Giant prostatic hypertrophy (GPH) is a poorly explored phenomenon, without large case series or definitive histological studies to define this as more than a rare subtype of BPH where the gland exceeds 200 g in mass.
GPH commonly presents with obstructive lower urinary tract symptoms and hæmaturia. Owing to the size of the gland, definitive treatment usually requires suprapubic prostatectomy [2][4], which our patient was reluctant to undergo. As a result, we were required to manage his GPH symptomatically with a combination of pharmacotherapy, repeated de-bulking TURPs for biopsy and therapeutic purposes, and finally selective prostatic artery embolisation for his recurrent hæmaturia, the first such case in the literature.
Whilst we understand that standard operative management of BPH would have had us definitively resect our patient’s prostate at the operation in July 2002, this was limited by a combination of a highly vascular gland, prolonged operating time and the choice to use spinal anæsthesia. Furthermore, prior to the development of giant hypertrophy, the patient’s symptoms were predominantly irritative rather than obstructive, as confirmed by the good pre-operative flow result (Q
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of 14.4mL/sec) (Figure 4). We presented the patient with the opportunity for an early repeat TURP to complete the initial procedure which he declined owing to subjective symptomatic improvement.
By the time the patient required further transurethral intervention, the combination of nephrogenic adenoma and giant hypertrophy further complicated the procedure and ruled out standard management techniques. Of note, even at this stage the patient’s symptoms defied the common presentation for this condition and were predominantly irritative with hæmaturia, rather than obstructive.
Nephrogenic adenoma
Nephrogenic adenomas are believed to represent shed renal tubular cells implanting into areas of damaged urothelial integrity [7]. Predisposing factors are known to include chronic inflammation, infection, calculi and urological surgery including TURP and renal transplantation [9].
Most features of our patient’s history are typical for recurrent nephrogenic adenoma. He was a middle-aged male with an initial urothelial insult in the form of a transurethral resection of the prostate in July 2002. The interval between this initial transurethral resection and the diagnosis of nephrogenic adenoma was 35 months, and his two subsequent recurrence-free intervals following TURP de-bulking were 14 months each.
Our patient’s PSA has remained between 1.7ng/mL and 2.4 ng/mL whilst on finasteride, with a brief rise to 6.1 ng/mL in late 2007 when this was temporarily halted (Figure 4). This reflects the benign nature of giant prostatic hypertrophy and the low to zero PSA expression in nephrogenic adenomas.
As in our case, macroscopic features consistent with nephrogenic adenoma included papillary and/or ulcerated lesions of the urinary epithelium which may superficially resemble prostatic adenocarcinoma. The microscopic features of resemble remnants of embryonal renal tissue, with small tubules located in the lamina propria and occasional papillary foci or thyroidisation. The lining cells are often cuboidal without atypia or mitoses. Nephrogenic adenomas also commonly express PAX2, a key renal embryonal transcription factor, which has come to be recognised as a specific and sensitive diagnostic marker for these lesions [10].
These histological features were present in our patient, but unfortunately our unit did not stain for PAX2 at the time, which would have served as an interesting but ultimately unnecessary additional piece of information in this case. For a thorough review of the histology of nephrogenic adenoma, see Kunju (2010) [6].
The largest case series of nephrogenic adenomas isolated to the prostate gland itself include 26 patients from The Johns Hopkins Hospital [11], and 8 cases from The University of Texas MD anderson Cancer Center [12]. Whilst the histological features described in these cases match those found in our patient, there have been no prior reports in the literature of nephrogenic adenomas occurring in giant prostatic hypertrophy, nor their treatment by selective prostatic artery embolisation.
Physiological role of PAX2
The nine PAX (paired homeobox) genes are a series of transcription factors that are critical in orchestrating normal embryogenesis in animal species. Each one appears to be expressed in a limited and specific range of developing tissues, with PAX2 apparently responsible for eye, ear, central nervous system and urogenital tract development [13].
Expression of PAX2 appears to be temporally and spatially modulated in the embryonic kidney by the expression of the Wilms’ Tumour protein (WT-1) [14]. These two factors coordinate to regulate the branching and survival of the ureteric bud and the differentiation of mesenchymal cells to epithelial cells [15] before PAX2 expression is then totally suppressed outside the collecting system. Over-expression of PAX2 beyond embryogenesis only appears to be seen in pathological conditions, including renal cell carcinomas, polycystic kidney disease and Wilms’ tumour.
However, and perhaps of greatest interest in our particular case, in vitro studies have demonstrated that PAX2 appears to be normally re-expressed in adult tubular cells following ischæmia/reperfusion injury [13].
This could well explain why a transcription factor whose expression beyond the renal collecting system normally terminates during embryogenesis appears to be re-expressed in nephrogenic adenomas and lead to such characteristic histological features - the shed tubular cells are attempting to regenerate normal tubular tissues at their site of implantation.
Certainly more work needs to be done to explore the specific growth factor environment which allows nephrogenic adenomas to take root and to reoccur despite multiple resections, but our particular case does suggest a possible link between the nesting of nephrogenic adenoma precursor cells in our patient’s TURP-traumatised prostate and the subsequent development of his giant prostatic hypertrophy.
Management of refractory prostatic hæmaturia
Traditional management options for BPH-related LUTS include pharmacotherapy (α-blockade and 5 α-reductase inhibition) and transurethral resection. Our patient was managed quite effectively on continuous 5 α-reductase blockade (finasteride) and 2 interim de-bulking TURPs between September 2006 and March 2009, after which his hæmaturia became refractory to pharmacotherapy.
Cases of TURP and/or fulguration-refractory gross hæmaturia as experienced by our patient are more difficult to manage, with only limited options available. Intravesical chemo-cautery with alum, formalin or silver nitrate have been described in the literature, along with hydrostatic pressure or balloon tamponade [16]. Depending on the particular therapy selected, adverse effects can include allergic reactions, aluminium toxicity, bladder fibrosis and urethral stricturing caused by the instillation agent, to renal impairment and bladder rupture. However, none of these reports specifically addressed giant prostatic hypertrophy.
Selective prostatic artery embolisation
The use of selective internal iliac arterial embolisation is in widespread use for the treatment of symptomatic uterine leiomyomata. It has also been described for the management of intractable hæmorrhage secondary to advanced pelvic malignancies, with good long-term outcomes [17].
There are however few studies exclusively reporting on the management of refractory gross hæmorrhage of prostatic origin by selective prostatic artery embolisation (SPAE). The largest case series to date was published in 2008 [18], involving 8 patients in total (6 with post-radiotherapy prostatic adenocarcinoma, 2 with BPH) and ascribing a 100% immediate cessation rate to SPAE following failure of conventional therapies. These benefits extended out to a median of 20 months follow-up in 6 of the 8 patients (1.5–86.3 month range).
The series reported by Liguori et al. in 2010 did include 15 patients with prostatic adenocarcinoma, but did not break down their outcomes according to primary pathology. They did achieve an 83% immediate control rate following selective internal iliac artery embolisation across all 44 patients in their study, but at a mean follow-up interval of 10.5 months (1–97 month range), permanent control was only achieved in 19 (43%).
There are other single case reports in the English-language literature specifically describing SPAE for prostatic hæmorrhage refractory to other therapies, with generally high levels of initial success, but listing them all would not be useful here.
SPAE has also been employed for the primary management of BPH without hæmaturia. A 2011 report by Pisco et al. described 15 patients with symptomatic BPH treated with SPAE who demonstrated moderate improvements in IPSS and Q
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that were sustained at a mean of 7.9 months follow-up (3–12 month range). In this study however, there was a clinical failure rate of 28.6% (4 patients) and one major complication of bladder wall ischaemia [19].
Whereas all of these studies are limited by their short follow-up periods, our case is the first to demonstrate the durable long-term results of SPAE in the treatment of refractory hæmaturia and LUTS secondary to GPH and nephrogenic adenoma. Our patient had recurrent rapid prostatic re-growth over the 4 years from 2005–2009, and despite 2 TURPs for debulking and symptom control, his hæmaturia eventually became refractory to pharmacotherapy with 5 α-reductase inhibitors. 36 months following embolisation, we have found no further increase in his prostatic volume on serial MRIs (but also no reduction), no further episodes of hæmaturia and no recurrence of his irritative LUTS or decline in his Q
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.