CASE OF THE MONTH

DESMOPLASTIC SMALL ROUND CELL TUMOR: A RARE CAUSE OF A PROGRESSIVE BRACHIAL PLEXOPATHY € JAN MATHYS, MD,1 ISTVAN VAJTAI, MD,2 ESTHER VOGELIN, MD,3 DIETER R. ZIMMERMANN, PhD,4 CHRISTOPH OZDOBA, MD,5 and EKKEHARD HEWER, MD2 1

Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland Institute of Pathology, University of Bern, Bern, Switzerland 3 Department of Plastic and Hand Surgery, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland 4 Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland 5 Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland Accepted 3 January 2014 2

ABSTRACT: Introduction: Desmoplastic small round cell tumor (DSRCT) is an uncommon, embryonic-type neoplasm, typically presenting as an abdominal mass in young men. A single case of DSRCT arising in the peripheral nervous system has been reported previously. Methods: The clinical course, imaging, electrophysiological, intraoperative, histopathological, molecular findings, and postoperative follow-up are reported. Results: A 43-year-old man presented with slowly progressive right brachial plexopathy. Magnetic resonance imaging revealed an enlarged medial cord with heterogeneous contrast enhancement. Histology showed a “small round cell” neoplasm with a polyphenotypic immunoprofile, including epithelial and mesenchymal markers. A pathognomonic fusion of Ewing sarcoma breakpoint region 1 and Wilms tumor 1 genes (EWSR1/WT1) was present. Treatment involved gross total excision and local radiotherapy. Conclusions: Our findings confirm the occurrence of DSRCT as a primary peripheral nerve tumor. Despite its usually very aggressive clinical course, prolonged recurrence-free survival may be reached. Histomorphology and immunoprofile of DSRCT may lead to misdiagnosis as small cell carcinoma. Muscle Nerve 49: 922–927, 2014

CASE REPORT

A 43-year-old man of Caucasian ancestry was admitted to the Department of Neurology of the University Hospital Bern for re-evaluation of an insidiously evolving brachial plexopathy of unknown origin. In January 2007, he noticed paresthesia and numbness at the fourth and fifth digits of the right hand. He also experienced pain in his right shoulder while abducting the arm. Some months later, he developed continuous burning pain in the right arm. The area with numbness slowly expanded to the ulnar forearm. Abbreviations: CAM5.2, cytokeratin 8/18; CT, computed tomography; DSRCT, desmoplastic small round cell tumor; EMA, epithelial membrane antigen; EWSR1, Ewing sarcoma breakpoint region 1; FDG, fluorodeoxyglucose; FISH, fluorescence in situ hybridization; Gy, Gray; MPNST, malignant peripheral nerve sheath tumor; MRI, magnetic resonance imaging; NRS, numerical rating scale; PET, positron-emission tomography; PLAP, placental alkaline phosphatase; TTF-1, thyroid transcription factor 1; WT1, Wilms tumor gene 1 Key words: brachial plexopathy; desmoplastic small round cell tumor; EWSR1/WT1 fusion nerve biopsy; positron emission tomography Correspondence to: E. Hewer; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V

Published online 7 January 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24165

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In January 2008, he developed weakness and, some weeks later, atrophy of the intrinsic muscles of the right hand. His past medical history included childhoodonset allergic asthma, considerable tobacco smoking, and, lately, occasional inhalation of marijuana for pain relief. At first neurologic evaluation in our clinic in August 2008, clinical examination revealed normal higher mental functions and intact cranial nerves. There was weakness and moderate atrophy of the hand muscles innervated by the right ulnar nerve in addition to the flexor carpi ulnaris muscle. Slight weakness was also noted in hand muscles innervated by the median nerve. The ipsilateral finger flexor reflex was absent. The fourth and fifth digits and the hypothenar eminence exhibited decreased sensation and anhidrosis. Electrodiagnostic studies demonstrated severe axonal neuropathy of the ulnar nerve (motor and sensory) and the median nerve (only motor). Computed tomography (CT) of the upper thoracic region and magnetic resonance imaging (MRI) of the cervical spine and brachial plexus showed no evidence of nerve compression and were deemed normal (Fig. 1a). Blood tests for infectious (HIV, T. pallidum, B. burgdorferi) and noninfectious etiologies (vasculitis) were normal. Analysis of the cerebrospinal fluid revealed 1 cell/ll and a slightly elevated protein concentration of 0.45 g/L. A lesion of the medial cord of the right brachial plexus was diagnosed, and on the hypothesis of a probable inflammatory etiology, an empiric steroid trial with prednisone was initiated. There was only minimal improvement of pain, without functional recovery. In 2009, the patient sought a second opinion at another institution, which failed to yield any novel insights. By mid-2010, on the assumption of a “thoracic outlet syndrome” supraclavicular revision of the brachial plexus and resection of the right first rib were performed without any improvement. MUSCLE & NERVE

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FIGURE 1. a,b: First MRI study in 2008. Coronal inversion recovery and gadolinium-enhanced axial T1-weighted sequences retrospectively show subtle enhancement of the right medial cord (arrow). c,d: Follow-up imaging in 2011. Same technique as above, showing hyperintense enlargement of the medial cord (arrow) in the coronal inversion recovery image with contrast enhancement in the corresponding axial T1-weighted view (arrow).

On re-examination in our clinic in autumn 2011, the patient suffered from intense stabbing and burning pain in the right arm, mostly 9/10 on a numerical rating scale (NRS), despite extended pain treatment, including opioids. Clinical examination revealed advanced atrophy of the intrinsic hand muscles, with complete paralysis of ulnar- and severe weakness of median-innervated muscles. Moreover, weakness and wasting of ipsilateral forearm muscles supplied by the ulnar and median nerves were evident. A Tinel sign could be elicited below the middle and lateral part of the clavicle. Sensory loss in the territory of the ulnar nerve was noticed along with reduced sensation and allodynia within the C8 and T1 dermatomes. MRI scan of the brachial plexus showed enlargement and slightly heterogeneous gadolinium uptake in the medial cord of the Desmoplastic Small Round Cell Tumor

brachial plexus (Fig. 1c, d). This finding was conspicuously replicated on total body fluorodeoxyglucose positron-emission tomography computed tomography (FDG-PET-CT) scan, whereby a single metabolically highly active lesion was evident in the infraclavicular area (Fig. 2). In retrospect, subtle contrast enhancement of the medial cord was noticed at the same site in the first MRI study (Fig. 1b). In the clinical context of a slowly progressive disease course, the differential diagnosis of a neoplasm was now entertained, and an open biopsy of the medial cord was undertaken. Intraoperatively, the medial cord appeared enlarged and pale with a firm texture (Fig. 3a). Electrical stimulation of the medial cord could not elicit any motor response. Histological analysis of the biopsy specimen showed a largely undifferentiated malignant neoplasm MUSCLE & NERVE

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FIGURE 2. FDG-PET and fusion FDG-PET-CT demonstrate intense metabolic activity at the right infraclavicular brachial plexus.

with “small round cell” characteristics infiltrating both within and along the perineurium of several nerve fascicles. Crowded nests of tumor cells alternated with strands of desmoplastic stroma. Immunohistochemically, the neoplastic cells were positive for pan-cytokeratin marker MNF116, cytokeratin 8/18 (CAM5.2), epithelial membrane antigen (EMA), placental alkaline phosphatase (PLAP), and desmin. The cytokeratin staining pattern was diffusely cytoplasmic (as opposed the juxtanuclear “dot-like” staining characteristic of small cell carcinoma). Desmin and PLAP immunostains often highlighted globular cytoplasmic condensations. Rare tumor cells were positive for CD56. The proliferation rate (Ki-67/MIB-1) averaged 50–55%. Conversely, negative results were obtained for synaptophysin, S100 protein, HMB45, CD45, CD79a, Pax-5, CD3, CD68, thyroid transcription factor 1 (TTF-1), and WT-1 (clone 6F-H2, directed against the N-terminus). Fluorescence in situ hybridization (FISH) revealed

break-apart of the Ewing sarcoma breakpoint region 1 (EWSR1) locus (not shown). Based on these findings, a diagnosis of malignant small cell neoplasm, most consistent with DSRCT was made. Weighing the presence of a highly aggressive tumor against the obviously lost nerve function of the medial cord, we opted for radical resection with subsequent local radiotherapy. In April 2012, the supra- and infraclavicular parts of the right brachial plexus were surgically re-explored. The affected medial cord was dissected, and adhesions to the posterior cord were cleared. The main resected nerve segment (medial cord including distal C8 and T1 roots) had a length of 6.5 cm and a diameter of 0.6 to 1.3 cm (Fig. 3b,c). Intraoperative frozen section assessment of the proximal and distal margins was negative for malignancy after several resection attempts. A nerve graft length of 15 cm would have been required to bridge the defect. Considering the long-lasting functional deficit of

FIGURE 3. a: Intraoperative view of the infraclavicular right brachial plexus. The enlarged medial cord (arrow) is pale compared with the adjacent posterior cord (on the left side) and the lateral cord (on the right side). b,c: Intraoperative view of the dissected (b) and resected (c) tumor. The distal part of the medial cord is marked by arrow. 924

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FIGURE 4. A: A cross-section of the resection specimen shows expansion of the cord. The neoplastic infiltrate exhibits tropism along individual nerve fascicles (asterisks). Solid aggregates of tumor cells (B) alternate with desmoplastic stroma (C,D). E: Spontaneous necrosis (arrows). F–H: Coexpression of epithelial antigens (CAM5.2; EMA) and desmin reflects DSRCT’s polyphenotypic antigenic profile. I: Globular condensation of desmin near the nucleus (arrows). J: Faint labeling by CD99 completes the immunohistochemical spectrum of primitive/undifferentiated neoplasia as a generic marker. K: Absence of immunostaining by S100 protein. L: Malignant rhabdoid tumor is ruled out by retained INI-1 immunoreactivity. M: Direct Sanger sequencing of the EWSR1/WT1. Reverse transcription polymerase chain reaction product reveals the boundary between EWSR1 exon 9 and WT1 exon 8 in the aberrant fusion transcript. Microphotographs not labeled otherwise represent hematoxylin–eosin stained slides. The immunoreactions depicted in (F) through (L) were visualized with 3,30 -diaminobenzidine as chromogen. Scale bar in (A) 5 500 lm in A; 200 lm in E–H,K,L; 125 lm in C; 100 lm in D; 60 lm in B; 50 lm in J; 25 lm in I, respectively. Desmoplastic Small Round Cell Tumor

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the medial cord, no reconstruction was performed apart from end-to-end neurorrhaphy of the C8 and T1 root endings to prevent neuroma formation. Histological and immunohistochemical findings in the resection specimen replicated those in the biopsy (Fig. 4). Axial resection margins were negative, while tumor cells reached the circumferential resection margin focally. Reverse transcription polymerase chain reaction revealed an EWSR1/ WT1 fusion (Fig. 4). In the fusion transcript a rather rare in-frame joining of EWSR1 exon 9 and WT1 exon 8 sequences was identified.1 Adjuvant local radiotherapy was performed with a cumulative dose of 56 Gy. The intense pain in the shoulder region decreased over the subsequent months (NRS 2–3). As a consequence, his preoperative daily dose of 70 mg methadone could be reduced to 5 mg, and pregabalin, at a daily dose of 450 mg, could be tapered off. Apart from twitches of the extensor muscles during active finger or wrist extension, there was no relevant change in motor function of the right upper limb. Eighteen months after resection, clinical follow-up and FDG-PET-CT scan did not show any evidence of recurrent disease. DISCUSSION

DSRCT is a rare, aggressive neoplasm of uncertain histogenesis that mainly affects young men. It was first described as a distinct clinicopathological entity by Gerald and Rosai in 1989.2,3 While the tumor arises mainly from the abdominal or pelvic peritoneum, sporadic reports of examples affecting the liver, kidneys, pancreas, ovary, heart, pleura, lung, bone, ethmoid sinus, parotid gland, soft tissue of the scalp, and central nervous system suggest that no extra-abdominal site might be spared.4–6 To the best of our knowledge, primary involvement of a peripheral nerve, specifically the brachial plexus, has only been documented in a single previous case.7 In its most frequent abdominal habitat, DSRCT tends to be recognized at an advanced stage, wherein symptoms are those of pronounced mass effect/distension, pain, ascites, and weight loss.8,9 Accordingly, the overall prognosis is dismal, as borne out by a mere 15% 5-year survival rate.10 In the patient described here, slow clinical progression over several years along with the detection of a slowly expanding peripheral nerve mass on imaging, prompted preoperative differential diagnosis to focus on some type of conventional nerve sheath neoplasm (schwannoma, neurofibroma, malignant peripheral nerve sheath tumor/ MPNST). On the other hand, in the absence of any indication of a lymphohematogenous malignancy, the rare alternative of neurolymphomatosis was deemed unlikely. The protracted course of 926

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neurological symptoms over 5 years might, in retrospect, be explained by the fact that the tumor was arising in a very sensitive region, so as to elicit significant functional impairment before reaching the threshold of visual detection. The diagnosis in this patient was protracted for various reasons. First, the initial MRI of the brachial plexus did not show any obvious pathology (retrospectively, subtle enhancement with gadolinium could have been seen in 1 of the axial images). Second, pertinent further diagnostic work-up is believed to have been altogether diverted from the actual problem by taking therapeutic action on a presumed “neurogenic thoracic outlet syndrome.” Third, pathological enhancement of the medial cord in a follow-up MRI after resection of the first rib was misinterpreted as postoperative change. As in the patient reported by Miwa et al., PET showed accumulation of FDG in the brachial plexus.7 The fusion of PET and CT images permitted precise localization of the lesion. Several case reports have found PET-CT to be useful for detection, staging, and monitoring of patients with DSRCT.11–14 Given the rarity of DSRCT, empirical evidence regarding therapeutic options is scant. Patients affected by intra--abdominal DSRCT are most likely to benefit from multimodal treatment including surgery, chemotherapy, and radiotherapy.15 Conversely, extra-abdominal tumors may be amenable to cure by surgery alone, depending on the extent of resection.16 Of note, the only previously reported DSRCT arising in the peripheral nervous system also involved the brachial plexus.7 A 29-year-old man was treated with caffeine-assisted chemotherapy, followed by radiation therapy with 60 Gy. As the tumor was intertwined with the brachial plexus, a resection was not attempted. After a follow-up period of 4 years, no local relapse or metastases were observed. With regard to progression-free survival, both the above patient and ours are at stark contrast with the majority of DSCRTs, in particular those evolving in the abdomen. This unexpectedly favorable course is likely attributable to the exquisitely sensitive tumor localization. Alternatively, the favorable course might relate to the rare in-frame joining of EWSR1 exon 9 and WT1 exon 8 observed in our patient. There is, however, no evidence for a prognostic impact of specific EWSR1/WT1 fusion transcripts in DSRCT in the literature to substantiate this assumption.17 Furthermore, previous reports regarding an analogous prognostic role of specific EWSR1/FLI-1 fusion transcripts in Ewing sarcoma (which would provide a proof of principle) have recently been challenged.18,19 The few reports on follow-up of DSRCT with fusion MUSCLE & NERVE

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between EWSR1 exon 9 and WT1 exon 8 do not suggest this fusion transcript to be associated with unifocal tumor manifestation or a particularly indolent clinical course.20–23 The rather unusual sites of these tumors (hand, paratesticular, and orbital regions) appear remarkable but may conservatively be seen in the context of a possible reporting bias in favor of uncommon presentations of DSRCT. Of note, the type of fusion transcript could not be characterized further in the patient reported by Miwa et al., because no resection was performed and the limited amount of available tissue from the biopsy only allowed for FISH with EWSR1 break-apart probes (H. Tsuchiya, personal communication). We are inclined to interpret our experience with this patient as a proof of principle that DSRCT may be controlled for a prolonged time if it is detected at a sufficiently early stage. Furthermore, the clinical course observed here suggests that DSRCT may have been present and caused symptoms for several years before forming a detectable mass, a most unexpected event given its high proliferative rate and usually aggressive clinical course. For the sake of completeness, we wish to point out that the probable growth rate of the tumor in our patient, as reconstructed on clinical grounds, i.e., from initiation to macroscopic detection, may be interpreted in terms of “Collins’ law” as applies to solid malignancies in less sensitive sites.24 In conclusion, this case report confirms that DSRCT can arise rarely in the brachial plexus. Especially in young men with a history of a slowly progressive plexus disorder, DSRCT should be considered as a rare differential item. For detecting small-sized DSRCT, imaging with FDG-PET-CT might be more sensitive than MRI or CT. In patients with a suspected neoplastic plexopathy, surgical exploration and open biopsy should be considered, as obtaining a histological diagnosis is essential for appropriate treatment. Given its polyphenotypic immunohistochemical expression pattern, including epithelial and neuroendocrine markers, DSRCT may be mistaken for metastatic or locally invasive small cell carcinoma on a biopsy, which may prevent curative therapy. The authors thank Prof. Th. Krause (Department of Nuclear Medicine, Inselspital, Bern University Hospital and University of Bern) for providing the PET/CT imaging data and Prof. A. Perren (Institute of Pathology, University of Bern) for helpful discussions on the histopathological findings.

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3. Gerald WL, Miller HK, Battifora H, Miettinen M, Silva EG, Rosai J. Intra-abdominal desmoplastic small round-cell tumor. Report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol 1991; 15:499–513. 4. Kallianpur AA, Shukla NK, Deo SV, Yadav P, Mudaly D, Yadav R, et al. Updates on the multimodality management of desmoplastic small round cell tumor. J Surg Oncol 2012;105:617–621. 5. Lae ME, Roche PC, Jin L, Lloyd RV, Nascimento AG. Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol 2002;26:823– 835. 6. Neder L, Scheithauer BW, Turel KE, Arnesen MA, Ketterling 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 2009;454:431–439. 7. Miwa S, Kitamura S, Shirai T, Hayashi K, Nishida H, Takeuchi A, et al. Desmoplastic small round cell tumour successfully treated with caffeine-assisted chemotherapy: a case report and review of the literature. Anticancer Res 2010;30:3769–3774. 8. Hayes-Jordan A, Anderson PM. The diagnosis and management of desmoplastic small round cell tumor: a review. Curr Opin Oncol 2011;23:385–389. 9. Thomas R, Rajeswaran G, Thway K, Benson C, Shahabuddin K, Moskovic E. Desmoplastic small round cell tumour: the radiological, pathological and clinical features. Insights Imaging 2013;4:111– 118. 10. 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 2005;40:251–255. 11. Kis B, O’Regan KN, Agoston A, Javery O, Jagannathan J, Ramaiya NH. Imaging of desmoplastic small round cell tumour in adults. Br J Radiol 2012;85:187–192. 12. Zhang WD, Li CX, Liu QY, Hu YY, Cao Y, Huang JH. CT, MRI, and FDG-PET/CT imaging findings of abdominopelvic desmoplastic small round cell tumors: correlation with histopathologic findings. Eur J Radiol 2011;80:269–273. 13. Ben-Sellem D, Liu KL, Cimarelli S, Constantinesco A, Imperiale A. Desmoplastic small round cell tumor: impact of F-FDG PET induced treatment strategy in a patient with long-term outcome. Rare Tumors 2009;1:e19. 14. Kushner BH, Laquaglia MP, Gerald WL, Kramer K, Modak S, Cheung NK. Solitary relapse of desmoplastic small round cell tumor detected by positron emission tomography/computed tomography. J Clin Oncol 2008;26:4995–4996. 15. Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Lindsley KL, Ghavimi F, et al. Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 1996;14:1526–1531. 16. Biswas G, Laskar S, Banavali SD, Gujral S, Kurkure PA, Muckaden M, et al. Desmoplastic small round cell tumor: extra abdominal and abdominal presentations and the results of treatment. Indian J Cancer 2005;42:78–84. 17. Murphy AJ, Bishop K, Pereira C, Chilton-MacNeill S, Ho M, Zielenska M, et al. A new molecular variant of desmoplastic small round cell tumor: significance of WT1 immunostaining in this entity. Hum Pathol 2008;39:1763–1770. 18. Romeo S, Dei Tos AP. Soft tissue tumors associated with EWSR1 translocation. Virchows Arch 2010;456:219–234. 19. Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PC, et al. Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 2010;28:1982–1988. 20. Hamazaki M, Okita H, Hata J, Shimizu S, Kobayashi H, Aoki K, et al. Desmoplastic small cell tumor of soft tissue: molecular variant of EWS-WT1 chimeric fusion. Pathol Int 2006;56:543–548. 21. Antonescu CR, Gerald WL, Magid MS, Ladanyi M. Molecular variants of the EWS-WT1 gene fusion in desmoplastic small round cell tumor. Diagn Mol Pathol 1998;7:24–28. 22. Adsay V, Cheng J, Athanasian E, Gerald W, Rosai J. Primary desmoplastic small cell tumor of soft tissues and bone of the hand. Am J Surg Pathol 1999;23:1408–1413. 23. Cliteur VP, Szuhai K, Baelde HJ, van Dam J, Gelderblom H, Hogendoorn PC. Paratesticular desmoplastic small round cell tumour: an unusual tumour with an unusual fusion; cytogenetic and molecular genetic analysis combining RT-PCR and COBRA-FISH. Clin Sarcoma Res 2012;2:3. 24. Patrone MV, Hubbs JL, Bailey JE, Marks LB. How long have I had my cancer, doctor? Estimating tumor age via Collins’ law. Oncology (Williston Park) 2011;25:38–43, 46.

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Desmoplastic small round cell tumor: a rare cause of a progressive brachial plexopathy.

Desmoplastic small round cell tumor (DSRCT) is an uncommon, embryonic-type neoplasm, typically presenting as an abdominal mass in young men. A single ...
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