NHS Report

Due to the very rare nature of Desmoplastic Small Round Cell cancer the NHS produced a special report on her and another young woman with the same type of cancer. A copy can be seen below, as supplied by Nicola's Consultant Dr Chris Williams.

"Desmoplastic small round cell tumour (DSRCT) is a rare sarcoma primarily affecting young men. We report two cases of DSRCT in young women presenting as a gynaecological malignancy, in one case with obstructed labour.

Cases

A 23 year-old women underwent caesarean section for obstructed labour. At surgery multiple tumour deposits were found throughout the abdomen and pelvis. Histology demonstrated typical features of DSRCT and PCR confirmed the characteristic 11;22 translocation. Despite chemotherapy the patient relapsed and died 27 months after diagnosis. A 29 year-old woman presented with abdominal distension and elevated Ca-125. Imaging demonstrated widespread tumour within the abdomen and pelvis. Histology confirmed DSRCT. Although attaining a complete response to chemotherapy she relapsed within 2 months and died 11 months after diagnosis.

Conclusion

DSRCT should be considered in the differential diagnosis of young women presenting with abdominal distension and multiple masses on imaging.

Introduction

Desmoplastic small round cell tumour (DSRCT) is a rare soft tissue sarcoma of the Ewing's family of tumours first described in 1987. It is characterised by a specific chromosomal translocation, t(11;22)(p13;q12) leading to the fusion of the WT1 and EWS genes [1].

The clinical pattern of disease is typically one of multiple intra-abdominal tumour deposits on serosal surfaces. prognosis is poor with median survival less than 30 months and few long-term survivors [2,3,4]. The tumour predominantly affects young adults (median age 19-25 years) and displays a striking male preponderance (82-95% of cases) [3,4].

DSRCT in females occurs at an earlier age than in males [1] and may present with abdominal distension, pelvic mass or elevated Ca125 [5]. We report two cases of DSRCT in young women, one mimicking epithelial ovarian cancer, the other presenting with obstructed labour, the first such report of its kind.

Case 1

In February 2003 a healthy 23 year-old pregnant woman was admitted to the
obstetric department of another institution in labour. Pregnancy had been unremarkable. On vaginal examination firm nodules were noted in the posterior fornix. As progress of labour was unsatisfactory oxytocic augmentation was commenced. Despite this there was no further progress in labour beyond 5cm dilatation and a caesarean section was performed. At surgery the initial finding was of unexpected ascites. Further inspection
revealed multiple large volume tumour deposits over the pelvic and abdominal peritoneum and an 8cm hard irregular pelvic mass obstructing labour.

Tumour biopsies were taken, but no attempt at debulking could be made. A healthy boy was delivered.

Stain Result

Histopathology of biopsy material demonstrated sheets of poorly differentiated cells with little cytoplasm and high mitotic rate. Immunohistochemical features are shown in table 1 (right). PCR of tumour tissue demonstrated the EWS-WT1 fusion transcript [1]. A diagnosis of DSRCT was made.

Staging CT confirmed widespread intra-peritoneal metastases and multiple cystic metastases within the liver (Fig 1a,1b). Bone marrow trephine revealed no evidence of tumour infiltration.

The patient was counselled about the rarity and poor prognosis associated with this tumour. In view of the parenchymal liver metastases aggressive debulking surgery was not performed. A major consideration in treatment planning was the need for the patient to spend time with her baby whilst receiving therapy. For this reason the dose intensive regimens [6] used in some centres for this disease were not considered appropriate.

An alternating regimen using standard doses of drugs effective in soft tissue sarcoma was chosen. This comprised cisplatin (100mg/m2 d1) and doxorubicin (25mg/m2 d1-3) alternating with TIP (paclitaxel 175mg/m2 d1, cisplatin 20mg/m2 d1-5 and ifosfamide 1g/m2 d1-5 with mesna uroprophylaxis). Six cycles of chemotherapy were given in total, ending in July 2003.

Initially the option of consolidation with high dose therapy with autologous stem-cell transplant was considered if complete or near complete response was attained with chemotherapy. However as repeat imaging during treatment demonstrated only modest tumour regression it was felt that high dose chemotherapy would not be beneficial. Restaging CT scan post-treatment (Fig 1c,1d) showed significant residual disease bulk. The potential role of aggressive debulking surgery in pelvis and liver was raised, but in view of the uncertain benefit of this approach, her lack of symptoms and good quality of life the patient declined.

The original pathology sample was tested for c-Kit (CD117) status as expression of the receptor has been noted in DSCRT [7] raising possibility of therapeutic response to imatinib. Unfortunately the tumour proved c-Kit negative on immunohistochemistry. A
policy of close observation until disease progression was decided upon.

Over subsequent months continued disease regression was observed. The patient
remained clinically well, and was able to care for her child. In June 2004 although the patient was asymptomatic, follow-up imaging demonstrated progressive disease within liver and around splenic hilum. This was not amenable to surgical debulking. In view of the lack of symptoms further treatment was not given.

However, in October 2004 symptomatic ascites developed, requiring paracentesis. A decision was made to commence further palliative chemotherapy using carboplatin (AUC 6 d1) and etoposide (150mg/m2 IV d1-3), 3 weekly cycles. Carboplatin was given at 80% dose in view of previous febrile neutropenia and high calculated creatinine clearance. Despite this the first cycle of treatment was complicated by febrile neutropenia and grade 4 thrombocytopenia. A further 20% reduction for both drugs was therefore made for subsequent cycles. A total of 6 cycles treatment were given until February 2005. The patient obtained significant palliation, not requiring further abdominal paracentesis whilst on treatment.

After some 6 weeks of symptomatic remission in April 2005 the patient developed further ascites and symptoms of gastric outflow obstruction. The clinical impression of progressive disease was confirmed on CT scan, which demonstrated significant increase in tumour bulk within the liver and multiple new peritoneal lesions. Unfortunately, the patient's clinical condition deteriorated rapidly, and despite further palliative
chemotherapy with carboplatin (AUC 5) and gemcitabine (1000mg/m2 d1,d8) she died in May 2005, 27 months after initial diagnosis."

Case 2

A 29 year-old woman presented in October 2004 with a two-week history of abdominal istension, discomfort and early satiety. She had no gynaecological, urinary or other gastrointestinal symptoms.

Clinical examination demonstrated ascites, confirmed on computerised tomography (CT),
which also revealed a mass in the pelvic floor involving uterus, and numerous peritoneal deposits (fig 2a). Radiological appearance of liver and lungs was normal. Serum Ca125 at presentation measured 196 Kiu/l (range 0-20). Abdominal paracentesis yielded 4.5L of fluid, cytologic analysis of which demonstrated pleomorphic malignant cells. She was referred to the department of gynaecological oncology where diagnostic laparoscopy confirmed disseminated intra-abdominal malignancy, revealing tumour deposits on all peritoneal surfaces and adherent to bowel (Fig 3). Disease was not amenable to surgical debulking. Biopsies demonstrated poorly differentiated tumour with desmoplastic background stroma. Immunophenotyping showed cytoplasmic co-expression of cytokeratin with desmin with focal CD99 positivity.

Unfortunately sufficient material was not available for molecular analysis. A diagnosis of DSCRT was made.

She received chemotherapy using alternating BEP (cisplatin 50mg/m2 d1,2 etoposide 120mg/m2 d1-3, bleomycin 30,000IU d2,8,15, 3 weekly cycle) and TIP (Cisplatin 20mg/m2 d1-5, ifosfamide 1g/m2 d1-5, paclitaxel 175mg/m2 d1, 3 weekly cycle), beginning November 2004. Treatment was well tolerated.

Ascites, which prior to treatment required weekly drainage, did not recur after commencement of chemotherapy. CT scan after four cycles of treatment demonstrated complete tumour response (fig 2b). Serum Ca125 fell to 6Kiu/l. Six cycles of chemotherapy were given in total, completed in March 2005.

In May 2005, six weeks after cessation of chemotherapy a further CT was performed to confirm response. This demonstrated disease recrudescence, revealing omental and peritoneal deposits (fig 2c). As the patient was asymptomatic, and any further treatment was likely to be palliative a policy
of close observation was decided upon.

However by July 2005 the patient developed symptomatic ascites. Further chemotherapy was commenced using CAP (cyclophosphamide 500mg/m2 d1, doxorubicin 50mg/m2 d1, cisplatin 50mg/m2 d1).

Unfortunately after the first cycle of treatment, the patient was admitted to hospital with increasing abdominal distension and symptoms of gastrointestinal obstruction. CT revealed significant increase in disease bulk and widespread dilatation of bowel. In view of the rapid deterioration and obstructive abdominal symptoms further chemotherapy was felt to be unlikely to be of benefit, and the patient was discharged home with palliative care support. She died in October 2005, less than 12 months after diagnosis.

Discussion

Since its recognition as a distinct entity in 1987 the pathological and clinical characteristics of DSRCT have been well described in a number of publications. DSRCT is a disease predominantly affecting adolescents and young adults [3,4]. Over 80% of those affected are male [2,3,4]. Most tumours occur in the abdomen, although thoracic and paratesticular primary sites have been described. Patients typically present with pain, palpable mass, abdominal distension, ascites or symptoms related to obstruction of viscus [1,2]. At diagnosis patients commonly have multiple serosal tumour deposits within abdomen and pelvis [4]. The most frequent sites of metastases are liver, lymph nodes, lung and bone marrow. CT is the radiological investigation of choice, and suspicion of DSRCT should be increased by imaging demonstrating multiple peritoneal soft tissue masses without obvious primary.

Laparoscopy can be used to confirm imaging findings and to provide sufficient biopsy material for molecular cytogenetics, an important element of the diagnosis. Histologically, DSRCT typically comprises nests of tumour cells surrounded by a dense desmoplastic stroma, with tumour cells coexpressing epithelial (cytokeratin, epithelial membrane antigen) mesenchymal (vimentin, desmin)
and less frequently neural (neurone specific enolase) cell markers [3,8]. Confirmation of diagnosis of DSRCT can be made by demonstration of the characteristic chromosomal translocation t(11;22)(p13;q12), an event thought to be pivotal in the disease pathogenesis, resulting in fusion of the Ewing sarcoma gene (EWS) localised to 22q12, to the Wilms' tumour suppressor gene
(WT1) localised to 11p13 [1,8].

The EWS gene encodes a 656 amino acid protein of unknown function, and is the gene most commonly involved in reciprocal sarcoma translocations. WT1 is a tumour suppressor gene expressed in the developing genitourinary tract and involved in development of a
subset of Wilms tumours [1,8]. It encodes a transcription factor that acts as a transcriptional repressor in-vitro [1,8]. The chimeric protein produced by the t(11;22)(p13;q12) fuses the amino terminal of EWS with the DNA binding domain of WT1 and likely functions as a transcriptional activator, [8] inducing production of endogenous platelet-derived growth factor (PDGF)
amongst other tumourigenic stimuli.

Treatments for DSRCT comprise chemotherapy, surgical resection and abdominal radiotherapy. An intensive alkylator-based chemotherapy regimen [6] appears to improve survival when compared with standard dose chemotherapy in retrospective series [4]. This regimen causes significant toxicity and requires intensive transfusional and antibiotic support. Surgical resection of more than 90% of disease is also associated with better prognosis, [4] although whether optimum resection is the cause of improved survival or the consequence of a more favourable disease phenotype is unclear.

Whole abdominal radiotherapy in 1.5Gy fractions to a dose of 30Gy is recommended
in some centres, although toxicity in the form of small bowel obstruction occurs in a third of patients. In a recent retrospective review of 66 patients treated at the Memorial Sloan Kettering Cancer Centre from 1972-2003 the use of multimodality treatment as detailed above was
associated with a significant improvement in survival [4].

In spite of aggressive therapy the prognosis of DSRCT is extremely poor, with median survival of less than 30 months and only 44% and 15% of patients alive at 3 and 5 years respectively after diagnosis [2,3,4]. Patients with hepatic parenchymal metastases have a dismal prognosis, with median survival of 18 months and no long-term survivors in one series [2]. Interestingly, our first patient survived 27 months from diagnosis, having had no surgery or radiotherapy and only standard dose chemotherapy, demonstrating the biological heterogeneity of the disease.

In spite of intensive efforts to improve outcomes in DSCRT through conventional therapies, breakthroughs in treatment are likely to be made through the use of novel treatment approaches. It is interesting to note that SU101, an inhibitor of the PDGF receptor pathway, produced rapid
symptomatic improvement and prolonged disease stabilisation in a patient
with refractory progressive DSRCT treated in a phase 1 trial [9]. However a recent phase II trial of the tyrosine kinase inhibitor imatinib (Gleevec) in relapsed paediatric tumours produced no responses in patients with DSRCT [10].

An alternative treatment approach of interest is the use of immunotherapies against DSRCT cell surface antigens or fusion protein neoantigens. Clearly, intense research efforts are needed in order to improve outcomes in this disease.

Conclusion

This is the first reported case of DSRCT presenting with obstructed labour. Aside from its extreme rarity however this report, together with our second case illustrates the characteristic clinical picture and dismal prognosis associated with this tumour. Gynaecological oncologists should be mindful of
the possibility of DSRCT in young women presenting with abdominopelvic symptoms and multiple peritoneal masses on imaging.

References

1. Gerald WL, Ladanyi M, de Alava E, Cuatrecasas M, Kushner BH, LaQuaglia MP, Rosai J. Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 1998;16(9):3028-36.

2. La Quaglia MP, Brennan MF. The clinical approach to desmoplastic small round cell tumor. Surg Oncol. 2000;9(2):77-81.

3. Ordonez NG. Desmoplastic small round cell tumor: I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol 1998;22(11):1303-13.

4. 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(1):251-5.

5. Parker LP, Duong JL, Wharton JT, Malpica A, Silva EG, Deavers MT. Desmoplastic small round cell tumor: report of a case presenting as a primary ovarian neoplasm. Eur J Gynaecol Oncol. 2002;23(3):199-202.

6. Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Lindsley KL, Ghavimi F, Merchant TE, Boulad F, Cheung NK, Bonilla MA, Crouch G, Kelleher JF Jr, Steinherz PG, Gerald WL. Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol. 1996;14(5):1526-31.

7. Chow WA, Chu P, Doroshow JH. Proc Am Soc Clin Oncol 2003; 22 page 826, (abstr 3321)

8. Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors; desmoplastic small round-cell tumors. Cancer Genet Cytogenet 2002; 1;138(1):1-10.

9. Adamson PC, Blaney SM, Widemann BC, Kitchen B, Murphy RF, Hannah AL, Cropp GF, Patel M, Gillespie AF, Whitcomb PG, Balis FM. Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101. Cancer Chemother Pharmacol 2004;53(6):482-8.

10. M. Bond, M. L. Bernstein, A. Pappo, K. R. Schultz, M. Krailo, M. Fouladi, D. A. Hill, M. Heinrich, S. Blaney, P. C. Adamson. Phase 2 trial of Imatinib mesylate (IM) for treatment of recurrent or refractory."

Please note that this report refers, in places, to figures that were not present in copy received.