Intraabdominal desmoplastic small round cell tumors

A diagnostic and therapeutic challenge

Abstract

BACKGROUND

Intraabdominal desmoplastic small round cell tumors (IDSRCT) are uncommon but aggressive tumors that occur in young males. To the authors' knowledge, only limited data are available on the natural history and optimal treatment of this disease.

METHODS

The authors reviewed 12 patients with IDSRCT who were treated at their institution between January 1991 and December 2001.

RESULTS

All patients were males, with a median age of 26 years. All patients were symptomatic at the time of presentation, with a mean duration of symptoms of 2 months. Common presenting symptoms and signs were abdominal pain (67% of patients), palpable abdominal mass (58% of patients), abdominal distension (42% of patients), and hepatomegaly (33% of patients). Six patients (50%) had distant metastases at presentation. Five patients underwent biopsy only. Surgical resection was attempted in seven patients and included macroscopic total resection in three patients and debulking in four patients. All of those patients subsequently developed recurrent or progressive disease, which required a second operation in six patients. Overall, 6 patients (50%) developed symptomatic intestinal obstruction requiring surgical management, and 3 patients (25%) developed ureteral obstruction. All 12 patients received multiagent chemotherapy. Seven patients (55%) also received radiation therapy. The median survival of patients who underwent surgical resection was 34 months, whereas the median survival of patients who underwent biopsy alone was 14 months. One patient remained alive 72 months after he underwent complete resection of primary and recurrent tumors, and 1 patient remained alive with disease 32 months after he underwent complete resection of a primary tumor.

CONCLUSIONS

Patients with IDSRCT presented with a short duration of nonspecific symptoms, and the disease was fatal almost uniformly, regardless of the treatment modality used. Surgical resection may prolong survival in some patients. Cancer 2005. © 2005 American Cancer Society.

Desmoplastic small round cell tumors (DSRCT) belong to a group of neoplasms known as small cell tumors, which predominantly affect young males in their second and third decades of life.1, 2 They occur mainly in the abdomen and pelvis, although paratesticular, thoracic, and intracranial primary sites have been reported.3, 4 These tumors have a tendency to spread along the peritoneum and mesothelial-lined surfaces, with organ involvement an inconsistent and secondary phenomenon. In the abdomen and pelvis, these tumors typically present in an advanced stage with a bulky primary mass, distant metastases, and peritoneal seeding. Tumors that present extraabdominally usually are less extensive.3 The histogenic origin of these tumors is unclear, although, because of its association with mesothelial-lined surfaces, it has been suggested that they are derived from the primitive mesothelium or submesothelial mesenchyme.2, 3 Generally, these malignancies demonstrate the typical histologic features of poorly differentiated, small round, or spindle-shaped cells within a desmoplastic stroma.5 They are characterized further by a specific immunohistochemical staining profile with trilineage coexpression of intermediate-filament proteins, including epithelial markers (cytokeratin and epithelial membrane antigen positivity), mesenchymal markers (desmin and vimentin staining), and neural markers (neuron-specific enolase reactivity).6 Genetic expression observed consistently in DSRCT reveals a unique reciprocal translocation t(11;22)(p13;q11 or q12), the result of fusion of exon 7 of the Ewing sarcoma gene EWS on chromosome 22 with exon 8 of the Wilms tumor suppressor gene WT1 on chromosome 11.6, 7

Because most of our understanding regarding the pathologic and clinical nature of this disease has been based on case reports and small series of patients, the development of standard methods for its diagnosis and management has been difficult. Consequently, to our knowledge there is no clear consensus regarding the optimal therapeutic modalities for treating these highly aggressive tumors. Herein, we present our experience in the diagnosis and management of this disease at our institution.

MATERIALS AND METHODS

Between 1991 and 2001, 12 patients were diagnosed with intraabdominal DSRCT (IDSRCT) and received the majority of their treatment at the study institution. The diagnosis of IDSRCT was made based on pathologic, immunohistochemical, and molecular analysis of tissue specimens, as described elsewhere.5 Patient histories, including the surgeon's operative notes, chemotherapy and radiation therapy records, and follow-up data, were reviewed for patient age, gender, presenting symptoms and duration, radiographic investigations, type of surgery performed, postoperative course, adjuvant chemotherapy, radiation therapy, and follow-up.

Partial tumor regression was defined as a reduction in all measurable tumors > 50%; progressive disease was defined as tumor growth > 25% in volume or the appearance of any new lesion. Macroscopic total resection was defined as surgical resection of all macroscopically visible disease, debulking was defined as removal of > 90% of the disease but with macroscopically residual intraabdominal disease, and biopsy was defined as the removal of tissue for diagnosis only. The study was approved by the Institutional Review Board.

RESULTS

Patient Characteristics, Clinical Presentation, and Diagnosis

All patients were male. There were eight white patients, two African-American patients, one Asian patient, and one Hispanic patient. The median age at the time of diagnosis was 26 years (range, 15–41 yrs). All patients were symptomatic at the time of presentation with a mean duration of symptoms of 2 months (range, from 1 wk to 9 mos). Abdominal pain (eight patients), abdominal distension (five patients), palpable abdominal mass (seven patients), and hepatomegaly (four patients) were the most common presenting symptoms and signs. Computed tomographic (CT) scans were the most frequent diagnostic imaging modality utilized (75%). The most common CT abnormalities were the presence of a pelvic mass (77%), retroperitoneal and mesenteric lymphadenopathy (67%), and hepatic lesions (44%).

The tumor involved both the abdomen and pelvis in 5 patients (42%), occurred predominantly in the pelvis in 5 patients (42%), and diffusely involved peritoneal surfaces without any dominant mass in 2 patients (16%). Five patients (42%) had disease metastatic to the liver, and 1 patient (8%) had metastatic axillary lymphadenopathy at presentation. Four patients (33%) subsequently developed metastasis, including 2 patients with hepatic metastasis, 1 patient with both pulmonary and osseous metastasis, and 1 patient with osseous metastasis alone. Two patients initially were misdiagnosed with Hodgkin lymphoma and cecal adenoma, respectively, and were treated elsewhere before their tumors were characterized correctly.

Surgical Treatment

Five patients underwent biopsy only, because their intraabdominal disease was too extensive for primary surgical resection (Table 1). In the other seven patients, a surgical resection was attempted. Primary macroscopic total resection of disease was accomplished in 3 of these patients, and the remaining 4 patients underwent major (> 90%) debulking of their intraabdominal disease. All patients who underwent macroscopic total resection subsequently developed recurrent or progressive disease, which required additional surgery in six patients, including secondary macroscopic total resection in two patients, debulking in one patient, and palliative treatment for gastrointestinal obstruction in three patients (Table 1).

Table 1. Characteristics of the Patients who Underwent a Primary Surgical Resection

Patient age in yrs	Extent of disease at diagnosis	Preoperative therapy	Surgical therapy	Postoperative therapy	Outcome	Survival (mos)
GTR: macroscopic total resection; IMAP: ifosfamide, mitomycin, doxorubicin, and cisplatin; GM-CSF: granulocyte-macrophage–colony- stimulating factor; cGy: centigrays; NED: no evidence of disease; DOD: dead of disease;.
27	Omental mass and pelvic mass	None		Intraperitoneal P^32; IMAP + GM-CSF	Recurrence at 36 mos with GTR of recurrent tumor after preoperative (4500 cGy) and intraoperative (1500cGy) radiation	Alive/NED (72)
18	Lower abdominal/pelvic mass	None	GTR	IMAP + GM-CSF	Recurrence at 23 mos with GTR of recurrent tumor after preoperative (3960 cGy) and intraoperative (1500 cGy) radiation and P^32; small bowel obstruction at 4 mos; subsequent local and distant recurrence 5 mos later	DOD (42)
22	Pelvic mass, liver and spleen metastasis, peritoneal and serosal implants	IMAP (minor response); radiation (4500 cGy)	GTR	IMAP + GM-CSF	Recurrence at 17 mos; no further surgery	Alive with disease (32)
28	Lower abdominal/pelvic mass, peritoneal and omental implants	None	Debulking	IMAP + GM-CSF and radiation (5600 cGy)	Disease progression with small bowel obstruction at 26 mos requiring diversion	DOD (36)
25	Lower abdominal/pelvic mass; peritoneal, serosal, and omental implants	IMAP + GM-CSF; (partial regression)	Debulking	IMAP + GM-CSF	Disease progression at 20 mos; biopsy only	DOD (34)
18	Pelvic mass; peritoneal and serosal implants; retroperitoneal implants; liver metastasis, mediastinal lymphadenopathy	Vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide (partial regression)	Debulking	Intraperitoneal mitoxantrone, radiation (2800 cGy), and intensive chemotherapy with peripheral cell transplantation	Disease progression with colonic obstruction at 6 mos requiring fecal diversion	DOD (10)
32	Peritoneal implants; liver metastases	IMAP (partial regression)	Debulking	Intraperitoneal P^32; IMAP + GM-CSF	Disease progression with small bowel obstruction at 7 mos requiring debulking; second recurrence with small bowel obstructio n 6 mos later requiring further debulking; renal insufficiency from ureteral obstruction	DOD (26)

Adjuvant Therapy in Patients who Underwent Surgical Resection

Three patients (Table 1) received preoperative chemotherapy with ifosfamide, mitomycin, doxorubicin, and cisplatin (IMAP) plus granulocyte-macrophage–colony-stimulating factor (GM-CSF) and one patient received a combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, which resulted in partial tumor regression in three patients and a minor response in the one patient who received the latter regimen. One patient who received IMAP plus GM-CSF chemotherapy also received 4500 centigrays (cGy) of preoperative external beam radiation therapy (EBRT). These patients then underwent surgical resection (macroscopic total resection in 1 patient and debulking in 3 patients) followed by adjuvant chemotherapy plus EBRT (2800 cGy) to the abdomen and pelvis in 1 patient and postoperative chemotherapy alone in 3 patients. Subsequent disease progression/recurrence was observed in all 4 patients after a median interval of 12 months (6 mos, 7 mos, 17mos, and 20 mos, respectively).

Three other patients underwent primary surgical excision (macroscopic resection in two patients and debulking in one patient) as initial treatment followed postoperatively by IMAP plus GM-CSF in two patients and IMAP alone in one patient. All 3 of these patients also developed progressive/recurrent disease after a median of 26 months (23 mos, 26 mos, and 36 mos, respectively). The 2 patients with recurrent disease were treated with preoperative EBRT (4500 cGy and 3960 cGy, respectively) followed by complete surgical resection of their recurrent disease and intraoperative radiation (1500 cGy) therapy. One patient was disease free 36 months after complete resection and preoperative and intraoperative irradiation for his recurrent tumor. The other patient developed local and distant disease recurrence 4 months after the second tumor extirpation (Table 1).

Three patients received intraperitoneal P³² (IP³²) (15 μC) as a part of their treatment regimen, including 2 patients who received it after surgery for their presenting disease, which was comprised of macroscopic resection (local recurrence 36 mos after IP³²) and debulking (disease progression 7 mos after IP³²). The other patient received IP³² after undergoing macroscopic resection of recurrent disease (local and distant recurrence 5 mos after IP³²) (Table 1). One patient received intraperitoneal mitoxantrone at the time of debulking of the presenting disease followed by chemotherapy and an autologous peripheral blood cell transplantation (disease progression 6 mos after IP³²) (Table 1).

Adjuvant Therapy in Patients who Underwent Biopsy Only

All 5 patients who underwent a biopsy only (Table 2) began treatment with multiagent chemotherapy, which involved a 5-drug combination of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide in 2 patients; a 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and cisplatin) plus external beam irradiation to the abdomen and pelvis (4500 cGy) in a third patient; and simpler drug combinations in the other 2 patients (ifosfamide plus etoposide in 1 patient and etoposide, cisplatin, and doxorubicin in 1 patient). The three patients who received the five-drug regimens experienced partial tumor regression, whereas disease progression was observed in the other two patients.

Table 2. Characteristics of the Patients who Underwent Biopsy without Primary Surgical Resection

Patient age in yrs	Extent of disease at diagnosis	Surgical therapy	Postoperative therapy	Response	Outcome	Survival (mos)
DOD: dead of disease; EBRT: external beam radiation therapy; cGy: centigrays.
27	Lower abdominal/retroperitoneal and pelvic mass; periaortic lymphadenopathy; mediastinal lymphadenopathy.	Biopsy	Ifosfamide, etoposide	Disease progression	Colonic obstruction requiring colostomy	DOD (7)
32	Lower abdominal/retroperitoneal and pelvic mass; peritoneal implants	Biopsy with palliative bypass	Vincristine, doxorubicin, cyclophosphamide, etoposide, cisplatin, and EBRT (4500 cGy)	Partial tumor regression	Ureteral obstruction.	DOD (4)
29	Pelvic mass; liver metastasis; retroperitoneal and paraaortic lymphadenopathy; osseous metastasis	Biopsy	Etoposide, cisplatin, doxorubicin	Disease progression	Ureteral obstruction.	DOD (21)
18	Pelvic mass; peritoneal disease; mesenteric, retroperitoneal, and pelvic lymphadenopathy	Biopsy	Vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide	Partial tumor regression		DOD (36)
15	Peritoneal implants, liver metastasis	Biopsy	Vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide	Partial tumor regression		DOD (14)

Outcome and Survival

Six of 12 patients developed symptomatic intestinal obstruction during the course of their disease that required surgical management, and 3 patients developed renal insufficiency from ureteral obstruction that required ureteral stents. Two patients were alive at last follow-up including 1 patient who survived 72 months after macroscopic total resection of his primary tumor and remained free of his disease 36 months after complete resection and radiation therapy of his recurrent tumor. The other survivor was alive with disease 32 months after complete macroscopic resection of his primary tumor. The median survival for patients who underwent biopsy alone was 14 months, whereas the median survival for patients who underwent surgical resection was 34 months.

DISCUSSION

In the current study, all the patients with IDSRCT were men, with a median age of 26 years. Nine of the 12 patients were between ages 10 years and 30 years, and the other 3 patients were in their 40s. Others have reported the occurrence of this tumor in very young children, in elderly patients, and in females.3, 5 Recent molecular and pathologic studies also have demonstrated significant histologic variability within this family of tumors.2, 3, 5 Whether these differences represent a spectrum of the disease or misdiagnosis will depend on future reports that consistently utilize accurate immunohistochemical and molecular diagnostic techniques.

The most common presenting symptoms and signs of IDSRCT (abdominal pain, distension, and a palpable abdominal mass) are nonspecific and nondiagnostic. Although the mean duration of symptoms experienced by our patients prior to diagnosis was 2 months, 3 patients presented with acute symptoms of abdominal pain and fever, including 1 patient who had overt signs of peritonitis. CT scanning, the most commonly utilized diagnostic modality, revealed no characteristic findings for IDSRCT, merely evidence of a disseminated intraabdominal malignancy. No ethnic predisposition was apparent in the current series of patients. Our demographic and clinical data are similar to those reported previously,1, 6, 8 confirming the nonspecific clinical presentation of this disease. Therefore, it is important to consider IDSCRT as a possible diagnosis when a young man presents with nonspecific abdominal symptoms and radiographic evidence of a disseminated, intraabdominal malignancy.

Similar to previous reports,1, 6, 8 we found that IDSRCT presented as a diffuse process within the abdomen and pelvis without any apparent organ of origin. Ten of the 12 patients in the current study presented with a mass in the lower abdomen or pelvis as the main focus of disease along with additional peritoneal implants, which varied from a limited number of distinct nodules or plaques to innumerable peritoneal implants throughout the abdomen and pelvis. Two patients had only diffuse peritoneal seeding without a dominant mass. Hepatic metastasis was observed at the time of presentation in five patients and developed subsequently during the course of the disease in two other patients. Skeletal metastasis occurred in two patients, one of whom also developed pulmonary metastasis. Intraabdominal and retroperitoneal lymph node involvement was noted in four patients, two of whom also had pathologically unconfirmed mediastinal lymphadenopathy. This pattern of disease spread reveals the predilection of these tumors to metastasize through both lymphatic and hematogenous routes, making effective systemic therapy a necessity in treating IDSRCT. Because of the tendency of IDSRCT to involve the peritoneal and serosal surfaces with desmoplastic implants during the course of disease, several of our patients eventually developed intestinal obstruction, which required either debulking with intestinal resections or palliative bypass.

To our knowledge, no consensus has been reached concerning the optimal strategy for managing IDSRCT. Furthermore, because of the heterogeneity of the therapeutic modalities utilized, it is difficult to compare the efficacy and effectiveness of various regimens. The current study data also reflect the lack of standard therapy. However, the current literature1, 6, 8, 9 and our results suggest that an aggressive approach involving total macroscopic tumor excision combined with chemotherapy and radiation may offer the best opportunity for disease control and disease-free survival. Because of the extensive involvement of this disease at the time of presentation, macroscopic resection of the tumor often is unfeasible technically, although we would suggest that an attempt be made to remove all macroscopic tumor. Primary complete or partial removal of macroscopic disease was possible in only 60% of the patients in the current series but was associated with a longer median survival. Although patients who underwent biopsy were more likely to have extensive disease and did not respond to their chemotherapy as well as the group of patients who underwent attempted surgical resection, we believe that extensive tumor reductive surgery may favor survival in this disease. The one patient in the current series who had long-term disease-free survival underwent macroscopic resection of both his primary and recurrent tumors. Although to our knowledge only a few long-term survivors have been reported to date, the majority underwent macroscopic surgical resection.1, 8 Another important role of surgery in IDSRCT is the relief of symptomatic gastrointestinal obstruction, which reportedly develops in half of the patients with this disease.

IMAP plus GM-CSF; the chemotherapy regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide; and the less complex regimens all were found to be less than satisfactory therapy for IDSRCT. Although initial partial tumor regression was reported in several patients, no permanent tumor control was appreciated. Our observations are consistent with those reported from other institutions6, 9, 10 regarding the efficacy of chemotherapy patients with in this disease. Farhat et al.10 reported one complete remission among five patients who were treated with cyclophosphamide, etoposide, doxorubicin, and cisplatin. In a review10 of 60 patients who were treated by chemotherapy with or without abdominal radiation, objective responses were noted in 17 patients, 8 of whom attained clinically complete tumor regression status. The chemotherapeutic regimens associated with complete response were those that included doxorubicin, cyclophosphamide, vincristine, and cisplatin. Kushner et al.8 suggested that the transient favorable response to chemotherapeutic agents noted in IDSRCT warrants attempts of consolidating disease regression using myeloablative chemotherapy with stem cell rescue. Recently, however, findings from a Phase II study11 with a high-dose chemotherapy regimen of ifosfamide, epirubicin, and vincristine did not report a significant improvement in survival in patients with DSRCT. In a subsequent prospective study,12 a similar regimen of high-dose chemotherapy was used along with autologous peripheral stem cell transplantation in conjunction with local treatment (surgery and/or radiotherapy). After a median follow-up of 35 months, the median overall survival in that study was 14 months, leading the authors to conclude that high-dose chemotherapy did not alter the clinical course significantly in these patients.12

Based on their experience, La Quaglia and Brennan4 from the Memorial Sloan-Kettering Cancer Center have recommended adjuvant abdominopelvic radiotherapy followed by surgery and chemotherapy. However, others have expressed concern about the efficacy of radiation with the diffuse peritoneal involvement of this disease and the potential toxicity to the adjacent organs, particularly the small bowel.10 In their review of 21 patients, Goodman et al.13 noted that patients who received the institutional chemotherapy protocol (cyclophosphamide, doxorubicin, vincristine, ifosfamide, and etoposide), followed by maximal surgical debulking and consolidative radiation to the abdomen and pelvis, had a better survival compared with contemporary reports. Although their patients developed significant acute hematologic and gastrointestinal toxicity, medically, they all were managed successfully and completed their treatment course. The most common long-term complication was small bowel obstruction, which occurred in approximately one-third of the patients. Late side effects, however, are difficult to assess because many patients develop complications from disease progression or do not live long enough after radiation therapy to manifest treatment complications.

The tendency of these tumors to involve the serosal surfaces within the abdomen and pelvis and the experience with pseudomyxoma peritonei was the rationale behind using intraperitoneal agents in certain patients. Although no significant impact was noted, the investigation of other potential intraperitoneal chemotherapeutic agents appears feasible given the ineffectiveness of systemically administered chemotherapy.

IDSRCT is an uncommon neoplasm. With increased awareness and improvements in diagnostic capabilities, more patients are likely to be diagnosed with IDSRCT. Despite the currently preferred multimodality approach, including surgery, chemotherapy, and radiation therapy, the prognosis for patients with this disease remains poor. The disseminated nature of the disease limits the efficacy of surgical therapy, making the development of truly effective adjuvant therapies imperative. Perhaps genetically specific molecular therapy can be developed for IDSRCT, similar to what has been accomplished for the treatment of gastrointestinal stromal tumors with imatinib.