggressive behavior of this tu­ mor was similar to DSRCTs arising from the peritoneal cavity and the few rare intracranial cases. Failure to attend follow-up outpatient appointments and possible noncom­ pliance with treatment may have also contributed to the poor prognosis in our patient. It is important to include DSRCTs in the differential diagnosis of an unusual supra­ sellar mass in young adults. Once the tumor is identified histologically, gross-total resection and radical postopera­ tive treatment involving radiotherapy, chemotherapy, and close surveillance are required because of its potential for an aggressive clinical course.

  5. Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Linds­ ley KL, Ghavimi F, et al: Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 14:1526–1531, 1996   6. Lal DR, Su WT, Wolden SL, Loh KC, Modak S, La Quaglia MP: Results of multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surg 40:251–255, 2005   7. Neder L, Scheithauer BW, Turel KE, Arnesen MA, Ketter­ ling RP, Jin L, et al: Desmoplastic small round cell tumor of the central nervous system: report of two cases and review of the literature. Virchows Arch 454:431–439, 2009   8. Ordóñez NG: Desmoplastic small round cell tumor: I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol 22:1303–1313, 1998   9. Quaglia MPL, Brennan MF: The clinical approach to desmo­ plastic small round cell tumor. Surg Oncol 9:77–81, 2000 10. Tison V, Cerasoli S, Morigi F, Ladanyi M, Gerald WL, Rosai J: Intracranial desmoplastic small-cell tumor. Report of a case. Am J Surg Pathol 20:112–117, 1996 11. Yachnis AT, Rorke LB, Biegel JA, Perilongo G, Zimmerman RA, Sutton LN: Desmoplastic primitive neuroectodermal tu­ mor with divergent differentiation. Broadening the spectrum of desmoplastic infantile neuroepithelial tumors. Am J Surg Pathol 16:998–1006, 1992

References

  1. Bouchireb K, Auger N, Bhangoo R, Di Rocco F, Brousse N, Delattre O, et al: Intracerebral small round cell tumor: an unu­sual case with EWS-WT1 translocation. Pediatr Blood Cancer 51:545–548, 2008   2. Gerald WL, Ladanyi M, de Alava E, Cuatrecasas M, Kush­ ner BH, LaQuaglia MP, et al: Clinical, pathologic, and mo­ lecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 16:3028–3036, 1998   3. Gerald WL, Rosai J: Case 2. Desmoplastic small cell tumor with divergent differentiation. Pediatr Pathol 9:177–183, 1989   4. Gerald WL, Rosai J, Ladanyi M: Characterization of the ge­ nomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc Natl Acad Sci U S A 92:1028–1032, 1995

Author Contributions

Conception and design: Thondam, Daousi. Acquisition of data: Thondam, du Plessis, Das, Haylock, Daousi. Drafting the article: Thondam, du Plessis, Cuthbertson, Daousi. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Thondam.

Correspondence

Sravan Kumar Thondam, University Hospital Aintree, Department of Endocrinology, Clinical Sciences Centre, 3rd Fl., Lower Ln., Liverpool L9 7AL, United Kingdom. email: [email protected].

J Neurosurg  Volume 122 • April 2015

777

Intracranial desmoplastic small round cell tumor presenting as a suprasellar mass.

Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive neoplasms that typically arise from abdominal and pelvic peritoneum in young adults...
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