Keywords
desmoplastic small round cell tumor - ovary - surgical debulking - adjuvant chemotherapy
- radiotherapy - immunohistochemistry
Introduction
Desmoplastic small round cell tumor (DSRCT) is a highly malignant, rare intraabdominal
neoplasm of mesenchymal origin with an extremely poor prognosis. It primarily affects
young men, with a reported male to female ratio of four to one.[1] Desmoplastic small round cell tumor has a propensity for serosal surfaces, and the
majority of the patients are in the late stages of the disease upon presentation.[2] Owing to the male predominance of this disease, DSRCT is rarely noticed in young
women with an abdominal or ovarian mass, so it presents a considerable diagnostic
challenge. Furthermore, given the overall low incidence rate,[3] uncertain histogenesis, and the diffuse nature of DSRCT, there is no consensus on
the most effective treatment modality. Up to now, only 16 cases of ovarian DSRCT have
been previously reported in women in the English literature, and no large population-based
studies on this topid exist.[2] The present report describes a case of DSRCT in a young woman who initially presented
with right ovarian mass and consequent abdominal distension. The aim of the current
review is to highlight all the issues encountered in diagnosing and treating the DSRCT.
Case Presentation
A 19-year-old nulliparous virgo, with unremarkable past medical history, initially
presented to our department with a feeling of abdominal fullness. Pelvic examination
revealed a painless right adnexal mass that was occupying the whole abdominal cavity.
The mass was firm, solid, of low mobility, and with hard-to-define boundaries. Transabdominal
and transvaginal ultrasonography revealed a predominantly solid and vascularized,
bilateral adnexal formation with an area of 80 mm. The level of the serum carbohydrate
antigen-125 was elevated to 271 U/ml (normal, < 35 U/ml), while other serum tumor
markers (β-HCG, AFP) were not elevated. The patient underwent an exploratory laparotomy.
Approximately 1,000 ml of amber-colored cytologically negative ascites were withdrawn
intraoperatively. Two large, irregular, and predominantly solid, bilateral ovarian
masses (both ∼ 20 cm) were found with small tumor implants on the sigmoid colon, omentum,
and cul-de-sac. The interiliac lymph nodes measured 4 cm, bilaterally. Using intraoperative
frozen section diagnosis, the tumor tissue of right ovary was interpreted as a malignant
tumor, probably dysgerminoma. A bilateral salpingo-oophorectomy, bilateral pelvic
lymphadenectomy, total abdominal hysterectomy, complete omentectomy, and resection
of the disseminated tumors with interiliac lymph node excision were performed. The
patient was optimally debulked with no residual tumor seen. Macroscopically, the right
and the left ovarian masses were pearly white, predominantly solid with partially
pseudocystic areas and necrosis. Conventional hematoxylin and eosin stained sections
demonstrated small and round tumor cell nests separated by a prominent desmoplastic
stroma. The mitotic count of the tumor cells was high (up to 26 mitotic figures per
10 high power fields), suggesting a poorly-differentiated carcinoma. Immunohistochemical
staining was performed using the antigen retrieval technique. The tumor cells were
diffuse positive for broad-spectrum cytokeratins (CK AE1/AE3), epithelial membrane
antigen (EMA), and vimentin. Polymerase chain reaction (PCR) analysis showed positive
results for Ewing sarcoma (EWS)—Wilms tumor 1 (WT1) fusion gene, while additional
confirmation of the DSRCT diagnosis was made via detection of the tumor-specific chromosomal
translocation t(11;22)(p13;q12). Based on the morphology and immunohistochemistry
findings, a final diagnosis of intraabdominal DSRCT with ovarian involvement was made.
Bone marrow biopsy was performed after a final pathologic diagnosis and within three
weeks after surgery, revealing normocellular pattern. Furthermore, a PET/CT scan demonstrated
enlarged paraaortic lymph node in projection of third lumbar vertebrae with cluster
of hyperdense nodes beside it, without metabolic activity. According to the CWS 2009
protocol scheme, she has received intensive chemotherapy treatment for metastatic
disease: 3 cycles of ifosfamide 9,000 mg/m2, vincristine 1,5 mg/m2, actinomycin 1,5 mg/m2 (IVA), 3 cycles of carboplatin 500 mg/m2, epirubicin 150 mg/m2, Vincristine 1.5 mg/m2 (CEV), and 3 cycles of ifosfamide 9,000 mg/m2, vincristine 1,5 mg/m2, etopozide 450 mg/m2 (IVE) with informed consent of the patient and her family. Only in first cycle of
IVA and in the first cycle of CEV she has received vincristine 3 × 1.5 mg/m2. Because of suspect malignancy propagation on positron emission tomography/computed
tomography (PET/CT) scan, we conducted a second debulking surgery (SDS), about 4 months
after initial surgical treatment. Intraoperative finding was a solid tumor (9 × 5 cm),
barely fixed with external iliac vessels. We performed successful tumor resection
with no residual tumor seen in the abdominal cavity. Cytological and immunohistochemistry
findings confirmed diagnosis of DSRCT. The patient received nine cycles of CWS protocol
overall. After the ninth cycle of CWS protocol, a disease remission was accomplished,
and the patient underwent high-dose chemotherapy (busulfan 600 mg/m2, melphalan 140 mg/m2) followed by autologous stem cell support. After the autologous stem cell support,
she received a couple of cycles of maintenance therapy (etoposide 2 × 25 mg/m2/day, idarubicin 4 × 5 mg/m2 and trofosfamide 2 × 75 mg/m2/day) but, due to drug induced high transaminase levels, we stopped it. The transaminase
levels have normalised soon after. Twelve months after the patient's admission, a
control PET/CT scan, pelvic and abdominal MRI were without evidence of eventual disease
reccurence. In accordance with the above mentioned clinical findings, our approach
was to provide a radiotherapy to the site of initial bulk disease (dose of 30.6 Gy
divided in 17 fractions). The only noticeable adverse effect during the course of
therapy was thrombocytopenia, which was extensive at one point, so it required treatment
with intravenous immunoglobulins and platelet transfusion. Up to date, she is in good
general condition without evidence of disease reccurence, 40 months after her initial
diagnosis.
Discussion
Desmoplastic small round cell tumor was first described in 1989 by Gerald and Rosai[4] as a rare tumor of uncertain histogenesis. The presenting symptoms of DSRCT are
usually related to the site of involvement, such as crampy abdominal pain, abdominal
distension with ascites, palpable mass, constipation, anorexia, or weight loss.[1]
[2] The most common primary location of DSRCT is the peritoneal cavity, but it can be
found at other sites, such as the ovary, kidney, or retroperitoneal space.[5] Primary DSRCT has also been reported in the posterior cranial fossa, scalp, ethmoidal
sinuses, paratesticular region, pleura, and chest.[6]
[7] The typical sites of metastas isinclude the groin, neck or mediastinum, lymph nodes,
liver, lungs, and bone marrow (5,10). Although the tumor markers in our case were
within th reference values range, β-HCG, AFP, LDH, and CA-125 should be measured in
all young women who present with a pelvic mass. Elevated serum tumor marker levels
may serve as an adjunct in the initial diagnosis, therapy monitoring, and posttreatment
surveillance. Conforming to tumor rarity and certain aggressive nature, it has low
overall survival rates with reported 3-year survival of 29%,[8] and median progression-free survival of 2.6 years.[9]
[10] The overall progression-free 5-year survival rate of patients is 18%.[11] The mean age of affected women reported up to this point is 20 years with life expectancy
range from 4 to 42 months ([Table 1]). Due to the rare occurrence of this disease, with up to 0.5 cases/million,[3] a definitive diagnosis is only obtained based on pathological conclusion. Our microscopic
findings indicated the DSRCT diagnosis ([Fig. 1]).[12] An additional important and useful diagnostic tool is the combination of immunohistochemical
staining and cytogenetic analysis. The characteristic DSRCT immunophenotype is the
coexpression of epithelial, mesenchymal, and neuroendocrine markers.[13] Furthermore, the small round cells in our material were focal positive for desmin
and Wilms tumor 1 (WT-1) genes and were negative for chromogranin, among others, thus
helping our pathologist to distinguish DSRCT from other forms of small round cell
tumors (e.g., ovarian small cell carcinoma of hypercalcemic type). The expression
of immunolabelings in the small round cells showed great level of variability ([Table 2]), with positive desmin and broad-spectrum CK being considered the most specific
immunological indexes of DSRCT. If the diagnosis is uncertain following microscopic,
immunohistochemical, or cytologic analysis, the PCR method or fluorescent in-situ
hybridization (FISH) can be helpful in providing supplemental diagnostic information.
Desmoplastic small round cell tumor exhibits a unique chromosomal transcription, resulting
in the fusion of EWS-WT-1 to create a gene that presumably acts as a transcriptional
activator for pro-tumorigenic genes.[14] Because this chromosomal transcription is not always present ([Table 2]), the efficiency of this diagnostic approach, considering the eventual costs of
the diagnostic tools used, is still controversial. Nevertheless, a lot of efforts
are still required towards a definition of the most adequate therapeutic modality
of choice. Although the multiple treatment strategies have been assessed, DSRCT survival
has not significantly improved ([Table 1]). Currently, a combination of surgical resection and chemotherapy are commonly used
for the initial treatment, although there is no consensus regarding whether surgical
debulking should be preceded or followed by chemotherapy.[2] In one reported study by Lal et al, there is a strong correlation between 3 and
5-year survival with multimodal therapy treatment. A systemic chemotherapy utilizing
the P6 regimen, aggressive surgical debulking with greater than 90% surgical resection,
and adjuvant radiotherapy combined demonstrated significant contribution to improved
overall survival.[15] In terms of choice of chemotherapy, DSRCT is alkylator-sensitive and dose-responsive,
compared to other small round-cell tumors.[16] Certain regimens, especially platinum-based ones, showed great overall safety profile
and should be considered even in the second and early third trimester of pregnancy.[17] Scheer et al[18] demonstrated the best results with the vincristine, adriamycin, ifosfamide, actinomycin
D (VAIA) scheme in a multivariable model proven by the Cox regression analysis as
an independent effect. The median event-free survival (EFS) of 15 patients treated
with VAIA was 29.4 months. Due to the poor prognosis and outcome for patients with
DSCRT, we have decided to treat the young girl according to guidelines established
by the Cooperative Weichteilsarkom Study (CWS) group in cooperation with the European
pediatric SoftTissue Sarcoma Study Group (EpSSG) protocol scheme treatment plan for
very high risk/metastatic patients, which we use at our department for the treatment
of soft-tissue sarcomas. The CWS guildelines differ from the P6 protocol in number
of cycles (P6 has 7 and CWS 9 cycles), and CWS lacks thecyclophospamide, but it has
introduced the carboplatin and epirubicine to the first-line chemotherapy treatment
(high-dose carboplatin has been used in the P6 protocol as a part of myeloablative
regimen with stem-cell rescue). A possible connection with Ewing sarcoma was observed
after we performed the PCR analysis and the EWS-WT1 fusion gene was revealed. Both
tumors share an EWS fusion protein and may also share molecular mechanisms promoting
proliferation and survival pathways. That explains why the vincristine, ifosfamide,
doxorubicin, etoposide (VIDE) regimen was chosen to treat some cases, for which Wong
et al[19] reported a median time to progression of 14.6 months, and Frank et al[20] reported survival of 19 months. In our report, the patient was treated with the
CWS chemotherapy protocol scheme used for the treatment of rare mesenchymal tumors.
The patient is still alive with EFS of 40 months. Furthermore, it is evident that
adjuvant chemotherapy following gross total tumor resection is necessary to achieve
long-term disease control in DSRCT, as shown in this particular case. Although the
P6 regimen has been the cornerstone of initial DSRCT therapy, with great response
in the majority of cases, it did not improve overall survival, suggesting an aggressive
nature of the disease but also a requisite for another systemic, targeted treatment
modality. There is no unique chemotherapy protocol in the treatment of DSRCT; thus,
the choice is based on clinician experience or patient protocol indulgement. To our
knowledge, our case is the first of all ovarian-involved DSRCT in the English literature
to use CWS chemotherapy protocol ([Table 1]) with remarkable success. It is important to emphasize that one of the main difficulties
in the treatment of DSRCT, due to its adhesive nature, is not achieving optimal surgical
debulking, with more than 10% of tumor left.[1]
[21]
[22]
[23]
[24]
[25]
[26]
[27] We found optimal surgical debulking to be necessary for local disease control and
for establishing better response on adjuvant treatment modalities. Other adjuvant
treatment modalities may include hyperthermic intraperitoneal chemotherapy,[21]
[22] yttrium microsphere,[22] or, as presented in our case, high-dose chemotherapy followed by autologous stem-cell
support. We demonstrated the efficienty of the treatment modality chosen in this case,
which combined primary and secondary surgical debulking, CWS chemotherapy protocol,
and boost radiotherapy joined with high-dose chemotherapy followed by autologous stem
cell support. The young woman from our case is still alive 40 months after the treatment,
with great probability of being the patient with the longest survival period observed,[23] since in her most recent follow-up appointment, in July of the present year, tno
tumor disease was observed and she presented good overall physical and mental condition.
Table 1
Overview of the 16 reported cases of ovarian desmoplastic small round cell tumor
|
Case (n)
|
Reference
|
Age (yrs)
|
Ovarian involvement
|
Treatment modalities
|
Chemotherapy protocol
|
Follow-up
|
|
1
|
Young et al[24]
|
15
|
Unknown laterality
|
PDS + SDS + CHT
|
Multi-agent protocol including carboplatin
|
Succumbed at 4 months
|
|
2
|
Young et al[24]
|
15
|
Bilateral
|
PDS + SDS
|
Not used
|
Unknown
|
|
3
|
Young et al[24]
|
14
|
Right
|
PDS
|
Unknown, ifused
|
Unknown
|
|
4
|
Zaloudek et al[25]
|
22
|
Bilateral
|
PDS + CHT
|
BEP
|
Succumbed at 18 months
|
|
5
|
Slomovitz et al[26]
|
11
|
Right
|
PDS + CHT + ASCS
|
Modified P6 + myeloablative chemotherapy
|
Succumbed at 11 months
|
|
6
|
Parker et al[27]
|
23
|
Right
|
PDS + CHT
|
Platinum and taxol chemotherapy
|
Unknown
|
|
7
|
Elhajj et al[23]
|
27
|
Bilateral
|
PDS + CHT
|
Delayed C/E followed by CAV
|
Succumbed at 42 months
|
|
8
|
Ota et al[1]
|
26
|
Bilateral
|
PDS + CHT + SDS + RT
|
P6
|
Succumbed at 23 months
|
|
9
|
Ota et al[1]
|
19
|
Bilateral
|
PDS + CHT + SDS
|
BEP
|
Succumbed at 11 months
|
|
10
|
Fang et al[14]
|
13
|
Left
|
PDS + CHT + RT
|
BEP
|
Succumbed at 21 months
|
|
11
|
Fang et al[14]
|
23
|
Bilateral
|
PDS + CHT
|
Myeloablative chemotherapy
|
Alive at 7 months
|
|
12
|
Engohan-Aloghe et al[12]
|
21
|
Bilateral
|
PDS + CHT
|
unknown
|
Alive at 7 months
|
|
13
|
Nakayama et al[28]
|
6
|
Bilateral
|
PDS + CHT + RT + CHT
|
P6 + IMC-A12 trial + temsirolimus
|
Succumbed at 28 months
|
|
14
|
Nakayama et al[28]
|
28
|
Right
|
CHT + SDS
|
Neoadjuvant P6 (with the removal of adriamycin) + topotecan after surgery
|
Succumbed at 40 months
|
|
15
|
Nakayama et al[28]
|
17
|
Right
|
PDS + CHT + SDS + RT
|
P6
|
Alive at 11 months
|
|
16
|
Xie and Shen[2]
|
30
|
Right
|
PDS + CHT
|
VAC
|
Alive at 15 months
|
|
17
|
Present case
|
19
|
Bilateral
|
PDS + CHT + SDS + RT + ASCS
|
CWS + Bu-Mel
|
Alive at 40months
|
Abbreviations: ASCS, autologous stem cell support; BEP, bleomycin, etoposide and cisplatin;
Bu-Mel, busulfan, melphalan; C/E, cisplatin/etoposide; CHT, chemotherapy; CWS, etoposide,
idarubicin, and trofosfamide; PDS, primary debulking surgery; RT, radiotherapy; SDS,
secondary debulking surgery; VAC, vincristine, adriamycin, and cyclophosphamide.
Source: Modified from Xie and Shen.[2]
Fig. 1 Microscopic finding of desmoplastic small round cell tumor, hematoxylin and eosin
staining. Source: Engohan-Aloghe et al.[12]
Table 2
Result of immunohistochemical studies—expression of immune labelings in part of reported
ovarian desmoplastic small round cell tumor cases
|
Reference
|
Des
|
AE1/AE3
|
CK7
|
Inh
|
Vim
|
EMA
|
NSE
|
Chr
|
Actin
|
WT1
|
EWS/WT1 (PCR)
|
|
1
|
+ +
|
+ +
|
−
|
N/A
|
N/A
|
+ +
|
N/A
|
−
|
−
|
+
|
NP
|
|
1
|
+ +
|
+ +
|
+
|
N/A
|
N/A
|
+ +
|
N/A
|
−
|
−
|
+
|
P
|
|
2
|
+ + (*)
|
+ +
|
N/A
|
−
|
+ +
|
+ +
|
−
|
N/A
|
N/A
|
N/A
|
N/A
|
|
12
|
+ + (*)
|
−
|
N/A
|
+
|
N/A
|
−
|
+ +
|
−
|
+
|
N/A
|
P
|
|
18
|
+
|
N/A
|
N/A
|
N/A
|
+
|
N/A
|
+
|
N/A
|
+
|
N/A
|
N/A
|
|
19
|
+
|
N/A
|
N/A
|
N/A
|
+
|
+
|
+
|
−
|
−
|
N/A
|
N/A
|
|
19
|
+
|
+ +
|
N/A
|
N/A
|
+ +
|
+ +
|
−
|
−
|
+ +
|
N/A
|
N/A
|
|
19
|
+
|
+ +
|
N/A
|
N/A
|
+
|
+ +
|
+ +
|
−
|
−
|
N/A
|
N/A
|
|
21
|
+
|
+
|
+
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
|
23
|
+
|
N/A
|
N/A
|
N/A
|
N/A
|
+
|
+
|
N/A
|
N/A
|
N/A
|
P
|
|
23
|
+ +
|
+ +
|
+ +
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
NP
|
|
23
|
+ +
|
+ +
|
+ +
|
−
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
−
|
P
|
|
Present case
|
+
|
+ +
|
−
|
+
|
+ +
|
+ +
|
−
|
−
|
−
|
+
|
P
|
Abbreviations: (-), negative; (*), dot-likepattern; (+ +), diffuse positive; (+),
focally positive; AE1/AE3; CK7, cytokeratin markers; Chr, chromogranin; Des, desmin;
EMA, epithelial membrane antigen; EWS/WT1, Ewins sarcoma/Wilms tumor 1; Inh, inhibin;
N/A, information not available or test was not done; NP, not present; NSE, neuron-specificenolase;
P, present; PCR, polymerase chain reaction; Vim, vimentin.
Conclusion
Desmoplastic small round cell tumor is an unusual and remarkably malignant tumor that
affects the young population, with a small number of long-term survivals. An increasing
number of patients has been diagnosed with DSRCT over past decade, and, with improvement
of our overall knowledge, especially about the molecular mechanisms and signal pathways
involved in the tumor pathogenesis, we can expect further advances in treatment. Although
the best therapy for patients with DSRCT has yet to be determined, combining complete
surgical resection, adjuvant chemotherapy, and radiotherapy is required to prolong
survival and to achieve proper quality of life.
