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Desmoplastic small round cell tumor 20 years after its discovery Jaume Mora*,1, Shakeel Modak2, Nai-Kong Cheung2, Paul Meyers2, Enrique de Alava3, Brian Kushner2, Heather Magnan2, Oscar M Tirado4, Michael Laquaglia5, Marc Ladanyi6 & Juan Rosai7
ABSTRACT Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy. On 18 March 1991, William L Gerald, a young pathologist in the Department of Pathology of Yale University Medical School (CT, USA), proposed at the US and Canadian Academy of Pathology (USCAP) meeting in Chicago, DSRCT as a new clinicopathological entity based on 19 cases that he and Juan Rosai had identified going over the consultation files from Rosai, then the Chief of Anatomic Pathology at Yale. Later that same year their publication appeared in The American Journal of Surgical Pathology [1] . The first proposal of the existence of this new entity actually goes back to the 1988 USCAP meeting in which Gerald and Rosai presented one case, published a year later in the Journal of Pediatric Pathology. In the short span of 2 years, Gerald and Rosai identified 19 similar cases, allowing them to define a new neoplastic entity belonging to the general category of small round cell tumors of infancy and childhood. They based their proposal upon a number of topographic, morphologic and immunohistochemical features that set this entity apart from all of the previously described members of this group. DSRCT, as Gerald posited in the 1991 paper, in clear distinction from the other small round blue cell tumors, is clinically characterized by male predominance (>5:1); primary (often exclusive) intra-abdominopelvic location with multiple peritoneal implants, initial incomplete response to chemotherapy followed by uncontrollable tumor relapse and a high mortality rate. From the histopathological standpoint, DSRCT was characterized by peritoneal nodules invading local structures like bladder, colon, liver and small bowel; clusters of small cells separated by a consistent and prominent cellular (‘desmoplastic’) stroma; invasive growth pattern; and a broadly positive immunohistochemical profile showing unusual
KEYWORDS
• adolescent and
young adult oncology • desmoplastic tumors • developmental cancer • EWS gene • small round cell tumors • William L Gerald • WT1 gene
Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain Department of Pediatrics, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 3 Department of Pathology, Hospital Virgen del Rocío, Sevilla, Spain 4 Sarcoma Research Group, Institut d’Investigació Biomèdica de Bellvitge, Barcelona, Spain 5 Department of Surgery, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 6 Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 7 Centro Consulenze Anatomia Patologica Oncologica, Milano, Italy *Author for correspondence: Tel.: +34 93 280 40 00 ext. 2361 (office), ext. 4398 (laboratory); Fax: +34 93 600 6119; [email protected] 1 2
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Review Mora, Modak, Cheung et al. coexpression of epithelial (EMA and keratin), neural (NSE) and mesenchymal (vimentin and desmin) markers (Figure 1) [1] . In the 1991 paper, the authors reviewed the literature for cases similar to what they had described. They identified earlier case reports that were likely DSRCT. One from Ordoñez et al., described a 28-year-old man with an extensive intra-abdominal small-cell tumor [2] . Another case reported by Gaffney et al. in 1989 described an 11-year-old girl with an intra-abdominal tumor characterized histologically by aggregates of small round cells, some with a rhabdoid appearance, and immunohistochemically with a multiphenotypic profile [3] . Three further cases were discussed by Gonzalez-Crussi et al. in a paper from 1990 [4] . Gerald and Rosai were able to review some of these cases personally and confirmed that two of them were consistent with DSRCT. Two cases reported by Variend in 1991 were described as ‘intra-abdominal neuro ectodermal tumors of childhood with divergent differentiation’ [5] . In their original description, Gerald and Rosai discussed extensively the differential diagnosis of DSRCT and looked specifically for clues to its histogenesis on the basis of its morphologic, immunohistochemical and clinical features. They speculated on the possibility of the tumor having a mesothelial histogenesis and thus be viewed as mesothelioblastoma [1,6] . Early in 1993, Ordoñez et al. reported
A
B
C
D
Figure 1. Characteristic histological features of classical desmoplastic small round cell tumor. (A) Low-power field (10x) view of nests of small round blue cells within abundant desmoplastic stroma. Analysis of the tumor by immunohistochemistry shows (20x) diffuse positivity for VEGFR2 (B), and coexpression of (epithelial) EMA (C) and (mesenchymal) desmin (D) markers.
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the experience from the MD Anderson Cancer Center with 19 additional cases [7] . They confirmed the initial description by Gerald of male predominance, widespread abdominal and pelvic peritoneal involvement, and a multiphenotypic pattern of differentiation. Subsequently, cases with involvement of other sites (including the CNS and the skeletal system) have been described [8–10] . In 1992, the cytogenetics of a case of DSRCT was first reported, featuring a diploid DNA content and t(11;22)(p13;q12) [11] . In 1994, five DSRCT karyotypes had been reported: in four of five tumors a break point in the 22q11.2-13 region was present as a translocation t(11;22) (p13;q11.2–12) [11–13] . Following the leads suggested by the break points at 22q12 and 11p13 (sites of the EWS and WT1 genes, respectively) Ladanyi and Gerald, both of them at the time in the Department of Pathology headed by Rosai at Memorial Sloan–Kettering Cancer Center (MSKCC) in New York, reported for first time in 1994 the consistent fusion of the EWS and WT1 genes in DSRCT [14] . Using Southern blotting with cDNA probes for EWS and WT1 that spanned the break-point cluster regions, they detected EWS and WT1 rearrangements comigrating in four of five cases of DSRCT. By northern blot, they identified aberrant EWS and WT1 transcripts of the same size, suggesting the existence of a chimeric EWS–WT1 RNA species resulting from the translocation. Finally, by realtime (RT)-PCR using primers for EWS exon 7 (as described for Ewing sarcoma) and WT1 exon 8 or 9, they were able to amplify a single RT-PCR product. Sequencing of the RT-PCR product showed an in-frame junction of EWS exon 7 to WT1 exon 8. This was the first experimental proof for the existence of WT1 as a new translocation partner for EWS and for EWS–WT1 as the genetic marker for DSRCT, thus defining it as a true separate entity of small round cell tumor as predicted by Gerald in 1991 [1] . In a subsequent publication in 1995, the MSKCC team led by Gerald and Ladanyi precisely described the characteristics of the genomic break points and fusion transcripts involved in the EWS–WT1 gene fusion of DSRCT [15] . They proved that DSRCT represents the third tumor type associated with a chromosomal translocation involving the EWS gene and the only tumor ever described to be associated with translocation of WT1. The chimeric transcript of two different tumor-associated genes was clearly
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Desmoplastic small round cell tumor 20 years after its discovery implicated in its oncogenesis. The translocation results in chimeric products containing the amino-terminal domain of EWS fused to most of the DNA-binding domain of WT1. Later in 1995, Enrique de Alava, a postdoctoral student in the Gerald laboratory, further validated the RT-PCR method as a very sensitive and specific test for diagnosing DSRCT in clinical samples [16] . The specificity of molecular assays such as the one described for DSRCT was becoming a much needed tool for the differential diagnosis of pediatric small round cell tumors [17–22] . The involvement of EWS and WT1 in the pathogenesis of DSRCT raised new potential histogenetic implications. On the one hand, the age of presentation, male predominance and primitive appearance of the neoplastic cells in DSRCT were all reminiscent of the Ewing sarcoma/PNET family of tumors. On the other hand, WT1 was known to be expressed in embryonal structures derived from the intermediate mesoderm, mesenchyme lining the coelom and mesenchyme of the primitive gonad. WT1 is a transcription factor intimately associated with a particular period in normal development the alteration of which may contribute to tumor formation in the primitive cells expressing the gene. Thus, the histogenetic hypothesis was raised of DSRCT possibly arising in the primitive mesenchyme of the coelomic cavities or gonads [23] . Soon after the initial molecular description of DSRCT, the MSKCC team published in 1996 the first therapeutic experience using intensive alkylator-based therapy following the P6 protocol for Ewing sarcoma/PNET family of tumors [24] . The report described 12 patients with a male to female ratio of 11:1. All patients responded but there were no complete pathological responses. Seven of the 12 patients achieved complete remission (CR) after intensive use of alkylator-based chemotherapy, aggressive surgery, radiation therapy to high-risk sites often including whole abdomen and pelvis [25] and myeloablative therapy with stem cell rescue in selected cases [26] . This first therapeutic report highlighted some interesting findings of DSRCT. Similar to other small round cell tumors of young people, DSRCT is an alkylator-sensitive and dose-responsive tumor. However, intensive chemotherapy or myeloablative doses of alkylating agents did not result in complete pathologic responses of large masses. Hence, aggressive surgery to remove bulk tumor was found to be a critical component of a curative strategy.
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Initially, patients who achieved a complete or very good partial response appeared to have a good prognosis [27] , however, it was later found that responses were not durable in most patients with recurrences being observed >3 years after diagnosis. A review from the MSKCC group of 66 patients with DSRCT treated from 1972 to 2003 reported 3- and 5-year survivals of 44 and 15%, respectively [28] , with achievement of CR being the only prognostic marker. A more recent report from the MSKCC group on 31 patients treated from 1992 to 2011 showed similar survival rates although radiation-a ssociated toxicities appeared to be decreased with the use of intensity-modulated radiotherapy [29] . In 1997, Gerald, working with Daniel Haber, reported the first downstream target of the EWS–WT1 fusion transcript, namely PDGFA [30] . Given that the chimeric EWS–WT1 product defines DSRCT, the analysis of the functional properties and mechanism of tumorigenesis was performed using an inducible expression system of EWS–WT1 in osteosarcoma cell lines since there were no available DSRCT cell lines at the time. Expression of EWS–WT1 induced PDGFA. Native PDGFA was not induced by native WT1 indicating target specificity of the EWS–WT1 fusion protein. The authors also showed that primary DSRCT expressed high levels of PDGFA and it was absent in tumors expressing WT1 and Ewing sarcomas expressing EWS-FLI showing the specificity of PDGFA expression correlating with the tumorigenic activity of EWS–WT1 [30] . PDGFA is a secreted growth factor that acts as a potent mitogen and chemoattractant for fibroblasts and endothelial cells, a possibly significant aspect because the histology of DSRCT is remarkable for the presence of a profuse stromal reaction. The potential growth advantage conferred by this stromal reaction, including vascular recruitment, is consistent with DSRCT specimens demonstrating active neoangiogenesis in the connective tissues surrounding tumor cells. In 2004, the first Phase I trial of the PDGFR pathway inhibitor SU101 (NCT00001573) was reported for children with refractory solid tumors [31] . Among 27 patients, there were no objective responses, but the authors’ highlighted one patient with rapidly progressive DSRCT who experienced symptomatic improvement and prolonged stable disease [32] . Similarly, other tyrosine kinase inhibitors such as imatinib, a partial inhibitor
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Review Mora, Modak, Cheung et al. of KIT and PDGFRα [33] , and the multikinase inhibitors sunitinib [34] and pazopanib [35] had very modest activity against DSRCT in early phase studies. Blockade of angiogenesis is currently being investigated at MSKCC in an upfront ‘window’ study of bevacizumab in combination with irinotecan and temozolomide in newly diagnosed patients with DSRCT (NCT01189643) [36] . The rationale for the study includes the markedly elevated expression of VEGFR-2 and VEGFA in DSRCT tumor samples and marked, long-term regressions of tumors seen in a xenograft model of DSRCT treated with irinotecan and bevacizumab [37] . In 2002 and 2003, William Gerald and Daniel Haber described new transcriptional targets of EWS–WT1: the beta chain of the IL-2/15 receptor (IL-2/15Rβ) and LRRC15, a cytokine signaling pathway and a protein implicated in migration/invasiveness, respectively [38,39] . In a comprehensive review of the role of EWS–WT1 in the tumorigenesis of DSRCT in 2005, Gerald emphasized the relationship of the histological features characteristic of DSRCT to the downstream targets of the EWS–WT1 [40] . In 2002, Nishio et al. were the first to report the generation of a fusion-positive DSRCT cell line called JN-DRSCT-1 [41] . For many years, it was the only in vitro model of DSRCT. In 2013, Markides et al. reported the establishment of nine DSRCT xenograft lines and five tissue culture lines [42] . Using the JN-DRSCT-1 model, Tirado et al., following their previous studies in Ewing sarcoma/PNET models, reported in 2005 that the mTOR inhibitor rapamycin downregulated the expression of EWS/WT1 and induced apoptotic death of JN-DSRCT-1 cells by simultaneously inducing the downregulation of Bcl-xL [43] . Rapamycin also caused upregulation of Bax by inhibiting the proteasome complex, a process independent of mTOR inhibition. Their results suggested that, being a highly effective inducer of apoptosis, rapamycin or other mTOR inhibitors could be active in the treatment of DSRCT. In 2010, one refractory DSRCT patient treated with temsirolimus showed stable disease for >40 weeks suggesting a possible clinical benefit for inhibition of the mTOR pathway [44] . A recent report suggests that DSRCT has a constitutively activated PI3K/Akt/mTOR pathway. p-Akt expression was detected in the nucleus of the tumor cells and p-mTOR was detected on Ser 2448, suggesting mTORC2 as the dominant form [45] .
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Consistent with the knowledge that the EWS– WT1 fusion protein modulates transcription of target genes containing WT1 binding motifs, Karnieli et al. in 1996 showed that EWS–WT1 recognizes and transactivates the IGF-1R promoter [46] . In 2002, the same group [47] showed that the IGF-1R gene is a molecular target of EWS–WT1. A clinical observation suggesting an important role for the IGF-1 signaling pathway in DSRCT was reported in 2010 [48] . Symptomatic hypoglycemia in a patient with DSRCT was found to be caused by an increased IGF-II/IGF-I ratio, typical of nonislet cell tumor hypoglycemia, in this case possibly related to the inappropriate production of IGF-II by the tumor. IGF-1R is known to play an important role in the growth and development of normal tissue as well as the initiation, maintenance, survival, progression and metastasis of many sarcomas. The introduction of humanized monoclonal antibodies that inhibit IGF-1R in clinical trials and the dramatic single-agent anti-IGF-1R activity observed in refractory sarcoma patients provided initial excitement in the sarcoma community. More than 25 agents acting via IGF-1R inhibition were in preclinical and clinical development during the first decade of the 2000. Given the preclinical rationale and early clinical data, an open-label, Phase II trial to evaluate the safety and efficacy of ganitumab a fully human, monoclonal antibody antagonist of IGF-1R that blocks IGF-1 and IGF-2 binding was initiated in patients with relapsed or refractory Ewing sarcoma/PNET or DSRCT [49] . In total, 16 patients with DSRCT were enrolled. Antitumor responses observed were comparable to those observed with other anti-IGF-1R antibodies evaluated as monotherapy. Four of 16 patients had objective responses or stable disease for more than 24 weeks [49] . Like IGF-1R, other cell surface tumor-associated antigens were discovered at the time for diagnosis and therapy of DSRCT. Using immunohistochemistry, the expression of two antigens, GD2 using antibody 3F8 and B7-H3 using antibody 8H9, was studied in a panel of 46 DSRCT [50,51] . In total, 70% of tumors were reactive with 3F8, 96% with 8H9, both antigens localized to the tumor cell membrane and stroma. One of the most salient clinical features of DSRCT is male predominance. The role of androgens in DSRCT was studied and reported
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Desmoplastic small round cell tumor 20 years after its discovery in 2007 [52] . A significant androgen receptor (AR) immunostaining pattern was found in ten of 27 DSRCT tumors studied and was confirmed by western blot in two patients. The functional status of the AR was demonstrated by stimulation of basal in vitro growth by supplemental testosterone and inhibition of basal and testosterone stimulated growth by flutamide. These results suggested that DSRCT may upregulate or downregulate AR possibly for survival purposes as a growth factor receptor. Of six heavily pretreated patients with positive AR status treated with a combination of androgen blockade (AR blocker and biculatamide preceding Lupron), one each had partial response, minor response and stable disease, although responses appeared to be short-lived [52] . At the same time as various potential targets were being identified and targeted therapies were being attempted, single institution experiences and observations of nontargeted chemotherapeutic agents were also being reported [28,53–54] . Minimal to modest responses were reported with a metronomic approach using vinorelbine plus cyclophosphamide [55] , irinotecan [56,57] and trabectedin [58–61] . The incorporation of dactinomycin to multimodality chemotherapy did not appear to significantly improve outcomes [62] . As in Ewing sarcoma/PNET, the benefit of high-dose chemotherapy and autologous hemopoietic stem cell transplant is controversial, at best. A retrospective analysis of 36 DSRCT patients registered at the International bone marrow transplant registry (CIBMTR) from 1999 to 2007 reported on 3-year overall survival (OS) of 57% and 28% for patients in CR and not in CR, respectively [63] . However, other groups have reported poorer outcomes. In 2010, the Italian group reported their experience with 14 DSRCT patients treated with three consecutive intensified chemotherapy combinations followed by stem cell rescue [64] . Three-year event-free survival and OS rates were 15.5 and 38.9%, respectively. This experience corroborated the initial description by the MSKCC group of the lack of improvement using myeloablative doses of alkylating agents like thiotepa [26] . A further chemotherapeutic approach adopted by the MD Anderson group was intraperitoneal instillation of cisplatin via hyperthermic intraperitoneal chemotherapy (HIPEC) similar to that used for colorectal carcinoma [65] in addition to multimodality therapy [66] . Their efforts focused on quality of life for DSRCT patients reinforcing
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outpatient clinic and home infusion settings. As described in other reports [28] , tumor burden was prognostic in patients receiving HIPEC. Patients who were able to achieve gross total resection and undergo HIPEC had improved survival compared with those patients who could not achieve significant debulking and were treated with chemotherapy alone. Similar to intraperitoneal radioimmunotherapy, the role of HIPEC in improving outcome in patients undergoing gross total resection is unclear [67–71] . Given that DSRCT is locoregionally disseminated at diagnosis, and disease burden and resectability appear to be prognostic, a staging system for DSRCT has been proposed incorporating the peritoneal carcinomatosis Index (PCI) score and presence of extra-abdominal disease [72] . Metastatic DSRCT typically involves distant lymph nodes, liver and lungs. Spread to bones and bone marrow is rare. Furthermore, it is well described that surgery after chemotherapy shows persistence of peritoneal or omental studding not seen by conventional anatomical imaging (CT/MRI). The role of PET scan in DSRCT imaging has been investigated by the MSKCC group [73] . FDG PET/CT accurately detected 97% of all DSRCT lesions [74] and hybrid PET-CT had superior overall sensitivity and specificity to PET or CT alone [75] . A retrospective review of seven patients with DSRCT who were imaged by FDG-PET and CT at diagnosis and after three cycles of chemotherapy showed that FDG-PET did not always correlate with response measurement by CT. A greater decrease in metabolic activity as compared with size was seen in all patients [75] . In 2009, Mora et al. published the first series of pediatric patients treated with Gemcitabine and Docetaxel as relapse therapy [76] . This series was notable for six patients with Ewing sarcoma and reported a very high complete response rate of 40%. Gemcitabine and Docetaxel drugs, not routinely used to treat pediatric malignancies, seemed to rescue relapsed sarcoma patients, induce tumor remission and, as maintenance chemotherapy, keep disease under control for prolonged periods of time (median duration of responses 10 months), even after two or more relapses. On the basis of these and other results, evaluation in a formal Phase II setting from GEIS for primary highrisk Ewing sarcoma patients is just completed (ClinicalTrials.gov identifier NCT01696669) [77] . The combination of gemcitabine and paclitaxel has shown clinical benefit for relapsed sarcoma
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Review Mora, Modak, Cheung et al. patients including Ewing family of tumors and DSRCT. Furthermore, histological and biological features of EWS-rearranged tumors suggest that albumin-bound paclitaxel particles (nabpaclitaxel [Abraxane], Celgene, NJ, USA) could be more active than paclitaxel. Following these
experiences, a formal clinical trial of Abraxane for DSRCT patients is currently being planned. Table 1 summarizes all the clinical trials reported with DSRCT patients and all the largest series of DSRCT patients reported in the medical literature.
Table 1. Lists the largest series of desmoplastic small round cell tumor cases reported in the medical literature until the first half of 2014 and references all the ten formal clinical trials reported including patients with desmoplastic small round cell tumor. First author (year)
DSRCT patients (n) Description of study
Hayes-Jordan A (2014) Zhang J (2014) Glade Bender JL (2013) Italiano A (2013) Arora VC (2013) Desai NB (2013)
26 48 2 8 65 31
Magnan H (2013) Chuk MK (2012) Ryan CW (2013) Tap WD (2012) Hayes-Jordan A (2012) Cook RJ (2012) Naing A (2012) Rekhi B (2012) Philippe-Chomette P (2012) Pinnix CC (2012)
7 1 NA 16 10 36 3 45 38 8
Hayes-Jordan A (2010) Chao J (2010) Bisogno G (2010) Liping Cao (2008) Bagatell R (2007) Bond M (2008) Saab R (2007) Bisogno G (2006) Biswas G (2005) Hassan I (2005) Chouli M (2005) Lal DR (2005) Adamson PC (2004) Goodman KA (2002) Lae ME (2002) La Quaglia MP (2000) Ordóñez NG (1998) Gerald WL (1998) Schwarz RE (1998) Kushner BH (1996) Tison V (1996) Gerald WL (1993) Ordóñez NG (1993) Gerald WL (1991)
24 2 14 18 1 12 11 3 18 12 13 66 2 21 32 40 39 109 31 12 1 46 19 19
Ref.
MD Anderson group. Multimodality treatment and HIPEC Retrospective review from China COG Phase I trial of pazopanib Case series using sunitinib MSKCC review of radiological features MSKCC review on intensity-modulated radiation therapy for whole abdominopelvic therapy MSKCC review on PET for response assessment Phase I of 24-h infusion of trabectedin by the COG A Phase II study of tasisulam sodium Phase II study of ganitumab HIPEC in pediatric patients: early experience and Phase I results CIBMTR retrospective analysis of autologous bone marrow transplant Cixutumumab combined with the mTOR inhibitor temsirolimus Retrospective review from India Retrospective review from the French group MD Anderson review on intensity-modulated radiation therapy for whole abdominopelvic therapy MD Anderson group. Multimodality treatment and HIPEC Phase II clinical trial of imatinib mesylate Italian autologous bone marrow transplant retrospective review Chinese group. Retrospective review Phase I study of Geldanamycin. COG trial Phase II study of imatinib mesylate. COG trial St Jude Children’s Research Hospital restrospective experience Phase II study of irinotecan. Italian group Retrospective review from India Retrospective review from the Mayo Clinic Retrospective radiological review from France MSKCC retrospective review on multimodal therapy Pediatric Phase I trial of the PDGF receptor pathway inhibitor SU101 MSKCC review on whole abdominopelvic radiotherapy Retrospective review from the Mayo Clinic MSKCC retrospective review on multimodal therapy First description of a large series of cases from the MD Anderson group First description of a large series of cases from the MSKCC group MSKCC group retrospective review on multimodal therapy First clinical trial ever to address DSRCT patients First description of an intracranial DSRCT case Histopathological description of the MSKCC first series Histopathological description of the MD Anderson first series Discovery series
[68] [78] [35] [34] [73] [29] [75] [59] [79] [49] [69] [63] [80] [81] [82] [83] [67] [33] [64] [84] [85] [86] [62] [57] [87] [88] [89] [28] [32] [90] [91] [92] [93] [23] [27] [24] [8] [6] [7] [1]
COG: Children’s Oncology Group; DSRCT: Desmoplastic small round cell tumor; HIPEC: Hyperthermic intraperitoneal chemotherapy; MSKCC: Memorial Sloan–Kettering Cancer Center.
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Desmoplastic small round cell tumor 20 years after its discovery
Review
Tribute to a brilliant physician scientist On 14 September 2008, William L Gerald died of metastatic skin cancer (Figure 2) [94] . In 1992, he had established his laboratory at MSKCC devoted to the study of DSRCT. He was a beloved teacher and mentor for a large family of pathology, molecular pathology, surgery and pediatric/medical oncology fellows who followed his footsteps, advancing biological knowledge to explain pathologic features and to guide therapeutics. As we have reviewed, William L Gerald contributed substantially to the establishment of DSRCT as a unique pathologic entity and, with deep insight and critical thinking, described most aspects of the disease as we know it today. While Rosai coined the disease DSRCT, the eponymous term for this clinically aggressive and biologically fascinating disease could justifiably be ‘Gerald tumor’. Conclusion The historical analysis of DSRCT highlights the fundamental contributions of a brilliant physician scientist, the late William L Gerald, MD PhD. The eponymous term for this clinically aggressive disease could reasonably be ‘Gerald tumor’. Future perspective The combination of chemotherapy, compartmental therapeutic approaches (surgery + HIPEC and/or radioimmunotherapy) and novel biologic strategies may hold the promise for long-term disease control of DSRCT. In 2014, the combination of polychemotherapy and aggressive surgery followed by whole
Figure 2. William L Gerald, MD, PhD (1954–2008).
abdominal radiation therapy represents the standard of care for DSRCT. Currently, patients having chemoresponsive disease and successful surgical cytoreduction appear to have the best outcome compared with patients who do not achieve both benchmarks [95] . The genomic and epigenomic landscape of DSRCT has not been thoroughly explored and current efforts are ongoing applying next
EXECUTIVE SUMMARY Historical perspective of a new entity ●●
Desmoplastic small round cell tumor was described as a new clinicopathological entity in early 1991, and in 1994 the
molecular definition of desmoplastic small round cell tumor was discovered as a chimeric fusion of the EWS and WT1 genes. ●●
In 1996, the backbone of multimodality treatment was described using intensive alkylator-based therapy following the MSKCC P6 protocol for Ewing sarcoma. It remains the standard of therapy as of today.
●●
In 1996, it was found that the EWS–WT1 fusion protein recognizes and transactivates the IGF-1R promoter. Target
therapy with IGF-1R inhibition was tested in the first decade of the 2000. Objective antitumor responses were observed as monotherapy in relapsed cases. ●●
The benefit of high-dose chemotherapy with autologous/heterologous hemopoietic stem cell transplant is not proven.
●●
Patients who achieve gross total resection and undergo hyperthermic intraperitoneal chemotherapy have an
improved survival compared with those patients who do not achieve significant surgical debulking and are treated with chemotherapy alone.
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Review Mora, Modak, Cheung et al. generation sequencing approaches to DSRCT cases collected worldwide. With such studies more druggable targets of clinical benefit will appear in the near future. The year 2013 was marked by major successes in immunotherapy for cancer [96,97] , one therapeutic modality that has yet to be explored for DSRCT. A combination of chemotherapy, compartmental therapeutic approaches and novel biologic strategies may be needed for long-term disease control of DSRCT. Following these studies, the MSKCC team has initiated a Phase I clinical trial of intraperitoneal injection References Papersof special note have been highlighted as: • of interest; •• of considerable interest 1
• 2
3
4
5
6
7
8
Gerald WL, Miller HK, Battifora H et al. 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. 15, 499–513 (1991). First historical report on the new entity desmoplastic small round cell tumor.
of radioiodinated 8H9 for radioimmunotherapy of DSRCT (NCT01099644) [98,99] . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Report of a case. Am. J. Surg. Pathol. 20, 112–117 (1996). 9
Bouchireb K, Auger N, Bhangoo R et al. Intracerebral small round cell tumor: an unusual case with EWS–WT1 translocation. Pediatr. Blood Cancer 51, 545–548 (2008).
10 Neder L, Scheithauer BW, Turel KE 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).
Ordóñez NG, Zirkin R, Bloom RE. Malignant small-cell epithelial tumor of the peritoneum coexpressingmesenchymal-type intermediate filaments. Am. J. Surg. Pathol. 13, 413–421 (1989).
11 Sawyer JR, Tryka AF, Lewis JM. A novel
Gaffney EF, Breatnach F. Diverse immunoreactivity and metachronous ultrastructural variability in fatal primitive childhood tumor with rhabdoid features. Arch. Pathol. Lab. Med. 113, 1322 (1989).
12 Rodriguez E, Sreekantaiah C, Gerald W et al.
Gonzalez-Crussi F, Crawford SE, Sun CC. Intraabdominal desmoplastic small-cell tumors with divergent differentiation. Observations on three cases of childhood. Am. J. Surg. Pathol. 14, 633–642 (1990).
13 Biegel JA, Conard K, Brooks JJ. Translocation
Variend S, Gerrard M, Norris PD et al. Intra-abdominal neuroectodermal tumour of childhood with divergent differentiation. Histopathology 18, 45–51 (1991).
14 Ladanyi M, Gerald W. Fusion of the EWS
Gerald WL, Rosai J. Desmoplastic small cell tumor with multi-phenotypic differentiation. Zentral bl Pathol. 139, 141–151 (1993).
•• Discovery of the molecular translocation defining the new entity, desmoplastic small round cell tumor. Investigations made from previous laboratory interests in Wilms tumor and Ewing sarcoma from the laboratories of William Gerald and Marc Ladanyi.
Ordóñez NG, el-Naggar AK, Ro JY et al. Intra-abdominal desmoplastic small cell tumor: a light microscopic, immunocytochemical, ultrastructural, and flow cytometric study. Hum. Pathol. 24, 850–865 (1993). Tison V, Cerasoli S, Morigi F et al. Intracranial desmoplastic small-cell tumor.
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reciprocal chromosome translocation t(11;22) (p13;q12) in an intraabdominal desmoplastic small round-cell tumor. Am. J. Surg. Pathol. 16, 411–416 (1992). A recurring translocation, t(11;22) (p13;q11.2), characterizes intra-abdominal desmoplastic small round-cell tumors. Cancer Genet. Cytogenet. 69, 17–21 (1993). (11;22)(p13;q12): primary change in intra-abdominal desmoplastic small round cell tumor. Genes Chromosomes Cancer 7, 119–121 (1993). and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 54, 2837–2840 (1994).
15 Gerald WL, Rosai J, Ladanyi M.
Characterization of the genomic breakpoint and chimeric transcripts in the EWS–WT1 gene fusion of desmoplastic small round cell
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tumor. Proc. Natl Acad. Sci. USA 92, 1028–1032 (1995). 16 de Alava E, Ladanyi M, Rosai J et al.
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36 Irinotecan, Temozolomide and Bevacizumab
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Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing’s sarcoma (EWS/FLI1) and Wilms’ tumor(WT1). PLoS ONE 8, e68985 (2013). 46 Karnieli E, Werner H, Rauscher FJ 3rd et al.
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Symptomatic hypoglycemia related to inappropriately high IGF-II serum levels in a patient with desmoplastic small round cell tumor. Case Rep. Med. 684045 (2010) (2010). 49 Tap WD, Demetri G, Barnette P et al.
Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J. Clin. Oncol. 30, 1849–1856 (2012). •• First ever trial of targeted therapies on EWS-related tumors including desmoplastic small round cell tumor. The relevance of IgF-1R in this disease was made evident with objective responses in desmoplastic small round cell tumor. 50 Modak S, Gerald W, Cheung NK.
Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor. Med. Pediatr. Oncol. 39, 547–551 (2002). 51 Modak S, Kramer K, Gultekin SH et al.
Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors. Cancer Res. 61, 4048–4054 (2001). 52 Fine RL, Shah SS, Moulton TA et al. Androgen
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Response to vinorelbine and low-dose cyclophosphamide chemotherapy in two patients with desmoplastic small round cell tumor. Pediatr. Blood Cancer 49, 864–866 (2007). 56 Rosoff PM, Bayliff S. Successful clinical
response to irinotecan in desmoplastic round blue cell tumor. Med. Pediatr. Oncol. 33, 500–503 (1999). 57 Bisogno G, Riccardi R, Scagnellato A et al.
No effect of irinotecan in patients with resistant desmoplastic small round cell tumor. Pediatr. Blood Cancer 54, 182–183 (2010). 58 Lopez-Gonzalez A, Cantos B, Tejerina E et al.
67 Hayes-Jordan A, Green H, Fitzgerald N et al.
Novel treatment for desmoplastic small round cell tumor: hyperthermic intraperitoneal perfusion. J. Pediatr. Surg. 45, 1000–1006 (2010). •
68 Hayes-Jordan A, Green HL, Lin H et al.
Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor. Ann. Surg Oncol. 21, 220–224 (2014). 69 Hayes-Jordan A, Green H, Ludwig J et al.
Toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric patients with sarcomatosis/carcinomatosis: early experience and Phase 1 results. Pediatr. Blood Cancer 59, 395–397 (2012).
Activity of trabectidin in desmoplastic small round cell tumor. Med. Oncol. 28(Suppl. 1), S644–S646 (2011). 59 Chuk MK, Aikin A, Whitcomb T et al. A
Phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis®, ET-743) in children and adolescents with relapsed or refractory solid tumors. Pediatr. Blood Cancer 59, 865–869 (2012). 60 Frezza AM, Whelan JS, Dileo P. Trabectedin
for desmoplastic small round cell tumours: a possible treatment option? Clin. Sarcoma Res. 4, 3 (2014). 61 Brunetti AE, Delcuratolo S, Lorusso V et al.
Third-line trabectedin for a metastatic desmoplastic small round cell tumour treated with multimodal therapy. Anticancer Res. 34, 3683–3688 (2014). 62 Saab R, Khoury JD, Krasin M et al.
Desmoplastic small round cell tumor in childhood: the St. Jude Children’s Research Hospital experience. Pediatr. Blood Cancer 49, 274–279 (2007). 63 Cook RJ, Wang Z, Arora M et al. Clinical
outcomes of patients with desmoplastic small round cell tumor of the peritoneum undergoing autologous HCT: a CIBMTR retrospective analysis. Bone Marrow Transplant 47, 1455–1458 (2012). 64 Bisogno G, Ferrari A, Rosolen A et al.
Sequential intensified chemotherapy with stem cell rescue for children and adolescents
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and management of desmoplastic small round cell tumor: a review. Curr. Opin. Oncol. 23, 385–389 (2011). •
A thorough review on desmoplastic small round cell tumor including the large and original experience of the MD Anderson’s group.
71 Jordan AH, Pappo A. Management of
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indicators in peritoneal carcinomatosis from gastrointestinal cancer. Int. Semin. Surg. Oncol. 2(1), 3 (2005). 73 Arora VC, Price AP, Fleming S et al.
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Solitary relapse of desmoplastic small round cell tumor detected by positron emission tomography/computed tomography. J. Clin. Oncol. 26, 4995–4996 (2008). 75 Magnan H, Abramson SJ, Price AP et al.
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Desmoplastic small round cell tumor 20 years after its discovery Jaume Mora*,1, Shakeel Modak2, Nai-Kong Cheung2, Paul Meyers2, Enrique de Alava3, Brian Kushner2, Heather Magnan2, Oscar M Tirado4, Michael Laquaglia5, Marc Ladanyi6 & Juan Rosai7
ABSTRACT Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy. On 18 March 1991, William L Gerald, a young pathologist in the Department of Pathology of Yale University Medical School (CT, USA), proposed at the US and Canadian Academy of Pathology (USCAP) meeting in Chicago, DSRCT as a new clinicopathological entity based on 19 cases that he and Juan Rosai had identified going over the consultation files from Rosai, then the Chief of Anatomic Pathology at Yale. Later that same year their publication appeared in The American Journal of Surgical Pathology [1] . The first proposal of the existence of this new entity actually goes back to the 1988 USCAP meeting in which Gerald and Rosai presented one case, published a year later in the Journal of Pediatric Pathology. In the short span of 2 years, Gerald and Rosai identified 19 similar cases, allowing them to define a new neoplastic entity belonging to the general category of small round cell tumors of infancy and childhood. They based their proposal upon a number of topographic, morphologic and immunohistochemical features that set this entity apart from all of the previously described members of this group. DSRCT, as Gerald posited in the 1991 paper, in clear distinction from the other small round blue cell tumors, is clinically characterized by male predominance (>5:1); primary (often exclusive) intra-abdominopelvic location with multiple peritoneal implants, initial incomplete response to chemotherapy followed by uncontrollable tumor relapse and a high mortality rate. From the histopathological standpoint, DSRCT was characterized by peritoneal nodules invading local structures like bladder, colon, liver and small bowel; clusters of small cells separated by a consistent and prominent cellular (‘desmoplastic’) stroma; invasive growth pattern; and a broadly positive immunohistochemical profile showing unusual
KEYWORDS
• adolescent and
young adult oncology • desmoplastic tumors • developmental cancer • EWS gene • small round cell tumors • William L Gerald • WT1 gene
Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain Department of Pediatrics, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 3 Department of Pathology, Hospital Virgen del Rocío, Sevilla, Spain 4 Sarcoma Research Group, Institut d’Investigació Biomèdica de Bellvitge, Barcelona, Spain 5 Department of Surgery, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 6 Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY, USA 7 Centro Consulenze Anatomia Patologica Oncologica, Milano, Italy *Author for correspondence: Tel.: +34 93 280 40 00 ext. 2361 (office), ext. 4398 (laboratory); Fax: +34 93 600 6119; [email protected] 1 2
10.2217/FON.15.32 © 2015 Future Medicine Ltd
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Review Mora, Modak, Cheung et al. coexpression of epithelial (EMA and keratin), neural (NSE) and mesenchymal (vimentin and desmin) markers (Figure 1) [1] . In the 1991 paper, the authors reviewed the literature for cases similar to what they had described. They identified earlier case reports that were likely DSRCT. One from Ordoñez et al., described a 28-year-old man with an extensive intra-abdominal small-cell tumor [2] . Another case reported by Gaffney et al. in 1989 described an 11-year-old girl with an intra-abdominal tumor characterized histologically by aggregates of small round cells, some with a rhabdoid appearance, and immunohistochemically with a multiphenotypic profile [3] . Three further cases were discussed by Gonzalez-Crussi et al. in a paper from 1990 [4] . Gerald and Rosai were able to review some of these cases personally and confirmed that two of them were consistent with DSRCT. Two cases reported by Variend in 1991 were described as ‘intra-abdominal neuro ectodermal tumors of childhood with divergent differentiation’ [5] . In their original description, Gerald and Rosai discussed extensively the differential diagnosis of DSRCT and looked specifically for clues to its histogenesis on the basis of its morphologic, immunohistochemical and clinical features. They speculated on the possibility of the tumor having a mesothelial histogenesis and thus be viewed as mesothelioblastoma [1,6] . Early in 1993, Ordoñez et al. reported
A
B
C
D
Figure 1. Characteristic histological features of classical desmoplastic small round cell tumor. (A) Low-power field (10x) view of nests of small round blue cells within abundant desmoplastic stroma. Analysis of the tumor by immunohistochemistry shows (20x) diffuse positivity for VEGFR2 (B), and coexpression of (epithelial) EMA (C) and (mesenchymal) desmin (D) markers.
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the experience from the MD Anderson Cancer Center with 19 additional cases [7] . They confirmed the initial description by Gerald of male predominance, widespread abdominal and pelvic peritoneal involvement, and a multiphenotypic pattern of differentiation. Subsequently, cases with involvement of other sites (including the CNS and the skeletal system) have been described [8–10] . In 1992, the cytogenetics of a case of DSRCT was first reported, featuring a diploid DNA content and t(11;22)(p13;q12) [11] . In 1994, five DSRCT karyotypes had been reported: in four of five tumors a break point in the 22q11.2-13 region was present as a translocation t(11;22) (p13;q11.2–12) [11–13] . Following the leads suggested by the break points at 22q12 and 11p13 (sites of the EWS and WT1 genes, respectively) Ladanyi and Gerald, both of them at the time in the Department of Pathology headed by Rosai at Memorial Sloan–Kettering Cancer Center (MSKCC) in New York, reported for first time in 1994 the consistent fusion of the EWS and WT1 genes in DSRCT [14] . Using Southern blotting with cDNA probes for EWS and WT1 that spanned the break-point cluster regions, they detected EWS and WT1 rearrangements comigrating in four of five cases of DSRCT. By northern blot, they identified aberrant EWS and WT1 transcripts of the same size, suggesting the existence of a chimeric EWS–WT1 RNA species resulting from the translocation. Finally, by realtime (RT)-PCR using primers for EWS exon 7 (as described for Ewing sarcoma) and WT1 exon 8 or 9, they were able to amplify a single RT-PCR product. Sequencing of the RT-PCR product showed an in-frame junction of EWS exon 7 to WT1 exon 8. This was the first experimental proof for the existence of WT1 as a new translocation partner for EWS and for EWS–WT1 as the genetic marker for DSRCT, thus defining it as a true separate entity of small round cell tumor as predicted by Gerald in 1991 [1] . In a subsequent publication in 1995, the MSKCC team led by Gerald and Ladanyi precisely described the characteristics of the genomic break points and fusion transcripts involved in the EWS–WT1 gene fusion of DSRCT [15] . They proved that DSRCT represents the third tumor type associated with a chromosomal translocation involving the EWS gene and the only tumor ever described to be associated with translocation of WT1. The chimeric transcript of two different tumor-associated genes was clearly
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Desmoplastic small round cell tumor 20 years after its discovery implicated in its oncogenesis. The translocation results in chimeric products containing the amino-terminal domain of EWS fused to most of the DNA-binding domain of WT1. Later in 1995, Enrique de Alava, a postdoctoral student in the Gerald laboratory, further validated the RT-PCR method as a very sensitive and specific test for diagnosing DSRCT in clinical samples [16] . The specificity of molecular assays such as the one described for DSRCT was becoming a much needed tool for the differential diagnosis of pediatric small round cell tumors [17–22] . The involvement of EWS and WT1 in the pathogenesis of DSRCT raised new potential histogenetic implications. On the one hand, the age of presentation, male predominance and primitive appearance of the neoplastic cells in DSRCT were all reminiscent of the Ewing sarcoma/PNET family of tumors. On the other hand, WT1 was known to be expressed in embryonal structures derived from the intermediate mesoderm, mesenchyme lining the coelom and mesenchyme of the primitive gonad. WT1 is a transcription factor intimately associated with a particular period in normal development the alteration of which may contribute to tumor formation in the primitive cells expressing the gene. Thus, the histogenetic hypothesis was raised of DSRCT possibly arising in the primitive mesenchyme of the coelomic cavities or gonads [23] . Soon after the initial molecular description of DSRCT, the MSKCC team published in 1996 the first therapeutic experience using intensive alkylator-based therapy following the P6 protocol for Ewing sarcoma/PNET family of tumors [24] . The report described 12 patients with a male to female ratio of 11:1. All patients responded but there were no complete pathological responses. Seven of the 12 patients achieved complete remission (CR) after intensive use of alkylator-based chemotherapy, aggressive surgery, radiation therapy to high-risk sites often including whole abdomen and pelvis [25] and myeloablative therapy with stem cell rescue in selected cases [26] . This first therapeutic report highlighted some interesting findings of DSRCT. Similar to other small round cell tumors of young people, DSRCT is an alkylator-sensitive and dose-responsive tumor. However, intensive chemotherapy or myeloablative doses of alkylating agents did not result in complete pathologic responses of large masses. Hence, aggressive surgery to remove bulk tumor was found to be a critical component of a curative strategy.
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Initially, patients who achieved a complete or very good partial response appeared to have a good prognosis [27] , however, it was later found that responses were not durable in most patients with recurrences being observed >3 years after diagnosis. A review from the MSKCC group of 66 patients with DSRCT treated from 1972 to 2003 reported 3- and 5-year survivals of 44 and 15%, respectively [28] , with achievement of CR being the only prognostic marker. A more recent report from the MSKCC group on 31 patients treated from 1992 to 2011 showed similar survival rates although radiation-a ssociated toxicities appeared to be decreased with the use of intensity-modulated radiotherapy [29] . In 1997, Gerald, working with Daniel Haber, reported the first downstream target of the EWS–WT1 fusion transcript, namely PDGFA [30] . Given that the chimeric EWS–WT1 product defines DSRCT, the analysis of the functional properties and mechanism of tumorigenesis was performed using an inducible expression system of EWS–WT1 in osteosarcoma cell lines since there were no available DSRCT cell lines at the time. Expression of EWS–WT1 induced PDGFA. Native PDGFA was not induced by native WT1 indicating target specificity of the EWS–WT1 fusion protein. The authors also showed that primary DSRCT expressed high levels of PDGFA and it was absent in tumors expressing WT1 and Ewing sarcomas expressing EWS-FLI showing the specificity of PDGFA expression correlating with the tumorigenic activity of EWS–WT1 [30] . PDGFA is a secreted growth factor that acts as a potent mitogen and chemoattractant for fibroblasts and endothelial cells, a possibly significant aspect because the histology of DSRCT is remarkable for the presence of a profuse stromal reaction. The potential growth advantage conferred by this stromal reaction, including vascular recruitment, is consistent with DSRCT specimens demonstrating active neoangiogenesis in the connective tissues surrounding tumor cells. In 2004, the first Phase I trial of the PDGFR pathway inhibitor SU101 (NCT00001573) was reported for children with refractory solid tumors [31] . Among 27 patients, there were no objective responses, but the authors’ highlighted one patient with rapidly progressive DSRCT who experienced symptomatic improvement and prolonged stable disease [32] . Similarly, other tyrosine kinase inhibitors such as imatinib, a partial inhibitor
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Review Mora, Modak, Cheung et al. of KIT and PDGFRα [33] , and the multikinase inhibitors sunitinib [34] and pazopanib [35] had very modest activity against DSRCT in early phase studies. Blockade of angiogenesis is currently being investigated at MSKCC in an upfront ‘window’ study of bevacizumab in combination with irinotecan and temozolomide in newly diagnosed patients with DSRCT (NCT01189643) [36] . The rationale for the study includes the markedly elevated expression of VEGFR-2 and VEGFA in DSRCT tumor samples and marked, long-term regressions of tumors seen in a xenograft model of DSRCT treated with irinotecan and bevacizumab [37] . In 2002 and 2003, William Gerald and Daniel Haber described new transcriptional targets of EWS–WT1: the beta chain of the IL-2/15 receptor (IL-2/15Rβ) and LRRC15, a cytokine signaling pathway and a protein implicated in migration/invasiveness, respectively [38,39] . In a comprehensive review of the role of EWS–WT1 in the tumorigenesis of DSRCT in 2005, Gerald emphasized the relationship of the histological features characteristic of DSRCT to the downstream targets of the EWS–WT1 [40] . In 2002, Nishio et al. were the first to report the generation of a fusion-positive DSRCT cell line called JN-DRSCT-1 [41] . For many years, it was the only in vitro model of DSRCT. In 2013, Markides et al. reported the establishment of nine DSRCT xenograft lines and five tissue culture lines [42] . Using the JN-DRSCT-1 model, Tirado et al., following their previous studies in Ewing sarcoma/PNET models, reported in 2005 that the mTOR inhibitor rapamycin downregulated the expression of EWS/WT1 and induced apoptotic death of JN-DSRCT-1 cells by simultaneously inducing the downregulation of Bcl-xL [43] . Rapamycin also caused upregulation of Bax by inhibiting the proteasome complex, a process independent of mTOR inhibition. Their results suggested that, being a highly effective inducer of apoptosis, rapamycin or other mTOR inhibitors could be active in the treatment of DSRCT. In 2010, one refractory DSRCT patient treated with temsirolimus showed stable disease for >40 weeks suggesting a possible clinical benefit for inhibition of the mTOR pathway [44] . A recent report suggests that DSRCT has a constitutively activated PI3K/Akt/mTOR pathway. p-Akt expression was detected in the nucleus of the tumor cells and p-mTOR was detected on Ser 2448, suggesting mTORC2 as the dominant form [45] .
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Consistent with the knowledge that the EWS– WT1 fusion protein modulates transcription of target genes containing WT1 binding motifs, Karnieli et al. in 1996 showed that EWS–WT1 recognizes and transactivates the IGF-1R promoter [46] . In 2002, the same group [47] showed that the IGF-1R gene is a molecular target of EWS–WT1. A clinical observation suggesting an important role for the IGF-1 signaling pathway in DSRCT was reported in 2010 [48] . Symptomatic hypoglycemia in a patient with DSRCT was found to be caused by an increased IGF-II/IGF-I ratio, typical of nonislet cell tumor hypoglycemia, in this case possibly related to the inappropriate production of IGF-II by the tumor. IGF-1R is known to play an important role in the growth and development of normal tissue as well as the initiation, maintenance, survival, progression and metastasis of many sarcomas. The introduction of humanized monoclonal antibodies that inhibit IGF-1R in clinical trials and the dramatic single-agent anti-IGF-1R activity observed in refractory sarcoma patients provided initial excitement in the sarcoma community. More than 25 agents acting via IGF-1R inhibition were in preclinical and clinical development during the first decade of the 2000. Given the preclinical rationale and early clinical data, an open-label, Phase II trial to evaluate the safety and efficacy of ganitumab a fully human, monoclonal antibody antagonist of IGF-1R that blocks IGF-1 and IGF-2 binding was initiated in patients with relapsed or refractory Ewing sarcoma/PNET or DSRCT [49] . In total, 16 patients with DSRCT were enrolled. Antitumor responses observed were comparable to those observed with other anti-IGF-1R antibodies evaluated as monotherapy. Four of 16 patients had objective responses or stable disease for more than 24 weeks [49] . Like IGF-1R, other cell surface tumor-associated antigens were discovered at the time for diagnosis and therapy of DSRCT. Using immunohistochemistry, the expression of two antigens, GD2 using antibody 3F8 and B7-H3 using antibody 8H9, was studied in a panel of 46 DSRCT [50,51] . In total, 70% of tumors were reactive with 3F8, 96% with 8H9, both antigens localized to the tumor cell membrane and stroma. One of the most salient clinical features of DSRCT is male predominance. The role of androgens in DSRCT was studied and reported
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Desmoplastic small round cell tumor 20 years after its discovery in 2007 [52] . A significant androgen receptor (AR) immunostaining pattern was found in ten of 27 DSRCT tumors studied and was confirmed by western blot in two patients. The functional status of the AR was demonstrated by stimulation of basal in vitro growth by supplemental testosterone and inhibition of basal and testosterone stimulated growth by flutamide. These results suggested that DSRCT may upregulate or downregulate AR possibly for survival purposes as a growth factor receptor. Of six heavily pretreated patients with positive AR status treated with a combination of androgen blockade (AR blocker and biculatamide preceding Lupron), one each had partial response, minor response and stable disease, although responses appeared to be short-lived [52] . At the same time as various potential targets were being identified and targeted therapies were being attempted, single institution experiences and observations of nontargeted chemotherapeutic agents were also being reported [28,53–54] . Minimal to modest responses were reported with a metronomic approach using vinorelbine plus cyclophosphamide [55] , irinotecan [56,57] and trabectedin [58–61] . The incorporation of dactinomycin to multimodality chemotherapy did not appear to significantly improve outcomes [62] . As in Ewing sarcoma/PNET, the benefit of high-dose chemotherapy and autologous hemopoietic stem cell transplant is controversial, at best. A retrospective analysis of 36 DSRCT patients registered at the International bone marrow transplant registry (CIBMTR) from 1999 to 2007 reported on 3-year overall survival (OS) of 57% and 28% for patients in CR and not in CR, respectively [63] . However, other groups have reported poorer outcomes. In 2010, the Italian group reported their experience with 14 DSRCT patients treated with three consecutive intensified chemotherapy combinations followed by stem cell rescue [64] . Three-year event-free survival and OS rates were 15.5 and 38.9%, respectively. This experience corroborated the initial description by the MSKCC group of the lack of improvement using myeloablative doses of alkylating agents like thiotepa [26] . A further chemotherapeutic approach adopted by the MD Anderson group was intraperitoneal instillation of cisplatin via hyperthermic intraperitoneal chemotherapy (HIPEC) similar to that used for colorectal carcinoma [65] in addition to multimodality therapy [66] . Their efforts focused on quality of life for DSRCT patients reinforcing
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Review
outpatient clinic and home infusion settings. As described in other reports [28] , tumor burden was prognostic in patients receiving HIPEC. Patients who were able to achieve gross total resection and undergo HIPEC had improved survival compared with those patients who could not achieve significant debulking and were treated with chemotherapy alone. Similar to intraperitoneal radioimmunotherapy, the role of HIPEC in improving outcome in patients undergoing gross total resection is unclear [67–71] . Given that DSRCT is locoregionally disseminated at diagnosis, and disease burden and resectability appear to be prognostic, a staging system for DSRCT has been proposed incorporating the peritoneal carcinomatosis Index (PCI) score and presence of extra-abdominal disease [72] . Metastatic DSRCT typically involves distant lymph nodes, liver and lungs. Spread to bones and bone marrow is rare. Furthermore, it is well described that surgery after chemotherapy shows persistence of peritoneal or omental studding not seen by conventional anatomical imaging (CT/MRI). The role of PET scan in DSRCT imaging has been investigated by the MSKCC group [73] . FDG PET/CT accurately detected 97% of all DSRCT lesions [74] and hybrid PET-CT had superior overall sensitivity and specificity to PET or CT alone [75] . A retrospective review of seven patients with DSRCT who were imaged by FDG-PET and CT at diagnosis and after three cycles of chemotherapy showed that FDG-PET did not always correlate with response measurement by CT. A greater decrease in metabolic activity as compared with size was seen in all patients [75] . In 2009, Mora et al. published the first series of pediatric patients treated with Gemcitabine and Docetaxel as relapse therapy [76] . This series was notable for six patients with Ewing sarcoma and reported a very high complete response rate of 40%. Gemcitabine and Docetaxel drugs, not routinely used to treat pediatric malignancies, seemed to rescue relapsed sarcoma patients, induce tumor remission and, as maintenance chemotherapy, keep disease under control for prolonged periods of time (median duration of responses 10 months), even after two or more relapses. On the basis of these and other results, evaluation in a formal Phase II setting from GEIS for primary highrisk Ewing sarcoma patients is just completed (ClinicalTrials.gov identifier NCT01696669) [77] . The combination of gemcitabine and paclitaxel has shown clinical benefit for relapsed sarcoma
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Review Mora, Modak, Cheung et al. patients including Ewing family of tumors and DSRCT. Furthermore, histological and biological features of EWS-rearranged tumors suggest that albumin-bound paclitaxel particles (nabpaclitaxel [Abraxane], Celgene, NJ, USA) could be more active than paclitaxel. Following these
experiences, a formal clinical trial of Abraxane for DSRCT patients is currently being planned. Table 1 summarizes all the clinical trials reported with DSRCT patients and all the largest series of DSRCT patients reported in the medical literature.
Table 1. Lists the largest series of desmoplastic small round cell tumor cases reported in the medical literature until the first half of 2014 and references all the ten formal clinical trials reported including patients with desmoplastic small round cell tumor. First author (year)
DSRCT patients (n) Description of study
Hayes-Jordan A (2014) Zhang J (2014) Glade Bender JL (2013) Italiano A (2013) Arora VC (2013) Desai NB (2013)
26 48 2 8 65 31
Magnan H (2013) Chuk MK (2012) Ryan CW (2013) Tap WD (2012) Hayes-Jordan A (2012) Cook RJ (2012) Naing A (2012) Rekhi B (2012) Philippe-Chomette P (2012) Pinnix CC (2012)
7 1 NA 16 10 36 3 45 38 8
Hayes-Jordan A (2010) Chao J (2010) Bisogno G (2010) Liping Cao (2008) Bagatell R (2007) Bond M (2008) Saab R (2007) Bisogno G (2006) Biswas G (2005) Hassan I (2005) Chouli M (2005) Lal DR (2005) Adamson PC (2004) Goodman KA (2002) Lae ME (2002) La Quaglia MP (2000) Ordóñez NG (1998) Gerald WL (1998) Schwarz RE (1998) Kushner BH (1996) Tison V (1996) Gerald WL (1993) Ordóñez NG (1993) Gerald WL (1991)
24 2 14 18 1 12 11 3 18 12 13 66 2 21 32 40 39 109 31 12 1 46 19 19
Ref.
MD Anderson group. Multimodality treatment and HIPEC Retrospective review from China COG Phase I trial of pazopanib Case series using sunitinib MSKCC review of radiological features MSKCC review on intensity-modulated radiation therapy for whole abdominopelvic therapy MSKCC review on PET for response assessment Phase I of 24-h infusion of trabectedin by the COG A Phase II study of tasisulam sodium Phase II study of ganitumab HIPEC in pediatric patients: early experience and Phase I results CIBMTR retrospective analysis of autologous bone marrow transplant Cixutumumab combined with the mTOR inhibitor temsirolimus Retrospective review from India Retrospective review from the French group MD Anderson review on intensity-modulated radiation therapy for whole abdominopelvic therapy MD Anderson group. Multimodality treatment and HIPEC Phase II clinical trial of imatinib mesylate Italian autologous bone marrow transplant retrospective review Chinese group. Retrospective review Phase I study of Geldanamycin. COG trial Phase II study of imatinib mesylate. COG trial St Jude Children’s Research Hospital restrospective experience Phase II study of irinotecan. Italian group Retrospective review from India Retrospective review from the Mayo Clinic Retrospective radiological review from France MSKCC retrospective review on multimodal therapy Pediatric Phase I trial of the PDGF receptor pathway inhibitor SU101 MSKCC review on whole abdominopelvic radiotherapy Retrospective review from the Mayo Clinic MSKCC retrospective review on multimodal therapy First description of a large series of cases from the MD Anderson group First description of a large series of cases from the MSKCC group MSKCC group retrospective review on multimodal therapy First clinical trial ever to address DSRCT patients First description of an intracranial DSRCT case Histopathological description of the MSKCC first series Histopathological description of the MD Anderson first series Discovery series
[68] [78] [35] [34] [73] [29] [75] [59] [79] [49] [69] [63] [80] [81] [82] [83] [67] [33] [64] [84] [85] [86] [62] [57] [87] [88] [89] [28] [32] [90] [91] [92] [93] [23] [27] [24] [8] [6] [7] [1]
COG: Children’s Oncology Group; DSRCT: Desmoplastic small round cell tumor; HIPEC: Hyperthermic intraperitoneal chemotherapy; MSKCC: Memorial Sloan–Kettering Cancer Center.
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Desmoplastic small round cell tumor 20 years after its discovery
Review
Tribute to a brilliant physician scientist On 14 September 2008, William L Gerald died of metastatic skin cancer (Figure 2) [94] . In 1992, he had established his laboratory at MSKCC devoted to the study of DSRCT. He was a beloved teacher and mentor for a large family of pathology, molecular pathology, surgery and pediatric/medical oncology fellows who followed his footsteps, advancing biological knowledge to explain pathologic features and to guide therapeutics. As we have reviewed, William L Gerald contributed substantially to the establishment of DSRCT as a unique pathologic entity and, with deep insight and critical thinking, described most aspects of the disease as we know it today. While Rosai coined the disease DSRCT, the eponymous term for this clinically aggressive and biologically fascinating disease could justifiably be ‘Gerald tumor’. Conclusion The historical analysis of DSRCT highlights the fundamental contributions of a brilliant physician scientist, the late William L Gerald, MD PhD. The eponymous term for this clinically aggressive disease could reasonably be ‘Gerald tumor’. Future perspective The combination of chemotherapy, compartmental therapeutic approaches (surgery + HIPEC and/or radioimmunotherapy) and novel biologic strategies may hold the promise for long-term disease control of DSRCT. In 2014, the combination of polychemotherapy and aggressive surgery followed by whole
Figure 2. William L Gerald, MD, PhD (1954–2008).
abdominal radiation therapy represents the standard of care for DSRCT. Currently, patients having chemoresponsive disease and successful surgical cytoreduction appear to have the best outcome compared with patients who do not achieve both benchmarks [95] . The genomic and epigenomic landscape of DSRCT has not been thoroughly explored and current efforts are ongoing applying next
EXECUTIVE SUMMARY Historical perspective of a new entity ●●
Desmoplastic small round cell tumor was described as a new clinicopathological entity in early 1991, and in 1994 the
molecular definition of desmoplastic small round cell tumor was discovered as a chimeric fusion of the EWS and WT1 genes. ●●
In 1996, the backbone of multimodality treatment was described using intensive alkylator-based therapy following the MSKCC P6 protocol for Ewing sarcoma. It remains the standard of therapy as of today.
●●
In 1996, it was found that the EWS–WT1 fusion protein recognizes and transactivates the IGF-1R promoter. Target
therapy with IGF-1R inhibition was tested in the first decade of the 2000. Objective antitumor responses were observed as monotherapy in relapsed cases. ●●
The benefit of high-dose chemotherapy with autologous/heterologous hemopoietic stem cell transplant is not proven.
●●
Patients who achieve gross total resection and undergo hyperthermic intraperitoneal chemotherapy have an
improved survival compared with those patients who do not achieve significant surgical debulking and are treated with chemotherapy alone.
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Review Mora, Modak, Cheung et al. generation sequencing approaches to DSRCT cases collected worldwide. With such studies more druggable targets of clinical benefit will appear in the near future. The year 2013 was marked by major successes in immunotherapy for cancer [96,97] , one therapeutic modality that has yet to be explored for DSRCT. A combination of chemotherapy, compartmental therapeutic approaches and novel biologic strategies may be needed for long-term disease control of DSRCT. Following these studies, the MSKCC team has initiated a Phase I clinical trial of intraperitoneal injection References Papersof special note have been highlighted as: • of interest; •• of considerable interest 1
• 2
3
4
5
6
7
8
Gerald WL, Miller HK, Battifora H et al. 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. 15, 499–513 (1991). First historical report on the new entity desmoplastic small round cell tumor.
of radioiodinated 8H9 for radioimmunotherapy of DSRCT (NCT01099644) [98,99] . Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Report of a case. Am. J. Surg. Pathol. 20, 112–117 (1996). 9
Bouchireb K, Auger N, Bhangoo R et al. Intracerebral small round cell tumor: an unusual case with EWS–WT1 translocation. Pediatr. Blood Cancer 51, 545–548 (2008).
10 Neder L, Scheithauer BW, Turel KE et al.
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11 Sawyer JR, Tryka AF, Lewis JM. A novel
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13 Biegel JA, Conard K, Brooks JJ. Translocation
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14 Ladanyi M, Gerald W. Fusion of the EWS
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•• Discovery of the molecular translocation defining the new entity, desmoplastic small round cell tumor. Investigations made from previous laboratory interests in Wilms tumor and Ewing sarcoma from the laboratories of William Gerald and Marc Ladanyi.
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reciprocal chromosome translocation t(11;22) (p13;q12) in an intraabdominal desmoplastic small round-cell tumor. Am. J. Surg. Pathol. 16, 411–416 (1992). A recurring translocation, t(11;22) (p13;q11.2), characterizes intra-abdominal desmoplastic small round-cell tumors. Cancer Genet. Cytogenet. 69, 17–21 (1993). (11;22)(p13;q12): primary change in intra-abdominal desmoplastic small round cell tumor. Genes Chromosomes Cancer 7, 119–121 (1993). and WT1 genes in the desmoplastic small round cell tumor. Cancer Res. 54, 2837–2840 (1994).
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Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J. Clin. Oncol. 14, 1526–1531 (1996). •
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36 Irinotecan, Temozolomide and Bevacizumab
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37 Magnan H, Chou T, LaQuaglia MP et al.
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