Journal of Pediatric Hematology/Oncology:
Management of Desmoplastic Small Round-cell Tumors in Children and Young Adults
Jordan, Andrea Hayes MD*; Pappo, Alberto MD†
*UT MD Anderson Cancer Center, Children’s Cancer Hospital, Houston, TX
†St Jude Children’s Research Hospital, Memphis, TN
The authors declare no conflict of interest.
Reprints: Andrea Hayes-Jordan, MD, Pediatric Surgical Oncology, UT MD Anderson Cancer Center, 1515 Holcombe Ave., Box 444, Houston, TX 77030 (e-mail: firstname.lastname@example.org).
Received January 24, 2012
Accepted February 1, 2012
Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma which is primarily abdominal in origin. Less than 200 cases have been reported. DSRCT presents with multifocal tumors believed to begin in the peritoneal surfaces of the abdominal cavity. Up to hundreds of tumors can be found in the abdominal cavity. Adolescent males are primarily affected. Because of the rarity of the tumor and the unusually aggressive presentation, treatment is challenging and has not been standardized. Here we summarize the clinical presentation, diagnosis and management options of this rare tumor.
Desmoplastic small round-cell tumor (DSRCT) is a rare and highly aggressive neoplasm of children, adolescents, and young adults that begins and spreads on the peritoneal surfaces. The organ of origin is the peritoneum. Less than 200 cases are reported in the world literature. DSRCT was first described in 1989 by Gerald and Rosai and is characterized by distinct clinicopathologic features.1,2 The tumor is composed of desmoplastic stroma with nests of small round blue cells. DSRCT is associated with a characteristic chromosomal translocation, t (11; 22) (p13; q12), which fuses the N-terminus of the Ewing sarcoma (EWS) gene to the C-terminus of the Wilms tumor (WT-1) gene.3,4 The presence of this translocation provides confirmation of the diagnosis.
DSRCT has a predilection for young males in their second and third decades of life, affecting mostly adolescent males. It usually presents with diffuse and multifocal abdominal disease similar in gross appearance to carcinomatosis. It can also metastasize to different locations including the intrathoracic cavity, pleura, paratesticular, and lymph nodes. Patients presenting with abdominal disease typically are in an advanced stage, with large masses and/or extensive seeding in the visceral and parietal peritoneal layers. DSRCT, almost always, is disseminated regionally. Unless found incidentally, multiple peritoneal based lesions are always seen.
Despite multiple strategies that include several chemotherapy regimens like those active for Ewing’s sarcoma, aggressive debulking surgery, whole-abdominal radiation, high-dose chemotherapy with autologous stem cell transplant, survival for patients with DSRCT continues to be poor. Despite prolonged hospital stays and morbidity associated with these various interventions, durable remissions remain rare. DSRCT has a 15% overall survival at 5 years, with most patients experiencing resistant and recurrent disease before the end of life.5 Inclusion of DSRCT in this rare tumors registry is thus pertinent in the multi-institutional data collection and analysis that will enhance the understanding of this rare but aggressive tumor.
DSRCT typically presents as a large intra-abdominal mass with numerous smaller peritoneal implants that spread along the peritoneal and mesothelial epithelium. Patients typically are aged 5 to 25 years at presentation, and 90% are male. Symptoms include abdominal pain and/or abdominal distension and possibly nausea or emesis. Vague abdominal pain is sometimes confused with constipation, but radiographic imaging readily reveals the diagnosis. There may also be ascites with intraparenchymal metastasis to the liver. The presence of ascites is the usual cause for the abdominal distension. The lesions are usually very large in size, 8 cm or greater, with smaller 3- to 5-mm lesions coating the peritoneum and impairing absorption of normal peritoneal fluid. The smaller lesions may evade imaging. The most common site of metastases is the liver. DSCRT can also metastasize to the lungs and or lymph nodes of the groin, neck, or mediastinum. Less common nonspecific clinical findings that should raise a suspicion of DSRCT in a young male are retroperitoneal lymphadenopathy, hydronephrosis, bowel obstruction, calcifications, and nodular peritoneal thickening, especially when these findings are supported by radiographic evidence of a disseminated intra-abdominal neoplasm.3,6,7
Imaging of the abdomen with ultrasound, computed tomography (CT), or magnetic resonance imaging reveals multiple tumor nodules “studding” the peritoneal cavity (almost always more than 1 nodule). Dozens or hundreds of nodules on the diaphragm can cause indentation or “scalloping” of the liver on CT scan. Large pelvic tumors are common. Open, laparoscopic, or image-guided biopsy is appropriate. The gold standard for the diagnosis of DSRCT includes histopathology and cytogenetics. The biopsy should be evaluated by cytogenetics to confirm the characteristic translocation and EWS WT-1 fusion.
Once abdominal imaging reveals multiple tumors, imaging of the chest with CT scan and/or total-body positron emission tomography scan are necessary as part of the staging evaluation. Presently, there is no formal staging system for DSRCT, but one is being proposed and is under review that incorporates abdominal disease burden (stage 1 or 2) and sites of metastasis such as liver (stage 3) or lung (stage 4).8 The extensive peritoneal disease seen in DSRCT may be more accurately described as multifocal abdominal disease. All patients are not stage 4.
Gross examination of DSRCT reveals large tumors that usually have multiple peritoneal implants. The cut surface shows areas of necrosis and may also have myxoid changes. Typical microscopic histologic features are clusters of blue tumor cells, in a round or elongated arrangement, distributed within abundant desmoplastic/cellular stroma. Tumor cells are small to medium in size with round/oval hyperchromatic nuclei and inconspicuous nucleoli. Cytoplasm is scant. Necrotic with necrotic cells and mitosis are common findings.3,9,10 The immunohistochemical profile of DSRCT shows divergent differentiation, a distinct feature, with immunohistochemical reactivity for epithelial (keratin, epithelial membrane antigen), mesenchymal (vimentin), neural (neuron-specific enolase and CD56), and myogenic (desmin) markers. Almost all DSRCT are positive for WT1, a polyclonal antibody against the amino terminus of the WT1 protein.11,12 A high serum cancer antigen 125 level may be a useful marker for DSRCT, permitting early diagnosis and treatment.13,14 Lae et al10 in a reported series of 32 cases of DSRCTs found that 84% of cases were immunoreactive for neuron-specific enolase, 81% for desmin, and 87% for keratin. Also, 91% of cases were positive for WT1. Similar findings were reported by other studies.9,15 DSRCT can be differentiated from other small round-cell tumors like EWS/PNET, small-cell sarcoma, lymphoma, neuroblastoma, WT, rhabdomyosarcoma, and malignant mesothelioma, with the demonstration of a divergent phenotype and the reciprocal translocation characteristic of DSRCT using cytogenetic studies. Further literature is available.4,16–18
Patients with DSRCT require aggressive multimodal therapy. Current treatment protocols with neoadjuvant chemotherapy, debulking of >90% of the tumor, and radiation therapy have been reported to prolong life but rarely achieve cure. Chemotherapy agents with known activity in DSRCT are very similar to those active in EWS. Both tumors share a EWS fusion protein and may also share molecular mechanisms facilitating proliferation and survival pathways. Alkylating agents such as cyclophosphamide and ifosfamide are important components of therapy. Currently, a well-recognized treatment schema has been reported by Kushner et al19 who described results in 12 DSRCT patients. This intensive alkylator-based therapy used cyclophosphamide, doxorubicin, vincristine alternating with ifosfamide and etoposide. Its combination with other treatment modalities such as surgery, radiation, autologous stem cell rescue, or the combination of all of the above was used. The median survival time was 19 months. For those achieving complete response, the median follow-up in this series was 22 months. The toxicity for this regimen can be substantial and often includes hospitalization not only for chemotherapy, but also for fevers associated with myelosuppression and mucositis. An alternative more tolerable outpatient regimen has more recently been used for DSRCT as documented in a case report.20 In this report, neoadjuvant chemotherapy included vincristine, ifosfamide, dexrazoxane/doxorubicin, and etoposide. Continuous hyperthermic peritoneal perfusion HIPEC with cisplatin was given after extensive cytoreductive surgery. This was followed by irinotecan+temozolomide monthly×2 and then abdominal radiation 30 Gy with simultaneous temozolomide. A total of 12 cycles of irinotecan and temozolomide were given and provided a disease-free interval of nearly 2 years. It permitted routine school attendance, and play activities were possible with an excellent quality of life.
Aggressive cytoreductive surgery is currently accepted to have a primary role in the achievement of prolonged survival of other malignancies involving the peritoneum.21–23 In DSRCT, La Quaglia and Brennan6 reported that 3-year overall survival was 58% in patients with gross total resection in comparison with 0% in the nonresection cohort. Other therapeutic modalities such as CHPP, also called hyperthermic intrapertitoneal chemotherapy (HIPEC), have been found to improve outcome in carcinoma involving the peritoneum.23–26 Recently, Hayes-Jordan and colleagues were the first to report on the combined use of cytoreductive surgery and HIPEC in 2 children with DSCRT. Both children received neoadjuvant chemotherapy, followed by cytoreductive surgery and intraoperative HIPEC using cisplatin. At the time of publication, both patients had no evidence of disease 6 and 10 months postoperatively.27 Currently, a phase I trial is ongoing using HIPEC at MD Anderson Cancer Center.8 A more recent series reports a median 3 year survival of 71% with HIPEC and 29% in those receiving chemotherapy and radiotherapy alone.
Difficulty achieving complete surgical excision and thus cure makes long-term follow-up important. Imaging studies are useful in providing follow-up information on tumor remission/recurrence and directly impact patient management. Timing of follow-up is at least 3-month intervals for 3 years and then every 6 months for until 5 years after the end of therapy but will depend on patients’ disease and the managing clinicians.
DSRCT is a highly aggressive tumor that usually occurs in young adult men. Despite its well-defined clinicopathologic properties, it is often misdiagnosed and difficult to manage. The diagnosis should therefore be suspected in young men with multiple heterogeneous peritoneal soft tissue masses, as early detection may influence disease containment, improving survival. Tumor markers like serum cancer antigen 125 may also be useful for early detection in patients suspected to have DSRCT. Better understanding of the disease by clinicians will also impact on early diagnosis and improve management options. There are presently no screening or preventive measures for this disease. Clinical trials are important for the development of DSRCT-specific protocols.
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sarcoma; children; pediatric; abdominal; metastasis; desmoplastic; stomach; abdomen; refractory
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