Appraisal of the role of radical prostatectomy for rhabdomyosarcoma in children: oncological and urological outcome

Abstract

The latest multimodal protocols for treatment of bladder/prostate rhabdomyosarcoma (RMS) have shifted the goal of treatment from patient survival to bladder preservation. Consistently, partial resections, such as radical prostatectomy (RP), are favoured when surgery is deemed necessary. We sought to determine the oncological risks – that is, failure to achieve disease control – and the possible benefits in terms of urinary continence associated with RP in RMS patients based on a review of our experience and the data reported in the literature. We identified 18 children undergoing RP for RMS (3 at our institution, 15 in the literature). In five cases, a pubectomy/symphisiotomy was performed to improve surgical exposure. Two cases experienced local relapse, suggesting that this approach can be viable to achieve local control. No clear-cut indications could be extrapolated from the literature, however, to determine how to select the patients most suitable for this approach. We offered this treatment to patients with evidence of disease localized only within the prostate on radiological and endoscopic re-assessment after chemo-/radio-therapy. Eight of the 18 cases (44%) eventually required lower urinary tract reconstruction, suggesting that often this approach does not allow for the preservation of urinary continence with volitional voiding. Finally, data about additional interesting outcomes such as erectile function and fertility in RMS patients undergoing RP are extremely sparse.

Introduction

The latest multimodal protocols for treatment of bladder/prostate rhabdomyosarcoma (RMS) have shifted the goal of treatment from patient survival to bladder preservation.^1–4 Consistently, radiotherapy is favoured over surgery to achieve local control after chemotherapy, and, in the case of persistent disease, partial resections are favoured over cystoprostatectomy.^5,6 Among partial resections, radical prostatectomy (RP) has occasionally been reported in patients with RMS.^7,8 However, concerns exist that the procedure might not allow achievement of the goal of attaining local control of the disease while preserving urinary continence.⁹ In the attempt to improve results, a trans-pubic approach has been proposed as an adjunct to widen the surgical field, and possibly ease tumour dissection and subsequent lower urinary tract reconstruction.^10–12

To gauge the oncological risks associated with RP and the possible benefits, in terms of urinary continence, we reviewed our experience and the data reported in the literature on patients undergoing RP for bladder/prostate RMS.

Material and methods

Between March 1986 and January 2015, 21 patients with histological diagnosis of bladder/prostate RMS were treated at our centre and registered from our institution into three consecutive protocols coordinated by the ‘Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) Soft Tissue Sarcoma Committee (STSC)’, denominated RMS88, RMS96 and RMS2005.

For this study, we selected patients undergoing RP in the context of the multimodal treatment strategy outlined below.

Diagnosis was based on biopsy (histological diagnoses were centrally reviewed) and was followed by intensive chemotherapy and radiotherapy. De-bulking surgery was not recommended at diagnosis. Surgery was instead considered in the case of disease persistence at follow-up imaging and on endoscopic biopsy after chemotherapy and radiotherapy, but in very young children (<3 years of age) where radiotherapy was avoided. All treatment protocols were approved by the local ethical committee and all patients/caregivers gave their consent for treatment of data for research purposes. Data were gathered by a data manager and subsequent data extraction was anonymized.

In addition, a post hoc literature review was conducted, employing the terms ‘genitourinary rhabdomyosarcoma’ and ‘bladder-prostate rhabdomyosarcoma’. We considered articles on RP for paediatric bladder/prostate RMS.

The study focused on the following outcomes: overall survival, development of local recurrences or metastases during postoperative follow up, urinary continence (defined as absence of incontinence and preservation of volitional voiding, postoperatively) and long-term erectile function and fertility.

Given the small numbers, only descriptive statistics were used.

Results

Three of the 21 patients underwent RP; their history is detailed in Table 1. Preoperatively, all patients had evidence of disease persistence on imaging, whereas endoscopic biopsies were negative for residual disease. A retro-pubic approach was performed in all but one case, who underwent a trans-pubic approach with pubectomy due to the suspicion of periosteal infiltration. The dissection of the prostate was always performed in an antegrade fashion (descending towards the apex) and using a nerve-spearing technique. The patient undergoing the pubectomy was also the only one for whom intraoperative frozen sections were positive for urethral involvement. Therefore, this patient underwent urethrectomy, bladder-neck closure and placement of a catheterizable conduit (appendicovesicostomy).

Table 1.

Characteristics of patients undergoing radical prostatectomy at our institution.

	Patient 1	Patient 2	Patient 3
Age at diagnosis (year)	8.3	10.8	0.5
Tumour histology	Embryonal RMS	Embryonal RMS	Botryoid RMS
Tumour location	Prostate/posterior bladder wall	Prostate	Prostate
cT stage	T2b	T2b	T2a
RMS protocol	RMS 88	RMS 88	RMS 2005
Chemotherapy	Cisplatin/etoposide 2 cycles VAIA 11 cycles	VAIA 3 cycles	IVA 4 cycles CD 3 cycles TVD 2 cycles IVE 2 cycles
Tumour response at 9 weeks	Partial response (volumetric reduction ⩾2/3)	Partial response (volumetric reduction ⩾2/3)	Stable disease
Preoperative radiotherapy	No	No	No
Tumour size before surgery (cm)	3.6 × 3.1 × 3.8	8.5 × 5.9 × 4.4	2.5 × 1.8
Approach	Retro-pubic	Trans-pubic (wedge resection of pubic symphysis for suspect periosteal infiltration)	Retro-pubic
Intraoperative histology	Negative	Involvement of posterior urethra. Lymph nodes negative	Negative
Surgical resection and lower urinary tract reconstruction	Radical prostatectomy and bladder–urethral anastomosis	Urethral resection, bladder-neck closed, placement of catheterizable conduit	Radical prostatectomy and bladder–urethral anastomosis
Final histology	Wide rhabdomyoblastic differentiation areas	Rhabdomyoblastic and myxoid differentiation	Well-differentiated RMS
Surgical margins	Positive (urethra)	Positive (urethra)	Positive (prostatic apex, where residual viable tumour was identified)
Further treatments	Cobalt radiation treatment (55 Gy, 28 Fx) delivered to the prostatic bed. CHT: CAV 7 cycles	EBRT (54 Gy) delivered to the prostatic bed. CHT: IVA 9 cycles	EBRT (41.4 Gy, 23 Fx) delivered to the prostatic bed
Follow up after surgery (year)	25.6	2.4	7.6
Oncological outcome	No recurrence	10 months after radiotherapy developed metastasis (bone, lungs) and local relapse (pelvic mass). Underwent further chemotherapy, but died 10 months after relapse	Acute myeloid leukaemia 3 years after radical prostatectomy. Currently in complete remission after chemotherapy
Functional outcome	8 years after radical prostatectomy required bladder augmentation and placement of a catheterizable conduit for stenosis of the bladder–urethral anastomosis and reduced bladder capacity. Now on CIC without evidence of incontinence	On CIC via catheterizable conduit without evidence of incontinence until death	Bladder capacity adequate for age. Able to void volitionally to completion. Diurnal urinary incontinence

CAV, cyclophosphamide, adriamycin, vincristine; CD, carboplatin, doxorubicin; CIC, clean intermittent catheterization; EBRT, external beam radiation therapy; Fx, fraction; IVA, ifosfamide, vincristine, actinomycin-D; IVE, ifosfamide, vincristine, epirubicin; RMS, rhabdomyosarcoma; TVD, topotecan, vincristine, doxorubicin; VAIA, vincristine, adriamycin, ifosfamide, actinomycin-D.

Pathology of the excised specimen revealed persistence of viable RMS tissue in all three cases. Pathology of the pubic symphysis was negative in the patient undergoing pubectomy. In all patients, there was evidence of disease reaching the excision margin distally towards the urethra. Further radiotherapy was administered to all cases and further chemotherapy to two.

Two patients are alive and disease-free after a follow up from RP of 25 and 7 years, respectively. One of the two developed an acute myeloid leukaemia 3 years after RP, but is currently in complete remission after additional treatment. The third patient died 2.4 years after RP, with evidence of local relapse and distant metastases.

All patients underwent periodical bladder–renal ultrasounds and at least one videourodynamic study at least 6 months after surgery to assess urinary function. The patient undergoing urethrectomy and bladder-neck closure performed CIC via the catheterizable conduit without evidence of urinary incontinence until he died. Another patient developed a stenosis of the bladder–urethral anastomosis associated with reduced bladder capacity, requiring augmentation cystoplasty and placement of a catheterizable conduit. Currently, he is on CIC without evidence of urinary incontinence. The remainder has a normal bladder capacity for age and is able to void volitionally to completion, but suffers from daytime urgency incontinence.

Erections were reported in both of the alive patients. One has azoospermia and receives testosterone replacement, whereas testicular function has not yet been assessed in the other, who is still pre-pubertal.

Overall eight studies were identified in the literature, including 15 cases undergoing RP (Table 2).^7,8,10–15 None of the studies detailed the indications for RP. A trans-pubic approach was used in four cases, a posterior sagittal approach in one, and a standard retro-pubic approach in the others. RP was combined with partial cystectomy in four cases, whereas none required urethrectomy.

Table 2.

Studies reporting results in patients with bladder/prostate rhabdomyosarcoma undergoing radical prostatectomy.

Reference	Age at diagnosis (years)	Initial treatment	Surgery (approach and type of resection)	Urinary reconstruction	Follow up (years)	Oncologic outcome	Urological outcome
Loughlin and colleagues7	1	CHT + RT	Retro-pubic approach RP	Not reported	10	Alive	Not reported
	3	CHT + RT	Retro-pubic approach RP	Not reported	3	Alive	Not reported
	2	CHT	Retro-pubic approach RP + partial cystectomy	Not reported	0.5	Died of local relapse and metastatic disease	Not reported
Duel and colleagues 8	4	CHT + RT	Retro-pubic approach RP	Bladder augmentation	9	Alive	Multiple augmentation cystoplasties + bladder-neck revision
	2	CHT + RT	Retro-pubic approach RP + partial cystectomy	Not reported	3	Died of metastatic disease	Not reported
	10	CHT + RT	Retro-pubic approach RP + partial cystectomy	Bladder augmentation	4	Alive	Multiple augmentation cystoplasties; bladder-neck revision; continent voids volitionally every 4 h
	1.2	CHT + RT	Retro-pubic approach RP	No further reconstruction	Not reported	Alive	Continent without further surgery
	4	CHT + RT	Retro-pubic approach RP	No further reconstruction	Not reported	Alive	Continent without further surgery
Adam and colleagues10	NR	NR	Trans-pubic RP + partial cystectomy	Vesico-urethral anastomosis	2.5	Died of metastatic disease, no local recurrence	Not reported
Nakada and colleagues13	3	CHT	Posterior sagittal approach RP	None	2	Alive	Continent
Kumar and colleagues11	3	CHT	Trans-pubic RP	Vesico-urethral anastomosis	Not reported	Alive	Continent; nocturnal erections
Pieretti and colleagues 12	2	CHT	Trans-pubic RP	Vesico-urethral anastomosis	6	Alive	Awaiting continence surgery
	1.5	CHT	Trans-pubic RP	Vesico-urethral anastomosis	2	Alive	Awaiting continence surgery
Heinzelmann and colleagues14	1.9	CHT	Retro-pubic approach RP + partial cystectomy	Mitrofanoff conduit	0.9	Alive	CIC via Mitrofanoff channel 5–8 times/day
Hishiki and colleagues15	0.9	CHT + RT	Retro-pubic approach RP	Cutaneous vesicostomy	9.7	Alive	Incontinent; scheduled for bladder augmentation
Present series	8.3	CHT	Retro-pubic approach	Augmentation cystoplasty and catheterizable conduit	25	Alive	On CIC without evidence of urinary incontinence
	0.5	CHT	Retro-pubic approach	Vesico-urethral anastomosis	7	Alive	Continent with daytime urgency. nocturnal erections
	10.8	CHT	Trans-pubic approach	Urethrectomy, bladder-neck closure and catheterizable conduit	2.4	Died of local relapse and metastatic disease	On CIC without evidence of urinary incontinence until death

CHT, chemotherapy; CIC, clean intermittent catheterization; RP, radical prostatectomy; RT, radiotherapy.

Three patients died during follow up, of which one had evidence of local recurrence. No data are available regarding objective assessment of urinary function by validated questionnaires or urodynamic. Of the 15 patients, studies clearly stated that the patient was continent at follow up in four, seven required continence surgery or were awaiting lower urinary tract reconstruction; the continence status was not detailed in the remaining four cases. Erectile function was documented in one case only, in which the patient had nocturnal erections. In no case was information about fertility provided.

Discussion

RP appeared to be effective in achieving local control in adjunct to chemo- and radiotherapy; however, a significant proportion of patients failed to maintain urinary continence with volitional urethral voiding after surgery.

RP is effective to achieve local control as confirmed by the fact that only 2 of the 18 cases we identified undergoing this procedure experienced local recurrence. This compares favourably with our experience and the data reported in the literature with more mutilating resections, such as cytsoprostatectomy.^1–4,16 Moreover, our case experiencing local relapse had a locally advanced disease at surgery already, as shown by positive intraoperative biopsies. This brings us to the key problem of the criteria for the selection of cases most suitable for RP. The literature does not help us to define objective selection criteria. We have offered this treatment to patients with evidence of persistent contrast enhancement limited within the prostate on radiological re-assessment after chemo- and radiotherapy. Moreover, all patients underwent endoscopic biopsies that were negative for residual macroscopic disease protruding into the urinary tract. Consistently with preoperative imaging, final pathology confirmed the presence of viable tumour within the prostate in all patients. Instead, positive margins were observed in all cases, although two also had negative intraoperative biopsies, which confirms the well-known unreliability of preoperative work-up and intraoperative histology in determining distal extension of RMS. The clinical significance of such microscopic remnants, however, remains unclear.¹⁶ Indeed, additional chemo- and radiotherapy can prevent recurrence from such remnants. More recently, adjuvant brachytherapy was suggested to be even more effective in achieving this goal, making it possible to limit resections to the removal of macroscopic disease only – namely, performing partial prostatectomies.^17,18

Data regarding functional outcomes after RP are indeed scarce. No study reported objective assessments of urinary function using validated questionnaires or urodynamics. The risk of anastomotic stricture, urinary incontinence and reduced bladder capacity, however, is not negligible. At least 8 of the 18 (44%) patients we identified required some form of lower urinary tract reconstruction to treat residual incontinence after RP. In this respect, one could wonder whether the efforts to preserve the bladder are worthwhile compared to cystoprostatectomy and continent urinary diversion.^3,19 No comparative data can be extrapolated about patients undergoing a retro-pubic versus trans-pubic approach. Moreover, it should be noted that other variables might influence the final achievement of urinary continence. Administration of radiotherapy can alter the healing process of the bladder–urethral anastomosis, thereby increasing the risk of anastomotic stricture and jeopardizing urinary continence.²⁰ Consistently, use of the latest irradiation techniques and of brachytherapy might also possibly improve continence results.^{1,12,14,17,18}

We performed a trans-pubic approach (pubectomy) in one patient only, and this was for the suspicion of bone involvement rather than to improve surgical exposure. The literature includes only four additional cases in which a trans-pubic approach was used.^10–12 Although numbers are too small to label the procedure as safe, no orthopaedic complications were reported in these four cases.^10–12 Authors claim that the trans-pubic approach allowed for an easier and safer tumour excision and subsequent bladder–urethral anastomosis, and recommended this approach particularly in the case of large tumours. The cut-off to define a tumour as large, however, remains quite subjective and the influence of this approach on final oncological outcome is a moot point.

Data on erectile function and fertility after RP are even more sparse and inconsistent. Both of our alive patients reported erections, and erections were documented in one of the cases reported in the literature. Reports suggest that erectile function can be preserved after multimodal treatment of bladder/prostate RMS.²¹ We could not find any information regarding fertility.

This is a retrospective, single-centre descriptive case series combined with a review of the literature. The inherent limitations of this type of study impair our ability to establish any definitive statistical findings. Therefore, the study should be considered only as hypothesis-generating.

Conclusion

In the context on a multimodal treatment of bladder–prostate RMS, RP can be a bladder-sparing surgery able to attain local control in selected patients with disease confined within the prostate. The criteria to select suitable patients, however, are not well defined; nor is the possible role of a trans-pubic approach, which might improve surgical exposure with limited orthopaedic morbidity, clear. Reportedly, RP does not allow for the preservation of urinary continence with volitional voiding in more than 40% of cases. Brachytherapy might be a useful adjunct to possibly improve local control of the disease and long-term urinary continence. Erectile function can be preserved, but data are extremely scarce, and more so for fertility.