Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report

  • Authors:
    • Katsutsugu Umeda
    • Satoshi Saida
    • Hideki Yamaguchi
    • Shinya Okamoto
    • Takeshi Okamoto
    • Itaru Kato
    • Hidefumi Hiramatsu
    • Tsuyoshi Imai
    • Takeshi Kodaira
    • Toshio Heike
    • Souichi Adachi
    • Ken‑Ichiro Watanabe
  • View Affiliations

  • Published online on: November 17, 2015     https://doi.org/10.3892/ol.2015.3928
  • Pages: 856-860
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Abstract

Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity‑modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT.

Introduction

Desmoplastic small round cell tumors (DSRCTs) are rare and aggressive neoplasms that predominantly occur in young adults, with ~90% of cases occurring in males (1). To date, <200 cases of DSRCTs have been reported in the literature. Patients typically present with a large intra-abdominal or pelvic mass with peritoneal and omental spread of the tumor, lymph node involvement, and multiple metastases to the liver, lungs and bone; however, spread to the bone marrow or the central nervous system (CNS) is rare (2). Typical symptoms include abdominal distension, abdominal pain and emesis. Characteristic histological findings include nests of small round cells, which are positive for epithelial (cytokeratins and epithelial membrane antigen), mesenchymal (vimentin), neural [neuron-specific enolase and cluster of differentiation (CD)56] and myogenic (desmin) markers, and embedded in desmoplastic stroma. The definitive diagnosis of DSRCT is based on the detection of the Ewing' sarcoma (EWS)/Wilm's tumor protein 1 (WT1) fusion gene (3).

The P6 protocol, a high-dose alkylator-based regimen, is the most common treatment for DSRCT; 90% of treated patients exhibit a partial or complete response (3). However, despite the combination of multi-agent chemotherapies, surgery and local irradiation treatments available, the outcome of DSRCT remains extremely poor, with a 5-year overall survival rate of ~15%, due to markedly high rates of disease progression and relapse (3,4). Generally, relapses present as a local recurrence and/or hematogenous or lymphogenous metastasis (1,3,4). Until now, CNS recurrence had not been reported. The present study reports the case of a 16-year-old male with metastatic DSRCT who developed recurrence in the CNS following aggressive multimodal treatment, including intensive chemotherapy using frequent autologous stem cell support. Written informed consent was obtained from the patient's family and the study was approved by the ethics committee of the Graduate School of Medicine, Kyoto University (Kyoto, Japan).

Case report

In May 2012, a 16-year-old male patient was admitted to Otsu Red Cross Hospital (Otsu, Japan) with a 2 month history of progressive abdominal pain, weight loss, dyschezia and hematochezia. The patient's medical history was unremarkable. Abdominal magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (CT) revealed the presence of a large tumor on the pelvic floor, multiple metastases to the liver, bone and lymph nodes, and right kidney hydronephrosis due to compression of the ureter (Fig. 1A–C). Right renal agenesis, an ipsilateral seminal vesicle cyst and ejaculatory duct obstruction were also incidentally detected, all of which are typical findings of Zinner syndrome caused by the congenital loss of paramesonephric duct derivatives (5). However, to date, the association between DSRCT and Zinner syndrome has not been investigated.

In June 2012, the patient was transferred to Kyoto University Hospital (Kyoto, Japan), and underwent open biopsy of the left groin lymph node metastasis. Histological observation of a biopsy sample revealed groups of small, round, undifferentiated cells embedded in a desmoplastic stroma (Fig. 2A). Immunohistochemistry of the specimen was positive for neuron-specific enolase, desmin, cytokeratin and WT1, focally positive for CD56, and negative for CD99, myogenic differentiation 1 and S100 (Fig. 2B–F). The patient was diagnosed with DSRCT based on detection of the EWS/WT1 fusion transcript by reverse transcription (RT)-polymerase chain reaction (PCR). Briefly, RT-PCR was performed using the PE7000 PCR detection system (Perkin-Elmer, Inc., Waltham, MA, USA). The reaction system contained 1 µl cDNA, 2 µl forward and reverse primers, 5 µl PCR buffer, 3 µl MgCl2, 0.2 µl rTaq enzyme, 5 µl dNTPs (2 mM) and 31.8 µl dH2O. PCR was performed under the following conditions: Initial denaturation step at 94°C for 2 min, followed by 35 cycles of 94°C for 30 sec, 62°C for 30 sec and 72°C for 1 min, with a final extension step at 72°C for 6 min. No metastatic disease was detected by bone marrow aspiration or MRI of the head.

The patient's clinical course is indicated in Fig. 3. In June 2012, following percutaneous nephrostomy and colostomy, the patient was initially treated with eight courses (18–21 day cycles) of multi-agent chemotherapy. A modified protocol of the P6 regimen (2) was used, as follows: Vincristine (2 mg/m2, day 1), doxorubicin (DOX; 37.5 mg/m2, days 1 and 2; using pirarubicin instead of DOX for the fifth and sevenths courses) and cyclophosphamide [Cy; 1.2 g/m2 (day 1) for the first course and 2.1 g/m2 (days 1 and 2) for the third, fifth and seventh courses], alternating with ifosfamide (IFO; 1.8 g/m2, days 1–5) and etoposide (VP16; 100 mg/m2, days 1–5). Peripheral blood stem cells (PBSCs), containing a total of 7.4, 4.5 and 5.0×106 cells/kg CD34+ cells, were harvested following mobilization with granulocyte-stimulating factor after the second, fourth and fifth courses of chemotherapy, respectively. To hasten the hematological recovery, PBSCs, containing a total of 1.2, 1.0 and 1.1×106 cells/kg CD34+ cells, were infused after the third, fifth and seventh courses of chemotherapy, respectively. Following the completion of eight courses of chemotherapy over 25 weeks, the primary tumor markedly regressed and all metastatic lesions except one at the caudate lobe of the liver disappeared (Fig. 1D and E). In November 2012, the patient underwent a gross total resection of the primary tumor on the pelvic floor, a subtotal resection of the caudate lobe of the liver, while sparing the rectum, bladder and ureter. Intraoperatively, multiple disseminated tumors were identified on the peritoneum and diaphragm, which had not been identified by preoperative imaging. Subsequently, radical resection of the disseminated tumors on the peritoneum and diaphragm was also performed. Histological examination of the excised primary and metastatic lesions revealed scattered viable cells embedded in a dense desmoplastic stroma (Fig. 4A–C). Subsequently, in January 2013, the patient received one 28-day course of post-operative chemotherapy using topotecan (Topo; 0.75 mg/m2, days 1–5) and Cy (250 mg/m2, days 1–5), a combination that is considered to have potent antitumor activity against DRSCT (6). Thereafter, the patient was treated with two 28-day cycles of high-dose chemotherapy using Topo (3 mg/m2, days 1–5) and Cy (1 mg/m2, days 3–5), followed by the infusion of 57 and 48 ml PBSCs, containing 1.8 and 1.6×106 CD34+ cells/kg, respectively.

There were no severe regimen-related toxicities and no serious infections during the pre- or post-operative chemotherapy treatment periods. Finally, in March 2013, the patient received whole abdominopelvic intensity-modulated radiation therapy at a dose of 30 Gy in 20 fractions for 28 days. The patient was discharged without any active lesions 11 months after the initial diagnosis.

Three months after discharge, the patient was asymptomatic, however, MRI of the upper extremities demonstrated bone metastases in the left humerus on follow-up (Fig. 1F). Furthermore, MRI of the head demonstrated a mass in the pineal body and multiple cerebellar lesions (Fig. 1G and H). No evidence of active disease was revealed by abdominal and spinal MRI or by cerebrospinal fluid (CSF) examination. The patient was treated with irinotecan (CPT11; 35 mg/m2, days 1–5) and temozolomide (TMZ; 120 mg/m2, days 1–5), without irradiation, with the expectation that synergistic antitumor activity would be exhibited and that TMZ could cross the blood-brain barrier. Subsequent to four 28-day cycles of chemotherapy, a partial response of the bone metastasis and pineal body was observed, whereas the response of the cerebellar lesions was stable disease.

In March 2014, the patient was readmitted to Kyoto University Hospital due to a severe headache, which had lasted for one week following seven 28-day cycles of chemotherapy. Fluid-attenuated inversion recovery MRI of the head demonstrated dilatation of the lateral ventricles, although the intracranial lesions had not increased in size (Fig. 5A). The CSF cell count was 20 cells/µl and CSF cytology was positive for malignant, small, round cells, indicating CNS dissemination of DSRCT. The CSF protein level was 34.9 mg/dl (normal range, 10.0–40.0 mg/dl) and glucose was 22 mg/dl (normal range, 40–75 mg/dl; serum glucose, 116 mg/dl, normal range, 78–110 mg/dl). Two days later, the patient suddenly exhibited a decreased level of consciousness and a head CT revealed a subarachnoid hemorrhage at the base of the brain (Fig. 5B). As a consequence, the patient succumbed due to progressive CNS disease 1 year and 9 months after the initial diagnosis. An autopsy was not performed, as permission could not be obtained from the family.

Discussion

Gross tumor resection is strongly associated with prolonging the overall survival of patients with DSRCT (4). Intensive chemotherapy, such as the P6 protocol, is initially effective for the majority cases of DSRCT (2). However, severe bone marrow suppression, even when granulocyte-stimulating factor is used, requires the intervals between treatments to be lengthened after a number of cycles. In a previous study, it was identified that the regrowth of chemotherapy-resistant tumors eventually hindered gross tumor resection, and that almost all patients undergoing incomplete resection succumbed to the disease within 2 years (4).

The following chemotherapy regimen was planned for the current patient in response to a large intra-abdominal DSRCT: Increasing dose-intensity by decreasing the interval between chemotherapy cycles, while maintaining an identical total dose throughout. As a result, sustained antitumor activity was observed following eight cycles of pre-operative chemotherapy using frequent PBSC support at ~3-week intervals, and gross total resection of the primary and intra-abdominal metastatic tumors was completed. Furthermore, no active disease was observed at the site of the abdominal or pelvic lesions at least 1 year and 9 months after the initial diagnosis. Thus, interval-compressed chemotherapy, in combination with surgery and local irradiation, is a promising treatment strategy, at least for the control of localized DSRCT.

There have been three reported cases of a primary CNS tumor in DRSCT to date (7,8), but this is the first report of DSRCT recurrence in the CNS (Table I). Although rare, reports of neuroblastoma or EWS recurrence in the CNS are on the increase, which may be associated with improvements in the outcome due to aggressive multimodal therapy (9,10). Notably, the present case exhibited multiple metastatic lesions in the internal table of calvaria at the initial diagnosis, which raises the possibility that the CNS involvement of DSRCT was associated with tumor extension through the dura or skull into the adjacent superficial brain parenchyma, as previously reported in neuroblastoma and EWS (9,10). Thus, further successful advances in treatments for DSRCT will require awareness of the potential for CNS recurrence and the identification of risk factors for such an unusual pattern of metastasis.

Table I.

Summary of cases of desmoplastic small round cell tumors with CNS involvement.

Table I.

Summary of cases of desmoplastic small round cell tumors with CNS involvement.

Age, years/genderDisease statusCNS lesionsSurgeryTreatmentOutcomeReference
24/MPrimaryPosterior fossaPartial resectionPCNU, CDDP, VP16, local irradiation, it-MTXAWD (unknown)5
37/MPrimaryCPA resectionPartial resectionCBDCA, TMZ, radiation [WB and local (CPA, spine)]DOD (24 months)6
39/MPrimaryCPA, spinePartial resectionCDDP, VP16, IFO, resection radiation [WB and local (CPA, spine)]AWD (27 months)6
16/MRelapsedPineal body, cerebellumNoCPT11, TMZDOD (21 months)Current case

[i] CNS, central nervous system; M, male; PCNU, nitrosourea; CDDP, cisplatin; VP16, etoposide; AWD, alive with disease; it-MTX, intrathecal methotrexate; CPA, cerebellopontine angle; CBDCA, carboplatin; TMZ, temozolomide; DOD, died of disease; WB, whole brain; IFO, ifosphamide; CPT11, irinotecan.

The three previously reported cases of a primary CNS tumor in DSRCT followed aggressive courses, similar to that of intra-abdominal DSRCT, despite an initial response to chemotherapy regimes, such as IFO, VP16, TMZ and carboplatin, in combination with whole-brain or spinal irradiation (Table I) (7,8). In the current case, the combination of CPT11 and TMZ was selected as salvage therapy for CNS recurrence of DSRCT, which has exerted an good antitumor effect for refractory or relapsed neuroblastoma and EWS (11,w). Indeed, the combination of CPT11 and TMZ was initially effective against the CNS metastatic lesions; however, the patient ultimately succumbed due to progressive CNS disease. Therefore, additional studies are required to establish a novel chemotherapy, in combination with craniospinal irradiation, to prevent or treat DSRCT of the CNS.

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Spandidos Publications style
Umeda K, Saida S, Yamaguchi H, Okamoto S, Okamoto T, Kato I, Hiramatsu H, Imai T, Kodaira T, Heike T, Heike T, et al: Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report. Oncol Lett 11: 856-860, 2016
APA
Umeda, K., Saida, S., Yamaguchi, H., Okamoto, S., Okamoto, T., Kato, I. ... Watanabe, K. (2016). Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report. Oncology Letters, 11, 856-860. https://doi.org/10.3892/ol.2015.3928
MLA
Umeda, K., Saida, S., Yamaguchi, H., Okamoto, S., Okamoto, T., Kato, I., Hiramatsu, H., Imai, T., Kodaira, T., Heike, T., Adachi, S., Watanabe, K."Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report". Oncology Letters 11.1 (2016): 856-860.
Chicago
Umeda, K., Saida, S., Yamaguchi, H., Okamoto, S., Okamoto, T., Kato, I., Hiramatsu, H., Imai, T., Kodaira, T., Heike, T., Adachi, S., Watanabe, K."Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report". Oncology Letters 11, no. 1 (2016): 856-860. https://doi.org/10.3892/ol.2015.3928