Primary Ewing sarcoma of the kidney: a symptomatic presentation and review of the literature

Abstract

The objective of this review is to discuss the unique nature of primary renal Ewing sarcoma, including incidence, presentation and management. We also report on a common pattern of presentation, consisting of acute flank pain mimicking a renal stone colic, with or without hydronephrosis, and a renal mass discovered during imaging studies of renal Ewing sarcoma. We present our case of renal Ewing sarcoma along with imaging and pathological analysis. We also performed a retrospective review of all cases of renal Ewing sarcoma using PubMed. A total of 48 cases of renal EWS sarcoma have been reported and analyzed in this review. A mean age of 30.4 years was found along with a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease. Primary Ewing sarcoma of the kidney is rare. The diagnosis of primary renal EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, fluorescence in situ hybridization (FISH) and light microscopy.

Introduction

Primary Ewing sarcoma (EWS) of the kidney is a rare tumor in adults. It was first described in 1975 by Seemayer and colleagues, and has since been sporadically documented in the literature [Seemayer et al. 1975; Parham et al. 2001]. Sources of renal EWS include neural cells that invaginate into the kidney during development [Parham et al. 2001; Bing et al. 2009]. Other authors theorize that embryonic neural crest cells migrate into the kidney and undergo tumorigenesis [Seemayer et al. 1975].

Here we review the literature and present a case of a localized primary EWS of the kidney. To the best of the authors’ knowledge, this is the first case of primary renal EWS surgically treated with robotic-assisted partial nephrectomy. We also discuss the identification of a pattern of presentation of this rare entity.

Materials and methods

We performed a PubMed search for primary renal EWS up to June 2012. A total of 104 manuscripts were identified and all reports not pertaining to ‘renal Ewing sarcoma’ were excluded. Thus, 18 manuscripts were included in this study. Review articles on renal EWS were excluded. All articles in which a case was presented and then a meta-analysis was performed were analyzed, and the case presented was included in our study. We excluded the meta-analysis data to ensure that there were no overlaps of data points.

Results

A 33-year-old man presented acutely to the emergency room with a 3-day history of nausea, emesis, and severe left flank pain concerning for renal colic. His medical history was unremarkable. The physical exam revealed left costovertebral angle tenderness. The patient’s urine analysis was unremarkable and his serum white blood cell count was 13,000 ng/dl. The patient did present with a slightly elevated creatinine at 1.4 ng/dl. Computerized tomography (CT) scan showed a 4.4 cm × 4.4 cm × 5.8 cm left lower pole renal mass with moderate hydronephrosis (Figures 1 and 2). Chest CT imaging was negative for metastasis, and urine cytology was negative for malignancy. The patient was admitted and a mercaptoacetyltriglycine renal scan showed a split function of 24% on the left and 76% on the right. On the left side, no excretion was noted after Lasix test, as it was obstructed secondary to compression of the lower pole renal mass. A 5 × 24 French double J stent was placed on the left side to relieve the obstruction and improve severe left flank pain. The patient underwent later an elective left robotic-assisted partial nephrectomy. Surgery was performed without hilar clamping. The total blood loss was 50 ml. Operative time was 100 minutes and robotic console time was 45 minutes. His postoperative course was uneventful other than some minor incisional pain. He was discharged on postoperative day 3. He has no evidence of disease at 12 months after surgery and refuses chemotherapy at this time.

Figure 1.

Parasaggital view demonstrating the left lower pole renal mass with hydronephrosis.

Figure 2.

CT scan showing the 5.8 cm × 4.3 cm left lower pole renal mass.

The renal mass weighed 51.4 g, measured 5.1 cm × 4.8 cm × 3.3 cm and was surrounded by a thin membranous capsule. The tumor was very cellular; the tumor cells were fairly uniform with round to oval nuclei, finely dispersed chromatin, inconspicuous nucleoli and ill-defined scant, pink cytoplasm (Figure 3). They stained strongly positive for CD 99 (Figure 4) and weakly positive for Synaptophysin. Fluorescent in situ hybridization (FISH) studies revealed positivity for EWFR1 (22q12) translocation consistent with extraskeletal EWS.

Figure 3.

Hematoxylin and eosin stain at 400× magnification with round to oval nuclei with finely dispersed chromatin and scant ill-defined cytoplasm.

Figure 4.

The cells at 400× magnification staining positive for CD99.

After having diagnosed this rare case, a total of 48 cases (from 18 manuscripts) of renal EWS were analyzed. A mean age of 30.4 years (4–46 years) was found. A total of 30 patients were male and the remaining 19 were female demonstrating a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease.

There is no clear consensus for the treatment of renal EWS. Of the patients, 37 had surgical resection alone and only one had a robotic partial nephrectomy performed (our case). A total of 31 patients had surgical resection follow by chemotherapy, and one had angio-embolization followed by radical surgery. A total of 13 patients had radiation therapy.

We have discovered an important presentation pattern not described before in the literature: 36 patients (73%) presented with acute flank pain mimicking renal stone colic with or without hydronephrosis, and a renal mass on imaging studies. Another, less common form of presentation is hematuria, found in 15 patients. It is important to remember that the contemporary form of presentation for kidney cancer is the incidental finding on imaging and no associated symptoms, which has not been the typical presentation of primary localized EWS of the kidney. This is why this pattern of presentation, reported for the first time in the literature, is of importance.

Despite aggressive treatment, the prognosis of renal EWS is poor. The most common site of metastasis was the lung, followed by the liver and bone. The median survival for advanced disease is only 5.6 months, and a total of 31 patients had chemotherapy. The chemotherapeutic treatment for renal EWS was extrapolated from the treatment regiments for osseous Ewing sarcoma. It is based on a combination of chemotherapeutic agents, including active drugs such as actinomycin, doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. A total of 14 patients had radiation therapy; of these, 13 had a combination of radiation, surgery and chemotherapy and one patient had radiation therapy and chemotherapy only.

Owing to its scarcity, a unified theory for treatment has not been established. The principal management for renal EWS is surgical resection followed by adjuvant chemotherapy. This management is reinforced by a case reported by Ohgaki and colleagues of a 21-year-old man who underwent surgical resection alone for renal EWS [Ohgaki et al. 2010]. Several months later, the patient had a recurrence in the liver with peritoneal dissemination. After undergoing salvage chemotherapy with partial response, the patient then underwent hepatectomy and resection of metastatic lesions. This patient was reported to have no evidence of disease, 21 months after.

Radiotherapy or chemotherapy alone or combined is not effective for the management of renal EWS. In the case presented by Saxena and colleagues, the patient had disseminated metastatic disease, and was treated with chemotherapy alone. This patient succumbed to the disease and had little to no response from the chemotherapy [Saxena et al. 2006]. Successful use of radiation was documented in patients who had residual disease in the regional lymph nodes [Thyavihally et al. 2008]. We believe that salvage radiotherapy in this setting is useful but should be avoided as first-line treatment.

Some authors diagnose renal EWS based on the pathological finding of small round blue cells with Homer–Wright rosettes in the renal specimen. In the absence of the EWS/FLI1 gene mutation, this diagnosis is a stretch as there is an overlap with small cell tumors of the kidney. Based on the literature, it is imperative that the diagnosis of renal EWS includes analysis for the gene mutation. We have excluded the report by Parham and colleagues, who reported 79 of 146 cases of primary malignant neuroepithelial tumors, and were considered to be renal EWS [Parham et al. 2001]. These data were excluded since only 14 cases had follow up, and it was unclear which cases were actually renal EWS.

Comments

EWS was first described by Stout in 1918. EWS was recognized by Stout to contain small round blue cells arranging into rosettes [Seemayer et al. 1975; Saxena et al. 2006; Stout, 1918]. Later, John Ewing further characterized these tumors describing them in the diaphysis of long bones [Stout, 1918]. These tumors are neural crest cells in origin belonging to a family of tumors called primitive neuroectoderm tumors (PNETs). The term peripheral primitive neuroectoderm tumors (pPNETs) was coined to encompass peripherally located tumors. pPNETs are part of the EWS family of tumors with EWS differing on the fact that it lacks neuroectodermal features [Seemayer et al. 1975; Ohgaki et al. 2010].

Table 1.

Complete data set.

	Study	Case	Age	Sex	Symptoms	Pathology	Treatment	Outcome
1	Angel et al. [2010]	1	31	M	Flank pain, hematuria, -metastasis at Dx	T(11:22) Trisomy 7, + CD 99, +NSE, +WT-1, - CD 45, Prostein s-100, EMA, CK7	Surgery plus chemotherapy: vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide	NED: 1 year
2	Saxena et al. [2006]	1	26	F	Flank pain, nausea, SOB, renal mass, weight loss	T(11:22) (q24:12) t(1;1)(p33;q25), i(3)(p10), +8, +8, -15, +18, +18, and +19, + CD 99, NSE, FLI-1, - S100, -WT1	Chemotherapy: vincristine, adriamycin, cyclophosphamide, and actinomycin	DoD 4-5 months
3	Ekram et al. [2008]	1	46	F	Flank pain,	T(11:22) (q22;q24)	Chemotherapy then surgical resection followed by a second round of chemotherapy: vincristine, adriamycin, cyclophosphamide, ifosfamide, and etoposide	NED: 6 months
4	Moustafellos et al. [2007]	1	32	M	Flank pain,	t(21;22) (q22;q12)	Surgery then chemotherapy: doxorubicin, cyclophosphamide, vincristine, and dactinomycin	NED: 2.5 years
5	Ohgaki et al. [2010]	1	21	M	Flank pain	t(11;22) (q24;q12), + CD99, +NSE, + 6vimentin, -C7K7, - CK20, thrombomodulin, and chromogranin A.	Surgery: salvage chemotherapy then surgical re-resection: doxorubicin, etoposide, ifosfamide, and cyclophosphamide	NED: 21 months
6	Kairouani et al. [2012]	1	40	F	Back pain	t (11; 22) (q24; q12), +CD99, + vimentin, S-100	Surgery plus chemotherapy: vincristine, adriamycin, and cyclophosphamide	NED: 5 months
7	Castro and Parwani [2012]	1 2	32 21	F F	Flank pain SOB	t (11; 22) (q24; q12) / t (11; 22) (q24; q12) + CD56, +Cytokeratine AE1/3, + Cam 5.2, +, bcl2, and + CD99 + CD99, +CD56, + synapthophysin, + PGP9.5, + BCL2, and + vimentin.	Surgery plus chemotherapy	NED : 1 year NED: 1 year
8	Fergany et al. [2009]	1	31	M	Hematuria	t (11; 22) (q24; q12), +CD 99	Surgery then chemotherapy: vincristine, doxorubicin, cyclophosphamide	NED: 2 years
9	Kang et al. [2007]	1	34	M	Hematuria, left flank pain, lower back pain	t (11; 22) (q24; q12), +CD 99, + vimentin, +NSE	Radiation then surgery	No mention of survival
10	Funahashi et al. [2009]	1	40	F	Hematuria, flank pain	t (11; 22) (q24; q12), + CD 99, + vimentin	Surgery then chemotherapy	NED: 19 months
11	Jimenez et al. [2002]	11	69,33, 41,32, 25,11, 31,29, 21,27, 50	6 M 5 F	Abdominal pain (6 cases), hematuria (3 cases), a palpable mass (3 cases), and night sweats	t (11; 22) (q24; q12), +CD 99, + FLI-1 (5/8)	Chemotherapy, radiation	8 /11 have follow up DoD: 5; Mean: 17.6 months NED: 3; 4, 6, 16 months
12	Maeda et al. [2008]	1	6	F	Abdominal pain, palpable mass	+EWS-FLI-1, +CD 99, + vimentin	Surgery then chemotherapy: vincristine, cyclophosphamide, dactinomycin, doxorubicin	NED: 90 months
13	Parada et al. [2007]	1	19	M	Left flank pain, fevers	+vimentin, + NSE, + CD99, T(11:22) (q22;q24)	Surgery then chemotherapy: vincristine, doxorubicin, cyclophosphamide, isofosphamide, and etoposide	No mention of survival
14	Rodriguez-Galindo et al. [1997]	4	18, 20, 4, 14	M 3 F 1	Abdominal pain (3 patients), hematuria (1), fever (1), bone pain (1)	+NSE, +Vimentin, +CD 99, T(11:22) (q22;q24) +NSE, +CD 99, Homer-Wright rosettes +NSE, +CD 99, +keratin,		No mention of survival
15	Thyavihally et al. [2008]	16	27 years median age	M 10 F 6	Abdominal pain (11 patents), abdominal mass (6), hematuria (5)	+CD 99, - NSE, - vimentin, + T(11:22) (q22;q24) 9( cases)	Surgery plus chemotherapy: vincristine, dactinomycin, adriamycin, cyclophosphamide, ifosfamide, and etoposide +/- radiotherapy (9 had radiation)	NED 4 patients Follow up 4-92 months
16	Mellis et al. [2011]	1	33	M	Intermittent hematuria, intermittent flank pain	+CD 99, + CD 117, T(11:22) (q22;q24)	Angio-embolization then surgery then chemotherapy: Adriamycin, methotrexate, and cyclophosphamide	No mention of survival
17	Ellinger et al. [2006]	1 2	39 28	M M	Hematuria, testicle pain. Flank pain and leg pain	+ CD99 and vimentin S-FLI1 translocation (7/5-type II) +CD56,+NSE, + CD99; No EWS-FLI1 translocation.	Surgery, then chemotherapy: etoposide, vincristine, adriamycin, and ifosfamide later radiation Surgery, then chemotherapy: etoposide, vincristine, adriamycin, and ifosfamide; later radiation	6 months NED, 15 months
18	Cabrera-Meirás	1	36	M	Flank pain, abdominal mass	+CD 99, +NSE, + vimentin	Surgery, then chemotherapy: vincristine, adriamycin and cyclophosphamide, ifosfamide, and VP16; later radiotherapy	NED 22 months
	Present case	1	33	M	Flank pain, nausea, hydronephrosis	+ CD 99, + CD 56, + synaptophysin, +EWS-FLI-1	Robotic surgical resection	NED 6 months
	Totals	49	30.4	M 30 F 19	34 presented with flank pain		37 had surgical resection 31 had surgical resection with chemotherapy 1 case of robotic surgery alone 13 had radiation 1 had angio-embolization then surgery	26.14 months mean follow

M, Male; F, Female; SOB, Shortness of breath; NED, no evidence of recurrence of disease; Dod, died of disease.

Approximately, 85–90% of EWS can be defined by a DNA translocation t(11;22)(q24;q12) [Ohgaki et al. 2010; Saxena et al. 2006]. The resultant gene fusion creates a functional oncogene. Under microscopy EWS forms spherical grouping of dark tumor cells around a central area that contains neurofibrils called Homer–Wright rosettes [Bing et al. 2009]. Diagnosis of EWS may be clouded by the fact that renal small cell carcinomas may display neural features similar to that of EWS. Histologically EWS and small cell carcinomas can both form Homer–Wright rosettes. The gene fusion EWS/FLI1 can be used to distinguish between these two entities [Bing et al. 2009]. The diagnosis of EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, FISH, and light microscopy [Seemayer et al. 1975; Saxena et al. 2006; Stout, 1918].

Renal EWS is an extremely rare entity, which has been documented throughout the literature as isolated case reports. It has been reported that most patients presenting with primary EWS of the kidney present at a median age of 28 years. It carries a slight preponderance in men, and a worse prognosis if metastases are present at the time of diagnosis [Bing et al. 2009].

Our review of the literature suggests that upfront surgical resection in combination with chemotherapy is necessary, as recurrence of renal EWS occurs and disseminates quickly. Chemotherapeutic regimens similar to that used for osseous EWS of the bone are sufficient. Radiotherapy use in the literature has been sporadic and not standardized.

We do not recommend renal biopsy and feel that it would only delay surgical resection if the tumor is localized, while some argue that biopsy is needed as the surgical specimen would most likely be fixed in formalin, making it unusable for chromosomal studies [Kang et al. 2007]. This will only delay life saving treatments. On the other hand, if the case presents as locally advanced or metastatic disease, we think that there is a definitive role for biopsy, due to the poor survival that has been reported in patients having these characteristics. In these case scenarios, a biopsy could define which treatment combination option to select first (surgery, or chemotherapy, followed by radiation therapy if necessary) based on the clinical scenario and staging.

Conclusions

In conclusion, treatment strategies for renal EWS include surgery, chemotherapy, and radiotherapy. Based on our case and review of the literature, we recommend upfront surgical resection with chemotherapy. Current standard chemotherapy includes doxorubicin, vincristine, and cyclophosphamide alternated with ifosfamide and etoposide. Postoperative radiotherapy may be added when locoregional lymph nodes are enlarged. Patients with localized EWS have shown excellent survival. The prognosis of patients with metastases is poor, with an overall survival rate of 5.6 months. In contrast to how most of the renal cell carcinomas present today, incidentally primary localized renal EWS presents with a common pattern of acute flank pain, with or without hydronephrosis, and localized renal mass.