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Successful Treatment of Idiopathic Detrusor Overactivity with Botulinum-A Toxin in a patient with Adult Alpha Acid-Glucosidase deficiency (Pompe’s Disease)

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This report is the first in the literature to describe successful treatment of detrusor overactivity in any glycogen storage disorder. 

Authors: O’Kelly F., Thomas A.Z., Gardner S., Joyce D., Lee P., Mulvin D.W., Lennon G.M.

Dept. of Urological Surgery, St. Vincent’s University Hospital, Dublin 4, Rep. of Ireland

Corresponding Author: Fardod O’Kelly,  Dept. of Urological Surgery, St. Vincent’s University Hospital, Dublin 4, Rep. of Ireland.   Email: [email protected]

 

Abstract
This report is the first in the literature to describe successful treatment of detrusor overactivity in any glycogen storage disorder, and involves a case of established adult Pompe’s Disease who presented to our institution with a four-year history of progressive urinary storage symptoms suggestive of an overactive bladder. Although the degradation of intracellular glycogen accumulation is not addressed with intravesical Botulinum toxin-A injection, it may nonetheless provide an inexpensive, readily available, acceptable treatment in those with adult-onset Pompe’s disease with moderate to severe lower urinary tract symptoms who are refractory, or intolerant to antimuscarinic therapy, or in those, for whom enzyme replacement therapy is unavailable.

 

Introduction
Pompe’s disease [acid maltase deficiency (OMIM # 232300)] is a rare glycogen storage disorder affecting approximately 1/40,000 live births. It occurs as a result of a deficiency of alpha acid-glucosidase (GAA), which normally functions by degrading lysosomal glycogen stores, and was first reported in 1932 in a girl of 7 months, who had succumbed to extreme hypertrophy of the heart [1]. A deficiency of this enzyme leads to progressive, excessive accumulation of intracellular glycogen stores, especially in cardiac, smooth and skeletal muscle and the kidneys, and leads to death from cardiac or respiratory failure. Two forms of the disease exist: infantile and juvenile/adult. Children typically present with severe hypotonia and cardiomegaly, and classically expire from cardiorespiratory failure within their first year. The manifestations of the adult form are dependent on residual, enzymatic function, and patients experience progressive muscle and respiratory weakness. However, the natural history of the adult form and associated morbidity is not well documented or understood, and may be difficult to diagnose even by neurologists [2]. We present for the first time, a case of established adult Pompe’s Disease who presented to our institution with a four-year history of progressive urinary storage symptoms suggestive of an overactive bladder, who was successfully treated with intravesical Botulinum toxin-A.

 

Case Presentation
A 52-year-old female, Para-3, Caucasian patient with adult Pompe’s Disease presented with a progressive 3-year history of frequency, urgency and suprapubic discomfort with associated significant urge-associated urinary incontinence and the use of 5-6 large TENA® incontinence pads per 24-hour period. She was predominantly wheelchair bound and was not receiving enzyme-replacement therapy, and denied any stress-associated urinary leakage. She also did not suffer from urinary tract infections or haematuria. Her routine serum haematological and biochemical parameters were normal, as was clinical examination. A routine urinalysis was also normal. She was commenced on a number of different oral (oxybutynin, tolterodine, fesoterodine, solifenacin, trospium chloride) and transdermal (oxybutynin) anti-muscarinic treatments to attempt to control her symptoms, however, these failed to ameliorate her symptoms and resulted in significant xerostomia, constipation and lethargy. The patient was counseled regarding the option of intravesical Botulium toxin-A injection and underwent pre- and six-week postoperative urodynamic testing (Table 1). She was also instructed in how to perform clean intermittent self-catheterization (CISC).

 

Table 1. Summary of Urodynamic characteristics pre-operative and 6-weeks post-operative Botulium Toxin-A intravesical injection
(Q max = Maximal flow; P det = Detrusor muscle pressure; PVR = Post-void residual) 

 

BJUIw-2012-004-web

The patient underwent rigid cystoscopy and injection of 150 I.U. intravesical Botulinum toxin-A (Btx-A), under spinal anaesthesia. She made an uneventful recovery and was discharged after 24-hours of urine output measurement. Her residuals were monitored with self-catheterization (Speedicath®, 12Fr). CISC was performed post-micturition routinely for a further two weeks and then discontinued. No post-operative complications were experienced. The patient was seen after six weeks in the outpatient department and had significantly improved with a reduction in frequency, urgency and urinary incontinence. Her use of TENA® incontinence pads per 24-hour period had dramatically decreased to 1-2 pads, and as a result, her mobility had also improved due to increased confidence levels. She was subsequently discharged back to her primary care physician for further follow-up.

Discussion

To our knowledge, this is the first reported case of detrusor overactivity in a patient with Pompe’s Disease in the world literature, and also the first report to use Btx-A in a patient with this progressive condition. Although it has not previously been described, it is plausible that glycogen would accumulate within smooth muscle cells present within the urinary tract, and that their disruption would result in ureteric paralysis and detrusor dysfunction.

Unlike skeletal muscle, smooth muscle fibres within the urinary tract are rich in type 1-muscle fibres, which are aerobic, and therefore have lower baseline glycogen levels than type 2 skeletal muscle fibres, which rely heavily on glycolysis for ATP production [3]. Smooth muscle fibres also contain mannose-6-phosphate receptors, and with less baseline glycogen accumulation, smooth muscle cells may take longer to progress to more severe muscle cell pathology, when the muscle fibrils and sarcomeres are replaced by cytoplasmic glycogen [4, 5].

Detrusor glycogen deposition content has also been shown in guinea pig models by De Jong et al. to reflect the history of bladder dysfunction; with the strongest glycogen deposition being found in bladders having experienced the highest pressures, most instabilities, lowest compliance and highest contractility [6].

Antimuscarinic therapy has been the primary treatment for bladder overactivity following lifestyle modification, however, compliance is an issue due to adverse effects of medication, insufficient beneficial effects, and unmet patient expectations 7. In those who have failed antimuscarinic treatment, Btx-A has been shown to be a safe and satisfactory alternative. A recent Cochrane review by Duthie et al. described a meta-analysis of nineteen studies exploring the efficacy of Btx-A treatment. They found Btx-A, to demonstrate superiority to placebo in all studies, with a dose-dependent duration lasting a number of months. Furthermore, the treatment was found to be safe, and patients did not demonstrate tolerance to the treatment [8]. There have been no reports in the literature describing the use of sacral neuromodulation in those with glycogen storage disorders.

In this index case, intravesical Btx-A injection led to a rapid improvement in quality of life and lower urinary tract symptoms, without the need for maintenance self-catheterization. Furthermore, there were no significant difference between pre- and post-operative voiding volumes, maximal urinary flow or maximal detrusor pressure (Unpaired T-test: Two-tailed P value = 0.8986) suggesting that this dose of Btx-A was safe to use, with no adverse side effects on detrusor function. It is possible that the effects of Btx-A treatment may be further augmented by the concurrent use of enzyme replacement therapy in this patient (ERT). Bernstein et al. described a small case series in which the use of ERT in Pompe’s Disease led to a dramatic improvement in gastrointestinal symptoms such as chronic diarrhea, post-prandial vomiting and abdominal pain [9].

Conclusion

This report, to our knowledge, is the first in the literature to describe successful treatment of detrusor overactivity in any glycogen storage disorder. Although the degradation of intracellular glycogen accumulation is not addressed with intravesical Btx-A, it may nonetheless provide an inexpensive, readily available, acceptable treatment in those with adult-onset Pompe’s disease with moderate to severe lower urinary tract symptoms who are refractory or intolerant to antimuscarinic therapy or in those, for whom enzyme replacement therapy is unavailable. It is currently unknown as to whether bladder overactivity in those with Pompe’s Disease is as prevalent as in the general population, however, it is felt to be under-reported due to the other systemic manifestations of this condition.

Additional studies are required needed to explore not only the underlying mechanism of urinary symptoms in adult onset Pompe’s Disease, but also to further document the frequency and severity of lower urinary tract, and storage symptoms, and their response to intravesical Btx-A treatment.

References

1. Van Gijn J., Gijselhart .J.P (2011) “Pompe and his disease” Ned Tijdschr Geneeskd. 155(51): A4419
2. Papadimas G.K., Spengos K., Papadopoulos C. et al. (2011) “Late Onset Glycogen Storage Disease Type II: Pitfalls in the Diagnosis” European Neurology 67(2): 65-68
3. Drost M.R., Schaart G., Van Dijk P. et al. (2008) “Both type 1 and type 2a muscle fibers can respond to enzyme therapy in Pompe disease” Muscle Nerve 37(2): 251–255
4. Fukuda T., Ahearn M., Roberts A. et al. (2006) “Autophagy and mistargeting of therapeutic enzyme in skeletal muscle in Pompe disease”, Molecular Therapeutics 14(6): 831–839
5. Fukuda T., Ewan L., Bauer M. et al. (2006) “Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease” Annals Neurology 59: 700–708
6. De Jong B.W., Wolffenbuttel K.P., Scheepe J.R. et al. (2008) “The detrusor glycogen content of a de-obstructed bladder reflects the functional history of that bladder during PBOO” Neurourol Urodyn. 27(5): 454-460
7. Hampel C. (2007) “Long-Term management of overactive bladder with antimuscarinic agents” European Urology Supplements 6(5): 432-437
8. Duthie J.B., Vincent M., Herbison G.P. et al. (2011) “Botulinum toxin injections for adults with overactive bladder syndrome” Cochrane Database Systems Review; 12: CD005493
9. Bernstein D.L., Bialer M.G., Mehta L. et al. (2010) “Pompe disease: Dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients.” Molecular Genetics and Metabolism. 101: 130-133

 

Date added to bjui.org: 15/08/2012

DOI: 10.1002/BJUIw-2012-004-web

 

Epidermoid cyst of the penis

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A case of a 25 year-old man with an epidermoid cyst of the penis is reported.

Authors:

TFEIL YAHYA MD (FWACS) Urologist Surgeon
Department of urology Faculty of Medicine- Nouakchott University

Corresponding Author: TFEIL YAHYA MD (FWACS) Urologist Surgeon, Department of urology Faculty of Medicine- Nouakchott University. E-mail: [email protected]

 

Abstract
Penile cysts are uncommon. A case of a 25 year-old man with an epidermoid cyst of the penis is reported. He was found to have an asymptomatic soft mass in the frenulum of his penis. Excision of the mass was performed, and the diagnosis of epidermoid cyst the penis was made. No recurrence has been noted within the year since excision. In such cases, clinicians should manage patients either by observation or excision of the cyst.

 

Introduction
Cutaneous epidermoid cysts may arise from all parts of the body, but penile epidermoid cysts are uncommon. Most are encountered in childhood [1] and are usually congenital. However, the etiology of penile epidermoid cysts in the elderly is not well understood. In previously reported cases, a penile epidermoid cyst has been described as a slowly growing mass [1, 2, and 3]. It has been reported that the period of growth varies from 2 to 8 years [2, 3]. We present a case of a rapidly growing penile epidermoid cyst that developed in a 6 month period of time.

 

Case Report 
A 25 year-old man was found to have an asymptomatic, slowly growing soft mass measuring 8X2X2 cm in the frenulum of his penis (Fig.1).

 

Figure 1.
Figure-1.-Appearance-of-the-cyst-on-the-penis

 

 

 

 

 

 

 

 

 

 

 

 

He had no history of trauma, inflammation, urinary tract infection, hematuria or dysuria. The elastic mass was non tender, freely movable within the dermis, and had a smooth surface (Fig.2).
Figure 2.

Figure2.-Appearance-of-the-cyst-after-dissection

There was neither a keratin-filled punctum nor any signs of inflammation. Excision of the cyst was performed under loco-regional anaesthesia through a semi-circular incision (Fig.3).
Figure 3.

Figure3.-Appearance-of-the-penis-after-excision-of-the-cyst-

Macroscopically, the cut surface of the mass appeared to be full of a cheesy material, and both cytology and culture results were negative. Histological examination revealed that the wall of the cyst was lined with stratified squamous epithelium and laminated keratin. It did not contain either skin appendages or germ cells. The final diagnosis was epidermoid cyst of the penis. No recurrence has been noted in the year since excision.

Discussion

Epidermal cysts are common benign tumors that may arise from the infundibular portion of the hair follicle spontaneously or subsequent to trauma, but penile epidermoid cysts are uncommon and usually congenital. The etiology is not clear. Some authors have adduced that it may develop from median raphe cyst, following an abnormal closure of the median raphe during embryogenesis [3]. Others have suggested that median raphe cysts are a different entity from epidermoid cysts [4]. These cysts may occur because of occluded hair follicles, the mechanical implantation such as that involving injection of epidermal fragments, and obstructed eccrine ducts [2]. The present case is more likely to have not originated from a median raphe cyst because of the patient’s age and the development of the cyst in a short period of time. Penile epidermoid cyst can be diagnosed by a careful examination with evaluation by ultrasonography and/or computerized tomography. Dermoid cyst, teratoma, and urethral diverticula should be considered in the differential diagnosis of the epidermoid cyst [2]. An epidermal cyst is lined by well-developed stratified epithelium, and often contains keratin, which can be expressed from the cyst, while a dermoid cyst contains skin and skin appendages, and a teratoma contains derivatives from other germ cells. Therefore, these lesions can be distinguished from an epidermoid cyst. Unlike the urethral diverticula, such cysts do not have a connection with the urethra (Fig.4).

Figure 4.

Fig.4.-retrograd-urethro-cystography

Although epidermoid cysts are benign lesions, neoplastic transformation of their epithelium has been reported to occur rarely [5, 6]. No cases of malignancy arising in the wall of an epidermoid cyst of penis have been reported previously [1, 3]. The best treatment of penile epidermoid cysts is total excision. One year after complete removal of the cyst, we did not note any local recurrence. There were no findings of malignancy in our case, similar to that reported by others [1, 3]. Although malignant transformation is very rare, it should be kept in mind and following excision of an epidermoid cyst, patients should undergo long term follow up.

Conclusion

In conclusion, epidermoid cyst of penis is rare, in the pediatric age group it can occur after a seemingly minor surgical procedure such as circumcision. The swelling may remain largely asymptomatic unless secondarily infected. Care needs to be taken while performing even minor surgical procedures to avoid this complication. The condition should to be treated by complete excision. The rare possibility of malignant transformation must be borne in mind.

References:

1-Suwa M, Takeda M, Bilim V, Takahashi K. Epidermoid cyst of the penis: A case report and review of the literature. Int J Urol 2000; 7: 431—433.
2- Khana S. Epidermoid cyst of the glans penis. Eur Urol 1991; 19: 176–177.
3-Rattan J, Rattan S, Gupta DK. Epidermoid cyst of the penis with extension into the pelvis. J Urol 1997; 158: 593–594.
4-Little Jr JS, Keating MA, Rink RC. Median raphe cyst of the genitalia. J Urol 1992; 148: 1872–1873.
5- Dini M, Innocenti A, Romano GF. Basal cell carcinoma arising from epidermoid cyst: A case report. Dermatol Surg 2001; 27: 585–586.
6- Lopez-Rios F, Rodriguez-Peralto JL, Castano E, Benito A. Squamous cell carcinoma arising in a cutaneous epidermal cyst: Case report and literature review. Am J Dermatopathol 1999; 21: 174–177.

 

Date added to bjui.org: 05/08/2012

DOI: 10.1002/BJUIw-2011-140-web

 

Laparoscopic heminephrectomy and ureterectomy for lower moiety urothelial carcinoma in a complete duplex right kidney

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Here, we present a rare case in which a urothelial carcinoma was located at the lower moiety of a complete duplex right kidney. 

Authors: PEI-YU LIN1, VICTOR CHIA-HSIANG LIN1,2, RENG-HONG WU3,  TSAN-JUNG YU1,2

Department of Urology 1, E-Da Hospital/I-Shou University, Kaohsiung City 2, Department of Radiology3, Chi-Mei Medical Center, Tainan City, Taiwan

Corresponding Author: Victor Chia-Hsiang Lin, M.D., Division of Urology, Department of Surgery, Minimally Invasive Surgical Center, E-Da Hospital/I-Shou University, Kaohsiung City 824,  Taiwan 824.   E-mail: [email protected]

 

Abstract
Total nephroureterectomy is usually considered to be the gold standard treatment for urothelial carcinoma involving the kidney, where nephron sparing surgery is seldom considered because of the concerns of tumor spillage. However, heminephrectomy with ipsilateral ureterectomy may be performed when the malignancy occurs in a patient with a renal fusion anomaly or in a single moiety of a complete duplex kidney. Here, we present a unique case with urothelial carcinoma in the lower moiety of a complete duplex right kidney. Laparoscopic right heminephrectomy with ureterectomy was performed, after preoperative evaluation with reconstructed 3-dimensional computed tomography angiography and intraoperative navigation with laparoscopic ultrasound.
Complete duplication of the collecting system is an uncommon congenital anomaly, occurring in approximately 1 in 125 individuals. Duplex kidneys can be associated with ectopic ureters, ureteroceles, and vesicoureteric reflux, and cause various clinical manifestations including incontinence, voiding dysfunction and urinary tract infection. A common disease variant in this entity is a ectopic ureteric orifice, associated with a dysplastic poorly functioning upper-pole renal moiety. Heminephrectomy is considered to be the treatment of choice for patients with certain pathologies. Here, we present a rare case in which a urothelial carcinoma was located at the lower moiety of a complete duplex right kidney. The patient underwent laparoscopic heminephrectomy with ureterectomy after thorough preoperative evaluation.

 

Case Report
An 82-year-old female presented with the chief complaint of intermittent painless gross hematuria for 3 months. Physical examination was unremarkable. Cystoscopy with retrograde pyelography revealed complete duplication of the right collecting system and a 2×2 cm filling defect located over the lower moiety of the duplex right kidney (Fig. 1 A & B).

 

Figure 1. Retrograde pyelography revealed duplication of the right collecting system. A. Hydronephrosis of the right upper moiety due to external compression indicated by a black arrow. B. The white arrow indicates a filling defect over the lower calyx of the right duplex kidney.

 

 

 

Reconstructed 3-dimensional computed tomography (3-D CT) angiography demonstrated a tumor in the lower moiety renal pelvis of the right duplex kidney and several parapelvic renal cysts compressing the upper moiety, causing hydronephrosis and hydrocalycosis. (Fig. 2 A & B).

 

Figure 2. A. Coronal view of a computed tomography (CT) scan showing a tumor in the duplex right renal pelvis as indicated by the white arrow. B. Reconstruction CT clearly demonstrated a soft tissue mass over the lower calyx of the duplex right kidney, as indicated by the white arrow.

 

 

After discussing the available options with the patient and her family, they agreed for her to undergo laparoscopic right heminephrectomy and ureterectomy.

 

Diagnostic ureteroscopy showed a large nodular tumor in the lower moiety of the duplex right kidney. Subsequently, a transperitoneal laparoscopic technique was adopted, taking down the mesocolon of the ascending colon from the hepatic flexure to the level of the bifurcation of the right iliac vessels. After deroofing the parapelvic renal cysts, the right renal hilum was carefully exposed and the supplying branches to the lower moiety were skeletonized individually. The arterial branch which supplied the lower moiety was confirmed and clamped using a surgical bulldog clamp. The lower moiety appeared cyanotic when its supplying branch was clamped correctly. The venous branch of the lower moiety was accompanied by the arterial branch and was positively identified. By first clipping and dividing the branches of the right renal artery supplying the lower moiety, a clear line of demarcation between the ischaemic lower moiety and the normal upper moiety was seen. Laparoscopic ultrasound further confirmed the upper margin of the lower moiety calyces, and cutting and division of the moieties were performed precisely and efficiently with electrocautery and ultrasonic shears. Hemostasis of the bare surface of the upper moiety was achieved with laparoscopic free-hand suture and knot-tying. The ureter of the lower moiety was skeletonized to the level of the right iliac vessels, and clips were put on the distal end to prevent extravasation of tumor cells. The specimen was then placed in an endobag. The extravesical bladder cuff excision was performed using an open approach through a right Gibson’s incision. When dissecting into the retroperitoneum, the distal ureter was identified, the endobag in which the lower moiety of the right kidney and its proximal ureteral segment were placed was removed thereafter. Retracting the distal ureter cephalad, dissection was continued distally until the bladder was reached. The bladder was incised just anterior to the ureter and the ureteric lumen was identified. The posterior portion of the ureter was excised and detached from the bladder cuff carefully under vision. The bladder defect was sutured with 1-0 chromic gut. There was no injury to the ureteric orifice of the upper moiety of the right kidney.
The patient’s postoperative recovery was prompt due to her undergoing minimally invasive surgery, and she resumed oral intake 12 hours postoperatively. She received a total amount of meperidine 150mg for postoperative pain relief. She was discharged after two  days. Due to a suspected urinary leak, a JJ stent was inserted to drain the right upper moiety on postoperative day 6. Final pathological examination demonstrated urothelial carcinoma of the lower moiety of the right duplex kidney, stage pT1. During two-years of follow-up, no tumor recurrence has been detected.

 

Discussion
Urothelial carcinoma in duplex kidneys is rare with only sporadic reports in the English literature.1,2 Nephron sparing surgery is well established for the treatment of small exophytic renal cell carcinoma.3 However, total nephroureterectomy is the treatment of choice to manage renal urothelial carcinoma. Nevertheless, nephron sparing surgery for upper tract urothelial carcinoma can still be considered in certain situations such as crossed renal ectopy or tumour in one moiety of a duplex system.4 Gur et al. demonstrated the feasibility of separating the involved kidney from its conjoint to treat patients with transitional cell carcinoma in a fused crossed ectopic kidney. Subsequent ureterectomy with bladder cuff excision was performed in our case with respect to oncological principles. We also advocate the importance of a thorough delineation of the involved renal vasculature using CT-angiography preoperatively.
Similarly, we used reconstructed 3-D CT angiography to delineate the involved renal vasculature. A radiologist also performed laparoscopic ultrasound to help decide precisely the cut-margin during the parenchymal transection. We believe these tools are extremely important in planning this type of surgery. To the best of our knowledge, this is the first case of urothelial carcinoma in one moiety of a complete duplex kidney treated by laparoscopic heminephrectomy and ureterectomy.
In our experience, laparoscopic heminephrectomy is a feasible and safe modality in treating urothelial carcinoma of the lower moiety in a duplex kidney in selected cases.

 

References
1. Lia-Beng Tan, Biing-Rorn Tserng, Wei-Hwang Huang, Chia-Jiuan Tarn. Synchronous bilateral carcinoma of the ureter in association with unilateral incomplete duplication of the ureter. Urol Int 56: 196-199, 1996.
2. Jenq-Daw Li, Johnny Shinn-Nan Lin, Wei-Jen Yao. Synchronous transitional cell carcinoma in both moieties of an incomplete duplex system. Urology 59: 944-945, 2002.
3. Alireza Moinzadeh, Inderbir S. Gill, Antonio Finelli, Jihad Kaouk and Mihir Desai. Laparoscopic partial nephrectomy: 3-year followup. J Urol 175: 459-462, 2006
4. Uri Gur, Ofer Yossepowitch and Jack Baniel. Transitional cell carcinoma in a fused crossed ectopic kidney. Urology 62: 748, 2003.

 

Date added to bjui.org: 21/07/2012
DOI: 10.1002/BJUIw-2011-108-web

 

Failed salvage of late presentation adult testicular torsion: cases discovered on serial testicular scintigraphy

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Here we report two cases of late presentation adult testicular torsion in which the patients had undergone a failed initial salvage trial, in which final decision for surgery were made on the basis of serial testicular scintigraphy. 

Authors: Young Hwii Ko,1 Gi Joeng Cheon,2 Tae Young Park,1 Sung Gu Kang,1 Du Geon Moon,1 Jun Cheon,1 Jeong Gu Lee,1 Je Jong Kim1

1. Department of Urology, Korea University School of Medicine, Seoul 136-705, Korea
2.  Department of Nuclear Medicine, Korea University School of Medicine, Seoul 136-705, Korea

Corresponding Author: Je Jong Kim, MD, PhD, Professor, Department of Urology, Korea University School of Medicine,  Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea.    E-mail: [email protected]

 

 

Abstract
Although successful manual detorsion relieves the acute symptoms of testicular torsion, which has traditionally been regarded to be rare in adulthood, about one-third of patients had been reported to have residual symptoms. In case of initial surgical exploration, the appearance of the testicle is the sole criterion in making a decision regarding testis removal or retention. Hence, serial radiologic workups after an initial salvage trial may provide an objective evaluation, enabling an informed surgical decision to be made for failed initial salvage cases. Here, we describe two cases of late presentation adult testicular torsion, in which the absence of normal blood flow was diagnosed by follow-up serial testicular scintigraphy, after an initial trial to salvage the affected testis by manual or surgical detorsion.

 

Introduction
The diagnosis of testicular torsion is made routinely with the aid of radiologic modalities including Doppler ultrasonography (US) or radionuclide imaging [1], in addition to the presence of typical symptoms concomitant with loss of the cremasteric reflex. Following diagnosis, urgent or semi-elective surgical exploration with/without manual detorsion can be tried as an initial attempt to salvage the testis. During surgery, the testis is observed for any improvement in color. A decision to remove or retain the affected testis is subjective and, although based on the appearance of the testis, is also likely to be influenced by the age of the patient and the degree and duration of torsion [2]. Using manual reduction alone, while successful untwisting relieves the acute symptoms, the repeat torsion rate can be 27.7% to 32% [3, 4]. Thus, serial radiologic evaluation after an initial salvage trial may provide objective evidence for the viability of the affected testis, in addition to being effective as an initial evaluation modality. For this purpose, radionuclide imaging may provide an additional advantage over US, avoiding operator-dependency, provided it can be conducted without delay.
Here we report two cases of late presentation adult testicular torsion in which the patients had undergone a failed initial salvage trial, in which final decision for surgery were made on the basis of serial testicular scintigraphy.

 

Case Report 1
A 49-year-old male presented to the outpatient department of our institute with acute pain in the left inguinal area and scrotum, which had begun 3 days previously. On physical examination, both testes were located normally in the scrotum, with tenderness only in the left testis with mild scrotal swelling. Urinalysis revealed no pyuria, but the cremasteric reflex on the left was reduced compared with that on the right side. US revealed maintained left testicular blood flow with mild enlargement of the epididymis. With the suspicion of testicular torsion, testicular scintigraphy using technetium 99m pertechnetate was performed. A definite photon defect was evident in the left testis with increased uptake in the surrounding area (Figure 1a).

 

Figure 1a. Initial testicular scintigraphy. Arrowhead indicates photon defect area in left testis with increased surrounding areas.

 

 

Then, as initial management, manual untwisting to the clockwise direction was tried at once in the outpatient setting, after which tenderness and left scrotal pain was abruptly decreased. Considering residual torsion concomitant with underline deformity in both scrotums, follow-up testicular scintigraphy and elective surgery were planned. Testicular scintiography taken the day after manual reduction revealed no interval change compared to the image recorded before manual reduction, regardless of improvement in symptom (Figure 1b).

 

Figure 1b. Follow-up testicular scintigraphy after manual detorsion on left testis. The photon defect area (arrowhead) showed no significant interval change compared with prior imaging.  

 


 

Elective surgical exploration revealed 180º counterclockwise torsion of left testis with partial bell-clapper deformity, then bilateral orchiopexy was performed. Follow up imaging taken the day after surgical correction showed significant improvement in photon defect (Figure 1c).

 

Figure 1c. Follow up testicular scintigraphy taken the day after surgical correction showed significant decreased in photon defect area (arrowhead).

 


 

 

Case Report 2  
 

 

A 23-year-old male presented to our emergency department complaining of abrupt development (11 hours previous) of left scrotal pain and swelling. Urinalysis revealed pyuria with 10-29 leukocytes in each high power field. US performed in the emergency setting showed decreased blood flow in left scrotum, with mildly enlarged epididymis. Under suspicion of testicular torsion, surgical exploration was performed 13 hours after the onset of pain. Testicular scintigraphy taken immediately before the operation confirmed a photon defect in left scrotum (Figure 2a).

 

Figure 2a. Initial testicular scintigraphy. The area for left scrotum showed no perfusion (arrowhead). 

 


 

In the operative field, a 360º counterclockwise torsion was found. After untwisting of the testis and soaking in warm saline for 10 minutes, return of fresh color on surface of the tunica albuginea was observed, with fresh bleeding upon a tentative small incision (Figure 2b).

 

Figure 2b. At surgical exploration, return of normal color with fresh bleeding upon a tentative small incision was observed (arrowhead).

 


Based on these findings, bilateral orchiopexy was performed. However, the patient still complained of a similar degree of scrotal pain one day after the operation. A follow-up testicular scintigraphy was performed, which revealed a perfusion defect on the left testis (Figure 2c)

 

Figure 2c. Follow-up imaging after orchiopexy. While increased compared with prior imaging, the scintigraphy still showed obvious photon defect with increased surrounding areas (arrowhead).

 

 

In a following orchiectomy the day after the initial operation, necrosis of whole left testis was revealed (Figure 2d). An orchiectomy concomitant with prosthesis insertion was conducted.

 

Figure 2d. Final specimen revealed totally necrotic change of left testis.

 

 

Discussion

 

Acute scrotal pain remains the most important differential diagnosis requiring exclusion or prompt management among urologic emergencies, as missed or delayed diagnosis of testicular torsion can lead to organ loss, cosmetic deformity, and compromised fertility. Although testicular torsion in adulthood is thought to be relatively unusual in adults, it may occur at any age. An estimated 39% of all cases of torsion develop in adulthood [5], including men in the sixth and seventh decades of life. The primary goal in management of testicular torsion is testicular salvage, with the goal of maintaining fertility. To achieve this, there is approximately a 4-8 hour window from the onset of torsion symptoms until surgical intervention is required to save the affected testis. Delay in diagnosis and subsequent delay in surgery risk testicular viability, with nearly 80% of affected testes infarcted after 10 hours from the onset of pain, and after 24 hours nearly 100% are infarcted and non-salvageable [6].
Age has been suggested as a variable effect on testicular salvage rate. Comparison with younger counterparts revealed that the reported testicular salvage is generally poor in adulthood [1, 7]. This likely is due to a lack of recognition of the potential for adult torsion by physicians, as well as differences in the severity of spermatic cord twisting in adults versus children [4]. A recent examination of 2248 men diagnosed with testicular torsion using a multivariate model estimating the probability of orchiectomy showed that only age was significant variable [8]. In the study, the prevalence of testicular torsion was 19% among those aged 1-9 years, 33% among those aged 10-17 years, and 41% among those aged 18-25 years. For every year increase in age, the adjusted odds of having an orchiectomy increased by 1.08 (95% CI, 1.03-1.13), or an increase of 8% in the odds per year.
The exceeded prevalence of testicular torsion in adults with higher orchiectomy rate indicates the importance of maintaining a high index of suspicion in acute scrotum symptoms in adulthood. After an initial trial to salvage the testis, the outcome should be monitored with care, as shown in these cases. While manual untwisting may allow prompt reperfusion of the testis, the resolution of symptoms does not necessarily correlate with the presence or absence of persistent torsion, because the testis may still be twisted, although to a lesser degree [3, 4]. Hence, radiologic evaluation should accompany this maneuver to confirm satisfactory detorsion. In case of surgical exploration, attempts should be made to salvage the testis if there is any sign of reperfusion after detorsion [2]. However, we believe that successful return of normal blood flow should also be followed by radiologic evaluation postoperatively, due to absence of reliable objective criteria at time of surgical decision. Regarding radiologic modality for follow up imaging, we chose testicular scintigraphy instead of US, which was presently performed as an initial radiologic modality upon suspicion of testicular torsion, presuming this approach to be more accurate [9] and objective, regardless of operator skill [10]. Actually, the blood flow detected by US was maintained in case 1, but the scintigraphy revealed a definite photon defect. Particularity in a follow-up setting, it can be performed electively. In this context, serial testicular scintigraphy after initial salvage trial to obtain objective evidence of procedural outcome enables adequate surgical decision for failed salvage cases.

 

Conclusions
In case of acute scrotal pain in adult, the applications of serial radiologic evaluation using testicular scintigraphy not only increase accuracy in diagnosis of testicular torsion, but also provide reliability on the outcome of initial salvage trial, enabling correct surgical approach.

 

References
1. Jaison A, Mitra B, Cameron P, Sengupta S. Use of ultrasound and surgery in adults with acute scrotal pain. ANZ J Surg. 2011; 81: 366-70.
2. Julia S. Barthold. Abnormalities of the testis and scrotum and their surgical management; in Campbell-Walth Urology 10th edition.  Editors Louise R. Kavoussi, Andrew C. Novick, Alan W. Partin, Craig A. Peters. Elsevier Sounders, 2011, Philadelphia, pp3590
3. Jefferson RH, Pérez LM, Joseph DB. Critical analysis of the clinical presentation of acute scrotum: a 9-year experience at a single institution. J Urol. 1997; 158 :1198-200.
4. Sessions AE, Rabinowitz R, Hulbert WC, Goldstein MM, Mevorach RA. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003; 169: 663-5.
5 Lee LM, Wright JE, McLoughlin MG. Testicular torsion in the adult. J Urol. 1983; 130: 93-4.
6. Davenport M. ABC of general surgery in children. Acute problems of the scrotum. BMJ. 1996; 312: 435-7.
7. Cummings JM, Boullier JA, Sekhon D, Bose K. Adult testicular torsion. J Urol. 2002; 167: 2109-10.
8. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005; 159: 1167-71.
9. Wu HC, Sun SS, Kao A, Chuang FJ, Lin CC, et al. Comparison of radionuclide imaging and ultrasonography in the differentiation of acute testicular torsion and inflammatory testicular disease. Clin Nucl Mel. 2002; 27: 490-3.
10. Ringdahl E, Teague L. Testicular torsion. Am Fam Physician. 2006; 74: 1739-43.

 

Date added to bjui.org: 15/07/2012
DOI: 10.1002/BJUIw-2011-128-web

 

Acquired haemophilia in a patient with bladder cancer

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This case is the first reported case of acquired haemophilia that is solely attributed to an underlying bladder tumour.

Authors: Fitzpatrick J, Aboumarzouk O, Ahmad S, Byrne D, Nabi G. Ninewells Hospital, NHS Tayside, Dundee, DD1 9SY, UK

Corresponding Author: Omar M Aboumarzouk,  Ninewells Hospital, NHS Tayside, Dundee, DD1 9SY, UK.  E-mail: [email protected]

 

Abstract
Acquired haemophilia is a rare bleeding disorder caused by the development of autoantibodies to coagulation factor VIII (FVIII). The clinical presentation varies, ranging from mild bleeding to acute and life-threatening haemorrhage, with mortality approaching 22%. Around 50 percent of cases are idiopathic, however, it is also associated with several underlying conditions, including malignancy. We report a case of acquired haemophilia in an 80-year-old patient with transitional cell carcinoma of the bladder (grade G3pT1), who underwent transurethral resection of bladder tumour (TURBT). Unfortunately, five weeks after admission, he died after being treated with recombinant factor VIIa, rituximab, and undergoing multiple transurethral resections and washouts for recurrent blood clots within the bladder. The repeated recombinant factor VIIa and rituximab lead to the formation of a thick and adhesive clot in his bladder requiring  these repeated procedures. This is the first reported case of acquired haemophilia that is solely attributed to an underlying bladder tumour.

 

Background
Acquired haemophilia (AH) is an autoimmune disease characterised by a deficiency in coagulation factor VIII (FVIII).[1,2] The pathophysiology of the disease can be explained by the acquisition of antibodies, which neutralise the procoagulant properties of FVIII, resulting in severe and often life-threatening haemorrhage.[3,4] AH tends to present later in life, with the mean age of onset at 65 years, and affects both genders equally.[2,3] In 50 percent of cases, there is an idiopathic aetiology, however, it is often associated with underlying conditions, including autoimmune diseases, solid tumours, lymphoproliferative disorders, drug hypersensitivity and pregnancy.[3,4,5,6] A laboratory diagnosis of AH is twofold; in the first instance, by a prolonged activated partial thromboplastin time (APTT), not corrected by incubation with normal plasma in the presence of a normal prothrombin time (PT), and secondly by reduced FVIII, with evidence of FVIII inhibitor measured by the Bethesda assay.[3,4] The principles of management are to control bleeding, primarily with recombinant factor VIIa (rFVIIa), and to introduce long-term eradication of autoantibodies by immunosuppression; this is often achieved by using a combination of steroids, cyclophosphamide, intravenous immunoglobulins and monoclonal antibodies.[1,3] Although acquired haemophilia is a rare condition, with an incidence of 1-4 per million/year, there is a significant morbidity associated with it; 90% of affected individuals will suffer a substantial bleed and up to 22% will not survive the episode.[1,4,7]

 

Case report
An 80 year-old male, with no significant past medical history, was referred to our urology department after presenting to his GP with frank haematuria. He subsequently underwent a CT scan (Image 1, 2) which showed three moderate-sized papillary lesions on the right lateral wall of the bladder. Flexible cystoscopy confirmed the diagnosis, subsequently shown to be a G3 pT1 tumour. The decision was for him to undergo a transurethral resection of bladder tumour (TURBT) and Mitomycin-C instillation.

 

Image 1. CT scan, coronal 

CT Image_Coronal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Image 2. CT scan, saggital

CT Image_Sagittal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The following week he presented to the Accident &Emergency Department with chest pain. His ECG was normal and his pain rapidly settled. He was therefore discharged and advised to contact his GP if his symptoms persisted. The following day, he attended his GP again complaining of chest pain with shortness of breath and further episodes of haematuria. He was referred directly to the urology ward.

On admission, he was noted to have extensive bruising across his arms, abdomen and flanks. There was no history of traumatic injury, although the bruising had become more extensive over the past week.
Blood tests confirmed that he was anaemic, with a haemoglobin of 7.1 g/dL. His coagulation screen showed a prolonged APTT of 76.3 sec (normal range 22-30 sec) with a normal PT of 9.7 sec (normal range 9-12 sec). His Troponin T level was grossly elevated at 852 ng/L (normal range 0-13 ng/L), however, this was not due to myocardial infarction, as there was no significant rise in the Troponin T level at 12 hours.
In light of the abnormal coagulation results, a haematology consult was sought. A FVIII assay result of 1.2 u/dl (normal range 50-150 u/dl) and a Bethesda assay result of 17.3 Beth.U confirmed a diagnosis of acquired haemophilia. He was transfused three units of blood and was commenced on rFVIIa (NovoSeven) at 90 µg/kg and prednisolone at 1 mg/kg, with proton pump inhibitor (PPI) cover. Subsequent testing, including autoimmune screening, anti-lupus anticoagulant and viral serology was carried out to try to determine the underlying aetiology, however, these failed to yield a positive result. A renal ultrasound scan was also normal. It was concluded, therefore, that the most likely explanation for the acquired haemophilia was his bladder cancer.
The decision was made to bring forward the planned TURBT in the hope that this would lead to a resolution of the acquired haemophilia. It was performed with preoperative and postoperative rFVIIa cover. Postoperatively, there appeared to be an early response following removal of the bladder tumour; FVIII levels improved from 1.2 u/dl to 6.5 u/dl, although he did require further blood transfusion. The haematuria settled and the catheter removed the following day.
Unfortunately, three days later, he developed clot retention. This became a recurring problem throughout admission, requiring multiple three-way catheter insertions, irrigation and bladder washouts. The clinical course has been summarised in Figure 1.
Figure 1. Clinical course summary

Figure 1fitzpatrick case rep

He developed acute abdominal pain with associated nausea. Blood tests revealed an amylase of 1641 units per liter (U/L) and he was diagnosed with pancreatitis. With no history of alcohol excess and no gallstones identified on prior imaging, the underlying aetiology was believed to be steroid-induced and his prednisolone was subsequently stopped. Treatment with intravenous fluids was successful, although he required further blood transfusion and rFVIIa. Rituximab was started by the haematologists.

In order to further investigate the continuing haematuria, an ultrasound scan was arranged. This revealed a substantial clot within the bladder, approximately 6 x 6 cm in size. He was taken to theatre and a transurethral evacuation of the clot was carried out. The procedure was technically difficult and took around three hours to perform. The clot was thick, adhesive and organised, with resected clot reattaching to the bladder wall (Image 3, 4). Unfortunately, only part of the clot could be successfully evacuated.
Image 3.

Image-3

 

 

 

 

 

 

 

 

 

 

 

 

Image 4.

Image-4

 

 

 

 

 

 

 

 

 

 

 

Two days later, he was taken back to theatre for a second attempt to evacuate the remainder of the clot. Rituximab and rFVIIa were given preoperatively. Once again, the resection was difficult and prolonged; after four hours of resection, only a small portion had been removed. The procedure was stopped, as the patient was becoming hypothermic and acidotic. Two units of blood were transfused.
Third and fourth evacuations were arranged to remove the residual clot. The third took approximately two hours. Warm irrigation fluid was used and some mobile organised clot remained at the end of the procedure. On the fourth attempt, the formed clot was cleared entirely. As with the previous resections, preoperative rVIIa and postoperative blood transfusion were required. It was encouraging to note that the APTT was improving gradually on rituximab and was now 68 sec.
As the APTT continued to improve, we decided to take a more conservative approach and see if it would correct with rituximab alone. The APTT improved further to 54 sec, however, repeat FVIII assay showed only a mild improvement (2.1 u/dL) and FVIII inhibitor was still present (17.8 Beth.U).
Unfortunately, over the next few days, the patient’s clinical condition deteriorated. A further seven units of blood were required during this time and his renal function worsened. An ultrasound scan revealed that, once again, there was a large formed clot in the bladder. A fifth cystoscopy was arranged, which confirmed a large organised clot occupying the whole bladder and blocking both ureteric orifices. The prognosis was poor and treatment had now become palliative. The clot was left in the hope that it might act to tamponade the bladder, however, the resulting obstructive uropathy meant that renal failure and hyperkalaemia developed; he passed away shortly after.

Discussion

The aetiology of AH is idiopathic in about 50 percent of cases, however, it is often associated with a variety of clinical conditions such as autoimmune disease (asthma, rheumatoid arthritis, systemic lupus erythematosus), solid tumours, lymphoproliferative disorders, drug hypersensitivity and pregnancy.[3,4,5,6] AH is associated with underlying malignancies in 7-15 percent of cases and is more prevalent in solid tumours than in haematological malignancies.[1,3,8,9] Reitter et al collated all published cases of cancer-associated FVIII autoantibodies from 1950-2010.[10] Although their analysis primarily targeted those cases in which FVIII autoantibodies developed following cancer surgery, their initial literature search also revealed those cases where AH had been diagnosed prior to surgery. Of the 57 cases uncovered, 32% (18/57) were associated with urological malignancies (14 prostate, 4 kidney), with prostate cancer the most prevalent amongst all cancer types.[10] Interestingly, there were no reported cases of AH secondary to bladder cancer; the only case found was in a patient who had developed FVIII autoantibodies following surgical treatment of a bladder tumour.[10]
AH due to underlying bladder cancer is extremely rare; a search of the literature only yielded two published cases, however, both have been multifactorial in their aetiologies.[11,12] In 2005, Kreuter et al reported AH in a patient with gram-negative urosepsis following resection of a rectal tumour, who underwent resection of a bladder tumour 6 months later.[11] Kato et al described AH in a patient with concomitant bladder and renal tumours.[12] To our knowledge, therefore, this is the first reported case of AH that can be attributed solely to bladder cancer.
The treatment of acquired haemophilia has been a much debated topic, in part due to its rarity and clinical diversity, with management plans often determined by the individual experiences of haematologists and on a case-by-case basis. As a result, data on the efficacy of anti-haemorrhage drugs is often retrospective.[1,13] There exists, however, generally accepted principles, primarily (1) controlling bleeding episodes, (2) avoiding invasive procedures that may precipitate further bleeding, (3) eradicating FVIII inhibitor through immunosuppression and (4) treating any underlying disease. [1,2,3,5]

Controlling bleeding episodes
The two main first-line agents that are licensed for the treatment of AH are rFVIIa (NovoSeven) and activated prothrombin complex concentrate (aPCC) (FEIBA; Factor VII inhibitor bypassing activity). [1,14] In our case, rFVIIa was adopted as the primary agent, using the standard recommended dose of 90 µg/kg.1 Such bypassing agents, however, are associated with an increased risk of arterial thrombosis, often in patients with underlying cardiovascular risk factors. A literature review demonstrated this in 7% of patients treated with rFVIIa.[14] The prothrombotic properties of bypassing agents are clearly useful in the cessation of bleeding episodes; however, it has been this very effect that has complicated our management. On one hand, rVIIa has been able to control bleeding and haematuria, however, it has also predisposed to the formation of further bladder clots, leading to recurrent catheter blockages and multiple clot resections.

Eradication of FVIII inhibitor
There is no definitive optimal regimen for inhibitor eradication. The most commonly adopted strategy is to use either corticosteroids alone or corticosteroids in combination with cyclophosphamide, with a lack of evidence supporting the choice of one over the other.[1,2,6] Previous studies have suggested that 70-80% of patients will achieve remission on either regimen; however, different durations of therapy were used in each.[13,15] In our case, prednisolone alone was used at 1 mg/kg; this is the dose most widely recommended in the current literature.1 The average time to remission with corticosteroids is about five weeks.[1,15] Unfortunately, we were forced to discontinue this treatment as our patient developed steroid-induced pancreatitis. It must be noted, however, that a mild improvement in APTT and FVIII levels had occurred up until this point.
If remission is not achieved with corticosteroids or cyclophosphamide, third-line immunosuppressive agents can be introduced. One of the most widely used drugs, which was used in our case, is rituximab. A cautious approach must be adopted with this therapy, particularly in elderly patients, due to potential serious side-effects; neutropenia and subsequent sepsis have been reported with associated increased patient mortality.[13] Despite this, rituximab has been shown to be successful in achieving remission of AH in a number of cases.[16,17,18]

Treatment of underlying disease
Although immunosuppressive therapy is paramount in inducing remission of AH, it is also important to treat the underlying aetiological disease.[1,2,3,5] In general, tumour-specific therapy has not been observed to cause the disappearance of FVIII inhibitors, however, there have been cases where surgical resection of causative tumours, following remission by immunosuppressive therapy, has prevented the recurrence of AH.[3,16,19,20] In contrast, however, there is some evidence to support the development of FVIII auto-antibodies following surgical resection of solid tumours.[10] Reitter et al report 13 cases where such antibodies were detected after an average of 3 months following uncomplicated cancer surgery.[10] These patients had not been diagnosed with AH prior their operation, determined by a normal APTT and no bleeding during and immediately after surgery.[10] It would appear that, although malignancies have been linked to causing AH, the development of FVIII inhibitors can be viewed as a paraneoplastic phenomenon.

Conclusion

The take home message is, that due to the tendancy of bladder tumours to bleed, and the occurrence of post-resection bleeding, haemophilia should be treated by taking into consideration the ensuing clot formation within the bladder. Furthermore, bladder tumours should be considered as part of the differential diagnosis for AH if all other causes have been excluded. This manuscript represents the first reported case of acquired haemophilia caused by a bladder tumour.

JF and OA both have first authorship contribution by writing the case report.

References
1. Collins P, Baudo F, Huth-Kühne A, Ingerslev J, Kessler CM, Castellano ME, Shima M, St-Louis J, Lévesque H. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes. 2010 Jun 7;3:161.
2. Morrison AE, Ludlam CA. Acquired haemophilia and its management. Br J Haematol. 1995;89(2):231–236
3. Baudo F, de Cataldo F. Acquired hemophilia: a critical bleeding syndrome. Haematologica. 2004 Jan;89(1):96-100.
4. Elezović I. Acquired haemophilia syndrome: pathophysiology and therapy. Srp Arh Celok Lek. 2010 Jan;138 Suppl 1:64-8
5. Baudo F, Caimi T, de Cataldo F. Diagnosis and treatment of acquired haemophilia. Haemophilia. 2010 May;16(102):102-6.
6. Moccia F, Tognoni E, Boccaccio P. Acquired factor VIII inhibitor associated with prostatic cancer: successful treatment with steroid and immunosuppressive therapy. Ann Ital Med Int. 2000 Apr-Jun;15(2):172-6.
7. Zeitler H, Ulrich-Merzenich G, Goldmann G, Vidovic N, Brackmann HH, Oldenburg J. The relevance of the bleeding severity in the treatment of acquired haemophilia – an update of a single-centre experience with 67 patients. Haemophilia. 2010 May;16(102):95-101. Epub 2008 Nov 14.
8. Ferre A, Arlet JB, Darnige L, Dupeux S, Pouchot J. Acquired hemophilia as the presenting manifestation of neoplasia: diagnostic workup and monitoring. Rev Med Interne. 2009 Jul;30(7):630-3. Epub 2008 Oct 23.
9. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. Thromb Haemost. 1981 Jun 30;45(3):200-3.
10. Reitter S, Knoebl P, Pabinger I, Lechner K. Postoperative paraneoplastic factor VIII auto-antibodies in patients with solid tumours. Haemophilia. 2011 Apr 4.
11. Kreuter M, Retzlaff S, Enser-Weis U, Berdel WE, Mesters RM. Acquired haemophilia in a patient with gram-negative urosepsis and bladder cancer. Haemophilia. 2005 Mar;11(2):181-5.
12. Kato T, Masui K, Yoshida T, Soma T, Mishina M, Okuno H, Okuno Y, Terashima T, Minamiguchi S. Acquired hemophilia A developing at bilateral renal bleeding: a case report. Hinyokika Kiyo. 2009 Apr;55(4):215-8.
13. Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CR; UK Haemophilia Centre Doctors’ Organisation. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood. 2007 Mar 1;109(5):1870-7. Epub 2006 Oct 17.
14. Sumner MJ, Geldziler BD, Pedersen M, Seremetis S. Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal. Haemophilia. 2007;13(5):451–461.
15. Collins PW. Treatment of acquired hemophilia A. J Thromb Haemost. 2007;5(5):893–900.
16. Ichikawa S, Kohata K, Okitsu Y, Suzuki M, Nakajima S, Yamada MF, Onishi Y, Yamamoto J, Suzuki S, Ishizawa K, Kameoka J, Harigae H. Acquired hemophilia A with sigmoid colon cancer: successful treatment with rituximab followed by sigmoidectomy. Int J Hematol. 2009 Jul;90(1):33-6. Epub 2009 May 30
17. Machado P, Raya JM, Martín T, Morabito L, Brito ML, Rodríguez-Martín JM. Successful response to rituximab in two cases of acquired haemophilia refractory to standard-therapy. Int J Hematol. 2008 Jun;87(5):545-9. Epub 2008 Apr 15.
18. Field JJ, Fenske TS, Blinder MA. Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy. Haemophilia. 2007 Jan;13(1):46-50.
19. Hayashi T, Morishita E, Asakura H, Nakao S. Two cases of acquired hemophilia A in elderly patients. Nippon Ronen Igakkai Zasshi. 2010;47(4):329-33.
20. Hauser I, Leckner K. Solid tumors and FVIII antibodies. Thromb Haemost 1999; 82:1005-7.

 

Date added to bjui.org: 02/07/2012

DOI: 10.1002/BJUIw-2011-098-web

 

A Case of Metastatic Penile Cancer Showing a Prolonged Disease Free Survival of over Five Years After Cisplatin and Gemcitabine Combination Chemotherapy

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This is the first reported case of prolonged survival of metastatic disease in penile cancer in a patient treated using this chemotherapy regime.

Authors: Nowicki, Stefan; Hendry, David; Russell, John

Corresponding Author: Stefan Nowicki, Beatson West of Scotland Cancer Centre, Glasgow, UK. Email: [email protected]

 

Introduction
 
Penile cancer is a rare cancer in the Western world with an incidence of 0.1-0.9/100 000 men in Europe. In the developing world however the incidence can be much higher accounting for up to 10% of male malignancy. The peak incidence occurs in the sixth and seventh decades of life and is associated with numerous risk factors, the strongest being phimosis, chronic inflammatory conditions, condylomata, sexual history and smoking. HPV infection has been shown to be a possible causative factor with viral DNA being present in up to 80% of tumour specimens; the majority by HPV-16 (1). This is a major cause of other genital malignancies and forms part of the vaccine to prevent cervical cancers in females. For this reason, it has been proposed as a potential preventative measure for penile cancer in the developing world (2).
Treatment of penile cancer can include surgery, chemotherapy or radiotherapy. The primary tumour and lymph nodes are treated separately. Early superficial tumours can be treated with wide local excision or radiotherapy, but partial or complete amputation is required for more advanced disease. Neoadjuvant chemotherapy is also used to downstage initially inoperable cancers. Clinically negative lymph nodes can be involved with metastatic cancer in 15% of cases.  In this situation, dynamic sentinel node biopsy has been shown to improve survival and reduce morbidity (3). Pathologically confirmed disease requires inguinal lymphadenectomy, with pelvic lymphadenectomy in N2 disease or extracapsular spread. In high risk cases adjuvant chemotherapy has also been advocated with cisplatin and 5-fluorouracil (4).
The use of chemotherapy is limited to locally advanced or metastatic disease, with cisplatin based treatments the most commonly used. Response rates are typically 30% at best but, due to the rarity of this disease, are based on small phase II studies and case series. We present a case of metastatic penile cancer which has been successfully treated with cisplatin and gemcitabine. This is the first reported case of prolonged survival of metastatic disease in penile cancer in a patient treated using this chemotherapy regime.

 

Case report

 

A 48 year old male presented with a large necrotic fungating mass replacing the glans penis and causing phimosis, currently looking for phimosis cure. No palpable lymph nodes or evidence of metastatic disease was detected clinically. Dynamic sentinel lymph node biopsy was not available, and no additional imaging was undertaken in accordance with local practice at the time. A partial penile amputation was undertaken and pathology showed a moderately differentiated squamous cell carcinoma. There was a margin of 26mm from the proximal surgical resection site but an area of lymphovascular invasion was identified. The patient recovered well from the operation but developed an enlarging left groin mass one month later. A CT scan showed a soft tissue density in the left groin (figure 1), in addition to several small bilateral soft tissue densities.

 

Figure 1. A CT scan showed a soft tissue density in the left groin

penile cancer 1

 

 

 

 

 

A fine needle aspirate of the lump confirmed squamous cell carcinoma and a bilateral groin dissection was undertaken. The left groin dissection revealed two out of thirteen positive lymph nodes, and the right groin dissection showed one out of ten positive lymph nodes with no evidence of extracapsular spread. He developed postoperative cellulitis and abscess formation which was successfully drained and treated with antibiotics. A CT scan of his chest showed no evidence of pulmonary metastasis and a bone scan was normal. He did not receive any adjuvant treatment and was to be followed up in the clinic every three months with a repeat CT scan every six months.
Four months later he developed suprapubic oedema and two small hard nodules superior to the shaft of his penis measuring 1cm in diameter each. These lesions increased rapidly in size over a period of two months with the further development of new lesions in the same area (figure 2).
Figure 2. CT scan:lesions increased rapidly in size over a period of two months

penile cancer 2

 

 

 

 

 

A fine needle aspirate of one of the lesions showed degenerate malignant squamous cells consistent with recurrence of his penile cancer. A CT scan of his chest, abdomen and pelvis showed no evidence of further disease. The recurrence was not amenable to surgical intervention so he was commenced on palliative chemotherapy.
The patient was started on a four weekly regime of Cisplatin (70mg/m2, D1) and Gemcitabine (1g/m2, D1,8,15) chemotherapy. He developed a complete clinical response to treatment after one cycle (figure 3).

Figure 3. The patient developed a complete clinical response to treatment after one cycle

penile cancer 3

 

 

 

 

 

He completed 5 cycles of chemotherapy with grade one mouth ulcers after the first cycle and a week delay at day 1 of the fifth cycle due to neutropenia. After his chemotherapy he developed erectile dysfunction. He continued to be followed up at three monthly intervals with six monthly CT scans.
Two years later the patient noticed a new hard lump at the base of his penis. This grew over a three week period reaching a size of 1cm2. A CT and bone scan were normal. The lesion was subsequently removed with a wide local excision, and histological examination confirmed moderately differentiated squamous carcinoma consistent with spread from the primary penile lesion. Resection margins were negative and there has been no further recurrence over the last five years. Follow up involved clinical examination every three months, and CT scan every six months, for the first two years. This was followed by six monthly clinical examination and yearly CT scans.

Discussion

Chemotherapy has been used with limited success in locally advanced and metastatic penile cancer. Its use has been based on small non-randomised trials, making comparisons between regimes difficult. The most commonly used chemotherapy doublet is cisplatin/5-fluorouracil which has a 20-30% response rate (5). Responses have also been seen with cisplatin/irinitican (6) and carboplatin/paclitaxol (7) in small case series. The largest response rates have been seen with triple-drug regimes but these are associated with marked toxicity. Cisplatin/methotrexate/bleomycin is the most commonly studied with response rates of 32.5% but with a mortality rate of 12.5%, mostly related to pulmonary complications (8). Its use is not advocated for this reason. Preliminary data from a neoadjuvant trial using paclitaxel/ifosfamide/ cisplatin showed encouraging response rates of 50% with less toxicity (9).
There is little evidence of cisplatin/gemcitabine use in penile cancer in the literature. It is however a common first line regime for the treatment of metastatic squamous cell carcinoma of the lung (10). In addition, squamous cell carcinoma at other sites have been shown to respond. These include carcinomas of the head and neck (11) and of the oesophagus (12). Cisplatin and gemcitabine are also used in other urological tumour types, and is the predominant regime in bladder cancer in both the neoadjuvant and palliative setting (13).
In relation to cisplatin/gemcitabine, there is a case series of two patients with metastatic penile cancer showing partial responses lasting over eleven months with a three weekly regime (14). The treatment, as in this case, was well tolerated with minimal side effects. The burden of metastatic disease was greater however, with both patients having pulmonary metastases as well as widespread lymphadenopathy. In addition, the pathology was more aggressive with both patients having poorly differentiated squamous cell carcinoma as opposed to moderately differentiated carcinoma in this case. This may explain the more prolonged response in our patient.
Our patient developed metastases within a few months post treatment. This is typical for most recurrences in this cancer, with the majority occurring within the first three years (15). Cases have been reported of recurrences occurring after ten years, so there continues to be the small possibility of further development of metastasis in this patient (16).
This case demonstrates a prolonged response to cisplatin/gemcitabine chemotherapy and salvage surgery, with a disease free period of over five years. It is a drug regime that is well established in other tumour types and has shown response in two other penile cancer cases. As the treatment options for metastatic penile cancer are limited, this regime should be studied further in the context of a clinical trial.

References

1. Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 2005 116(4):606-16.
2. Guiliano AR. Human papillomavirus vaccination in males. Gynaecol Oncol 2007 107(suppl 1):S24-S26.
3. Lont AP, Horenblas S, Tanis PJ, Gallee MP, Van Tinteren H, Nieweg OE. Management of clinically node negative penile carcinoma: improved survival after the introduction of dynamic sentinel node biopsy. J Urol 2003 170(3):783-6.
4. Pizzocaro G, Piva L, Bandieramonte G, Tana S. Up-to-date management of carcinoma of the penis. Eur Urol 1997 32(1):5-15.
5. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol 1992 147(3):630-632.
6. Theodore C, Skoneczna I, Bodrogi I, Leahy M, Kerst JM, Collette L, Ven K, Marreaud S, Oliver RD for the EORTC Genito-Urinary Tract Cancer Group: A phase II multicentre study of irinotecan in combination with cisplatin in metastatic or locally advanced penile cancer. Ann Oncol 2008 19(7):1304-1307.
7. Joerger M, Warzinek T, Klaeser B, Kluckert JT, Schmid HP, Gillessen S. Major tumour regression after paclitaxel and carboplatin polychemotherapy in a patient with advanced penile cancer. Urology 2004 63(4):778-780.
8. Haas GP, Blumenstein BA, Gagliano RG, Russell CA, Rivkin SE, Culkin DJ, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol 1999 161(6):1823-1825.
9. Pagliaro LC, Williams DL, Daliani D, Williams MB, Osai W, Kincaid M et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 2010 28(24):3851-7.
10. Smit EF, van Meerbeeck JP, Lianes P, Debruyne C, Legrand C, Schramel F et al. Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group–EORTC 08975. J Clin Oncol 2003 21(21):3909-17.
11. Hitt R, Castellano D, Hidalgo M, García-Carbonero R, Peña M, Brandariz A, Millán JM, Alvarez Vincent JJ, Cortés-Funes. Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck. Ann Oncol 1998 12:1347-9.
12. Millar J, Scullin P, Morrison A, McClory B, Wall L, Cameron D, Philips H, Price A, Dunlop D, Eatock M. Phase II study of gemcitabine and cisplatin in locally advanced/metastatic oesophageal cancer. Br J Cancer 2005 93(10):1112-6.
13. Von der Masse H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin and cisplatin in advanced or metastatic bladder cancer: results of a large randomised multinational multicentre phase III study. J Clin Oncol 18(17):3068-77.
14. Power DG, Galvin DJ, Cuffe S, McVey GP, Mulholland PJ, Farrelly C et al. Cisplatin and gemcitabine in the management of metastatic penile cancer. Urol Oncol 2009 27(2):187-90.
15. Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008 54(1):161-8.
16. Lichtenauer P, Scheer H, Louton T. On the classification of penis carcinoma and its 10-year survival. Recent Results Cancer Res. 1977 (60):110-9

 

Date added to bjui.org: 01/07/2012

DOI: 10.1002/BJUIw-2011-124-web

 

Myelosuppression following adjuvant mitomycin C for upper tract urothelial carcinoma

/by

To our knowledge, this is the first documented case of myelosuppression following adjuvant mitomycin C for upper tract urothelial carcinoma in the absence of evidence of chemotherapeutic agent extravasation.

Authors: Henry Han-I (HH) Yao1, Miguel Suhady (MS) Cabalag1, Antonio (A) DeSousa1, Gideon Adam (GA) Blecher1, Richard (R) McMullin1

1. Department of Urology, Ballarat Base Hospital, Ballarat, Victoria, Australia

Corresponding Author: Richard McMullin, Consultant Urologist, Ballarat Base Hospital, Drummond Street North, Ballarat, Victoria, Australia 3350  Email: [email protected]

 

Abstract
 
A 56-year-old Caucasian female with a background of left nephroureterectomy for upper tract urothelial carcinoma was diagnosed 14 months later with a right renal pelvis urothelial carcinoma. This was managed by open resection of the affected segment and preservation of her solitary kidney. Adjuvant upper tract mitomycin C therapy was started six weeks later. Prior to each cycle, a retrograde pyelogram was performed intra-operatively following the insertion of ureteral ureteric catheter, and this did not demonstrate contrast extravasation on any occasion. Eleven days following her fourth cycle, she presented with febrile neutropaenia and pancytopaenia. She was admitted to hospital and successfully managed with broad spectrum antibiotics. Her bone marrow biopsy revealed bone marrow suppression with no significant blast population. Her leucocyte and platelet counts eventually improved without transfusional support. Therefore, her myelosuppression was most likely secondary to the systemic absorption of mitomycin C instilled into her renal tract. To our knowledge, this is the first documented case of myelosuppression following adjuvant mitomycin C for upper tract urothelial carcinoma in the absence of evidence of chemotherapeutic agent extravasation. Clinicians should have a heightened awareness of this complication and monitor patient’s blood counts before and during adjuvant upper tract mitomycin C therapy.

 

Introduction
 

 

The use of adjuvant therapy in nephron sparing management of upper tract urothelial carcinoma has been documented for over a decade (1-3). However, due to the rarity of upper tract urothelial carcinoma, there is limited data evaluating the safety and efficacy of such practices (4, 5). To the best of our knowledge, we hereby report the first case of myelosuppression following adjuvant mitomycin C for upper tract urothelial carcinoma in the absence of evidence of chemotherapeutic agent extravasation.

 

Case Report

 

A 56-year-old Caucasian female who had undergone left nephroureterectomy for left upper tract urothelial carcinoma presented to a urological practice 14 months later with haematuria and right loin pain. Apart from a history of urothelial carcinoma and upper lip squamous cell carcinoma, both surgically treated in the past, the patient did not have an immunosuppressive medical condition nor was she taking any immunosuppressive medication. She was investigated with a computed tomography intravenous urogram which revealed a suspicious filling defect in the right renal pelvis consistent with a recurrent urothelial carcinoma. After careful discussion and counselling, this was managed by an open resection of the affected right renal pelvis segment and preservation of her solitary right solitary kidney. Cystoscopy, retrograde pyelogram (Figure 1) and limited ureteroscopy were performed prior to the excision and did not reveal any identifiable lesion in the bladder and ureter.

 

Figure 1. Intra-operative retrograde pyelogram demonstrating a suspicious filling defect in the right renal pelvis.

Figure-1web-2012-049

Histology of the right renal pelvis lesion subsequently confirmed it to be a urothelial carcinoma with no evidence of muscle invasion. Following further discussion and counselling, she consented for a six weeks course of adjuvant right upper tract mitomycin C therapy. The first course of mitomycin C was started 6 weeks following the initial operation.

For each upper tract mitomycin C therapy, the patient underwent a theatre-based approach for the placement of ureteral ureteric catheter. Cystoscopy was performed under general anaesthesia, the right ureteral ureteric orifice was visualised and cannulated with a slippery wire over which a 5 French ureteric catheter was passed through. Intra-operative retrograde pyelogram was performed each time and did not demonstrate contrast extravasation on any occasion (Figure 2).
Figure 2. Intra-operative retrograde pyelograms prior to the instillation of the second, third and fourth courses of upper tract adjuvant mitomycin C therapy, respectively from A to C.

Figure-2web2012-049

The ureteral ureteric catheter was secured to a two-way urinary catheter at the completion of each procedure. Post-operatively, pre-made prepared mitomycin C was instilled into the ureteral ureteric catheter over two hours and was allowed to drain out freely from the urethral catheter. Both the ureteral ureteric and urethral catheters were removed post-procedure. Her first mitomycin C instillation was delivered via a syringe driver which delivered 40mg of mitomycin C in 40mls of sterile water at a rate of 20mls per hour. However, her subsequent instillations each consisting of 40mg of mitomycin C in 80mls of sterile water were delivered by an infusion bag hanged hung at approximately one metre above the kidney level, at a rate of 40mls per hour.

The patient experienced some associated nausea, vomiting and irritative urinary symptoms with each cycle of chemotherapy, all of which were self-limiting. However, following her fourth cycle of chemotherapy, she became progressively unwell with worsening nausea, vomiting, anorexia and malaise. She also developed symptoms of mucosal bleeding, alopecia and a metallic taste in her mouth. On retrospective questioning, she developed haematuria only following the third and the fourth cycles of chemotherapy. Eventually, eleven days following her fourth cycle of upper tract mitomycin C, she presented with a fever which was subsequently diagnosed as febrile neutropaenia with a neutrophil count of 0.1 × 109/L. She also developed pancytopaenia with a haemoglobin of 81 g/L, leucocyte count of 0.2 × 109/L and platelet count of 27 × 109/L. The source of her infection was later found to be urosepsis from a sensitive Escherichia coli.

The patient was admitted and successfully treated with broad spectrum antibiotics, fluid management, monitoring of her blood counts and further investigations. Her bone marrow aspirate and trephine revealed marked bone marrow hypoplasia with no abnormal cells seen to suggest a leukaemic process. Subsequent flow cytometry showed no significant blast population (~2%). The patient’s leucocyte and platelet counts gradually improved over the next two weeks in the absence of transfusional support. Given these findings, the most plausible explanation for her pancytopaenia would be myelosuppression secondary to the absorption of mitomycin C instilled into her renal tract. Eleven days following her initial presentation and after receiving a transfusion of two units of red blood cells transfusion, she was discharged home on oral antibiotics and regular blood count monitoring. Adjuvant mitomycin C therapy was ceased following this episode.

Four months following her initial surgery, she underwent a surveillance right flexible ureteroscopy which did not reveal any recurrence of cancer in the renal pelvis, ureter, bladder or urethra. A retrograde pyelogram performed intra-operatively did not reveal any filling defect. Similarly, her repeat computed tomography scan around that time was essentially unremarkable. However, her upper tract washings at the time of flexible ureteroscopy did reveal cells suspicious for malignancy. She was investigated with a repeat flexible ureteroscopy and intra-operative retrograde pyelogram three months later, which once again did not reveal any visible recurrence (Figure 3).
Figure 3. Intra-operative retrograde pyelogram six months following open resection of affected renal pelvis segment.

Figure-3-web-2012-049

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

This time, upper tract washings performed intra-operatively was negative for malignancy. Her next flexible ureteroscopy will once again be in a further 3 months time.

Discussion

Upper tract urothelial carcinoma is rare and accounts for only approximately 5% of all urothelial neoplasms (4, 6, 7), with an estimated annual incidence of one to two new cases per 100,000 inhabitants in Western countries (7). As such, the role of adjuvant therapy in non-muscle invasive upper tract urothelial carcinoma has not been firmly established due to its rarity (4, 5). In the literature, there is only limited data consisting of mainly small retrospective studies and expert opinions to guide clinicians in decision making (6). To our knowledge, there has not been any randomised controlled trials evaluating this clinical question (4, 5).

For a localized upper tract urothelial carcinoma in a solitary kidney, an open nephron-sparing surgery may be indicated (7) and preferred over laparoscopic partial nephrectomy which has a significant likelihood of tumour spillage and subsequent implantation (8). Given the presence of residual urothelium following a nephron sparing surgery, the risk of recurrence of urothelial carcinoma remains. The use of adjuvant therapy in nephron sparing management for upper tract urothelial carcinoma with the goal of not compromising the oncological outcome (5) have been documented for more than a decade (1-3). Small observational studies have shown some response to adjuvant therapy (2, 9-12). However, there has been no documented statistical improvement in survival and recurrence rates with the use of adjuvant therapy over no adjuvant therapy (5). Therefore, the use of adjuvant therapy in upper tract urothelial carcinoma remains to some extent anectodalanecdotal (5).

There is no clear evidence favouring the use of one adjuvant agent over another (5). Despite more limited data available on the use of mitomycin C, it may be a safer option due to the risk of tuberculosis infection associated with adjuvant Bacillus Calmette-Guérin therapy (13, 14). When used intravesically, the most commonly reported adverse effects of mitomycin C are chemical cystitis and allergic skin reactions (15). Other rare localised adverse effects of intravesical mitomycin C have also been reported in the literature and includes incrusted cystitis (16), eosinophilic cystitis (17), bladder perforation (18), necrosis of the corpus spongiosum (19) and distal ureteral stenosis (20). However, the systemic absorption of mitomycin C is very limited due to its high molecular weight of 334.33 (5, 15). As a consequence, reported systemic side effects of intravesical mitomycin C such as prolonged haematuria, fever, chills, nausea, vomiting and fatigue is usually mild and rare (15, 21, 22). Severe myelosuppression, a known toxicity of systemic mitomycin C (23), is certainly extremely rare following intravesical mitomycin C with only a few reported cases (15). In the use of mitomycin C for upper tract urothelial carcinoma this has only been documented in a fatal case of extravasated mitomycin C (9).

The case reported here demonstrates that systemic absorption of mitomycin C, albeit rare, is a possibility even in a urinary tract shown to be intact by retrograde pyelogram just prior to therapy. The only difference in our procedure compared with those previously documented was the delivery technique. Although there are no firm evidence, previous reports have raised concern over increased intrarenal pressure from using syringe drivers or hanging the bag of mitomycin C more than 30cm above the kidney level (5). The first cycle of mitomycin C in this case was delivered by a syringe driver at a rate of 20mls per hour, and the second to fourth cycles of mitomycin C was delivered by an intravenous bag suspended at 1m above the kidney level delivering the medication at a rate of 40mls/hour. Therefore, this may have been a contributing factor to the absorption of mitomycin C in this case. However, Keeley et al. however, documented a technique of infusing 10mls of mitomycin C over 2 minutes followed by clamping of the ureteral ureteric catheter for 10 minutes without any systemic absorption (2), even though the intra-renal pressure is likely to be raised by this.

Conclusion

Systemic absorption of mitomycin C causing myelosuppression can occur when used as an adjuvant therapy for nephron sparing management of upper tract urothelial carcinoma. Clinicians should take this into consideration when counselling patients and planning management. Previous reported methods of reducing pressure of mitomycin C delivery to the renal tract including avoiding the use of syringe drivers or hanging the bag less than 30cm above the kidney level should be employed. Furthermore, clinicians should have heightened awareness of this complication during treatment and patients should have monitoring of blood counts before and during the course of adjuvant mitomycin C therapy.

References

1. Jarrett TW, Sweetser PM, Weiss GH, Smith AD. Percutaneous management of transitional cell carcinoma of the renal collecting system: 9-year experience. J Urol. 1995 Nov;154(5):1629-35.
2. Keeley FX, Jr., Bagley DH. Adjuvant mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma. J Urol. 1997 Dec;158(6):2074-7.
3. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW. Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Urology. 1996 Jun;47(6):819-25.
4. Latchamsetty KC, Porter CR. Treatment of upper tract urothelial carcinoma: a review of surgical and adjuvant therapy. Rev Urol. 2006 Spring;8(2):61-70.
5. Nepple KG, Joudi FN, O’Donnell MA. Review of topical treatment of upper tract urothelial carcinoma. Adv Urol. 2009:472831.
6. Smith ND. Management of upper tract urothelial carcinoma. Adv Urol. 2009:492462.
7. Roupret M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011 Apr;59(4):584-94.
8. Flanigan R. Urothelial Tumours of the Upper Urinary Tract. 9th ed. Wein A, Kavoussi L, Novick A, Partin A, Peters C, editors. Philadelphia: Elsevier; 2007.
9. Martinez-Pineiro JA, Garcia Matres MJ, Martinez-Pineiro L. Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. J Urol. 1996 Aug;156(2 Pt 1):377-85.
10. Katz MH, Lee MW, Gupta M. Setting a new standard for topical therapy of upper-tract transitional-cell carcinoma: BCG and interferon-alpha2B. J Endourol. 2007 Apr;21(4):374-7; discussion 7.
11. Thalmann GN, Markwalder R, Walter B, Studer UE. Long-term experience with bacillus Calmette-Guerin therapy of upper urinary tract transitional cell carcinoma in patients not eligible for surgery. J Urol. 2002 Oct;168(4 Pt 1):1381-5.
12. Nonomura N, Ono Y, Nozawa M, Fukui T, Harada Y, Nishimura K, et al. Bacillus Calmette-Guerin perfusion therapy for the treatment of transitional cell carcinoma in situ of the upper urinary tract. Eur Urol. 2000 Dec;38(6):701-4;discussion 5.
13. Yokogi H, Wada Y, Mizutani M, Igawa M, Ishibe T. Bacillus Calmette-Guerin perfusion therapy for carcinoma in situ of the upper urinary tract. Br J Urol. 1996 May;77(5):676-9.
14. Bellman GC, Sweetser P, Smith AD. Complications of intracavitary bacillus Calmette-Guerin after percutaneous resection of upper tract transitional cell carcinoma. J Urol. 1994 Jan;151(1):13-5.
15. Bolenz C, Cao Y, Arancibia MF, Trojan L, Alken P, Michel MS. Intravesical mitomycin C for superficial transitional cell carcinoma. Expert Rev Anticancer Ther. 2006 Aug;6(8):1273-82.
16. Pascual Regueiro D, Garcia Sanchez S, Oliva Encina J, Remon Garijo ML, Martinez Bengoechea J, Abril Baquero G. [Incrusted cystitis after Mitomicin-C]. Actas Urol Esp. 2005 Jul-Aug;29(7):715-8.
17. Clark T, Chang SS, Cookson MS. Eosinophilic cystitis presenting as a recurrent symptomatic bladder mass following intravesical mitomycin C therapy. J Urol. 2002 Apr;167(4):1795.
18. Racioppi M, Porreca A, Foschi N, Delicato G, Destito A, D’Addessi A. Bladder perforation: a potential risk of early endovesical chemotherapy with mitomycin C. Urol Int. 2005;75(4):373-5.
19. Neulander EZ, Lismer L, Kaneti J. Necrosis of the glans penis: a rare complication of intravesical therapy with mitomycin c. J Urol. 2000 Oct;164(4):1306.
20. Oehlschlager S, Loessnitzer A, Froehner M, Hakenberg OW, Manseck A, Wirth MP. Distal ureteral stenosis after early adjuvant intravesical mitomycin C application for superficial bladder cancer. Urol Int. 2003;70(1):74-6.
21. Wajsman Z, Dhafir RA, Pfeffer M, MacDonald S, Block A, Dragone N, et al. Studies of mitomycin C absorption after intravesical treatment of superficial bladder tumors. J Urol. 1984 Jul;132(1):30-3.
22. Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin North Am. 1992 Aug;19(3):529-39.
23. Bradner WT. Mitomycin C: a clinical update. Cancer Treat Rev. 2001 Feb;27(1):35-50.

Date added to bjui.org: 22/06/2012

DOI: 10.1002/BJUIw-2011-149-web

Segmental testicular infarction mimicking a testis tumor in a 64-year-old man

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We report a case in which a 64-year-old man presented with a painful left hemiscrotum and focal mass in the left testis that mimicked a testicular tumor.

Authors: R.A.L. Jacobs1, E. Degreef2, K. De Laet1

1. Department of Urology, Maxima Medical Center, Veldhoven, The Netherlands
2. Department of Pathology and Medical Microbiology (PAMM), Eindhoven, The Netherlands

Corresponding Author: R.A.L. Jacobs, Department of Urology, Maxima Medical Center, Veldhoven, The Netherlands.Email: [email protected]

Introduction
Segmental testicular infarction (STI) is an uncommon testicular condition. We report a case in which a 64-year-old man presented with a painful left hemiscrotum and focal mass in the left testis that mimicked a testicular tumor.

 

Case report
 
A 64-year-old man with no relevant medical history presented to his general practitioner with acute left hemiscrotal pain and slight swelling of the left epididymis. He was treated with antibiotics for acute epididymitis. One week later, the patient was referred to the urology department because of persistent left sided scrotal pain.
There was no history of trauma and the patient experienced no fever or chills. He had not noted dysuria, hematuria or lower urinary tract symptoms. In the previous few months he had lost 11 kilograms in weight, which according to the patient, was due to his son’s death from melanoma.
Clinically, both testicles were normally positioned. The scrotal skin was devoid of erythema or thickening. The right testicle and epididymis were normal and non tender. The left epididymis was tender to palpation, but not enlarged. A firm non tender mass was palpated deep in the left testis. No pathological supraclavicular lymph nodes, abdominal masses or gynaecomastia were detected.
Ultrasonography revealed a heterogenous hypoechogenic oval shaped lesion in the upper third of the left testis with a size of 9.6mm x 1.8mm, suspicious of a tumor. Color Doppler ultrasound showed an avascular central zone in the lesion (Figure 1).

 

Figure 1. Color Doppler ultrasound showed an avascular central zone in the lesion
a) 

 

echo testis 1b) 
echo testis 2
Several hypoechogenic spots were observed, adjacent to the lesion. There were no signs of invasion of the tunica vaginalis. The right testis and both epididymes were normal on ultrasound.
Tumor markers for testicular cancer were within their normal ranges: αFP 3.3 μg/l (normal <7 μg/L), β-HCG <0.10 IU/l (normal: <3 IU/l) and LDH 240 U/l (normal: <248 U/l). The white blood cell count was 7.8.109/l (normal range: 4.0-10.0.109/l), creatinine 67 μmol/l  (normal 64-104 μmol/l), hemoglobin 10.1 mmol/l (normal 8.5-11.0 mmol/l) and hematocrit was 0.46 l/l (normal 0.40-0.50 l/l). Dipstick analysis of the urine was normal. A CT-scan of the chest and abdomen did not reveal any abnormalities.
Based on the clinical picture and ultrasound findings, a testicular tumor was suspected and a left inguinal exploration was performed. Correction of a small left indirect inguinal hernia was performed simultaneously. At exploration, the left testis appeared normal. No decolorization was noticed. A firm mass deep in the parenchyma was palpable. An inguinal orchiectomy was then performed. No complications occured and the patient made an uneventful recovery.
Pathological examination revealed an area of extensive infarction of the seminiferous tubules. In the surrounding testicular tissue no signs of intraepithelial germ cell neoplasia were present (Figure 2).

 

Figure 2. No signs of intraepithelial germ cell neoplasia presentT11-39855

 

Discussion
 
Unlike global testicular infarction, segmental testicular infarction (STI) is an uncommon testicular condition resulting from partial ischemia of the testis. STI commonly affects males between the second and fourth decades of life.1 However, several cases of STI in children have been reported.[1-3]
STI usually presents with acute scrotal pain and may resemble orchido-epididymitis or torsion of the spermatic cord. The condition can, however, present without pain. Sometimes swelling of the testis is present. In early stages palpation of the testis is normal, however, in more advanced cases an indurated testicular mass can be detected.[4]
Partial ischaemia of the testis is thought to be secondary to venous thrombosis, for which various local and systemic disorders have been reported as causal factors. Such factors include sickle cell anemia, polycythemia, vasculitis, iatrogenic vascular injury, trauma, arterial intimal fibroplasia and previous epididymo orchitis.[5-8] Another possible mechanism reported only recently by Adachi et al. is cholesterol embolism-associated STI.[8] However, the majority of cases have been reported as idiopathic.[5]
In this case the patient was initially treated for acute epididymitis with antibiotics by his general physician. Although it may be possible that this patient developed an STI secondary to epididymitis, our patient had no clinical, laboratory, or echographical signs for this condition. In addition, there was no history of systemic disease or genital trauma. In this  case therefore, the STI could be considered idiopathic.
The majority of cases of STI reported in the literature underwent a (partial) orchiectomy because of the suspicion of malignancy or the need for histology for definitive diagnosis.[5] However, a conservative approach to STI is possible and safe if the diagnosis is reached with a high degree of certainty.[9,10] In this patient we had not reached a high degree of certainty. The age of the patient, the acute onset of pain and negative tumor markers were suggestive of a non malignant condition. However, acute scrotal symptoms may occur in patients with testicular tumors.[11] On the other hand, weight loss of 11 kilograms and the firm mass palpable within the parenchyma were more suggestive of a possible malignancy.
Although ultrasound is the first choice diagnostic tool in evaluating scrotal pain, distinguishing the hypoechogenic lesion from a testicular tumor on ultrasound was difficult in this case. This difficulty in distinguishing between testicular infarction and testicular tumor, especially in small sized lesions, is also reported by other authors.[4,12] STI in adults usually is wedge shaped on ultrasound as is demonstrated by the study of Fernández-Pérez et al.[13]  In our patient, the lesion was oval shaped. Several studies have also reported a round morphology. [5,6,13]
Color Doppler ultrasound showed an avascular central zone with several peri-lesional spots with low colour signals. However, on Color Doppler ultrasound it can be difficult to detect increased blood flow in tumors less than 2 cm in size.[14] In any case, the presence of hypervascularity is not specific for the diagnosis of malignancy, because of the frequent hypovascular pattern of testicular tumors.[15] Therefore, an intratesticular tumor could not be excluded in our patient despite the absence of blood flow in the center of the hypoechogenic lesion.
When a discrepancy between clinical and ultrasonographic findings exists, MRI with contrast may provide additional information over ultrasound, occasionally showing a well-circumscribed hypo-intense area with an enhanced rim, indicating an STI.[13] Nevertheless, definite exclusion of a testicular tumor is not always possible because MRI may demonstrate different findings for different stages of infarction, showing lesions that are lacking the typical features previously mentioned.[16] The use of contrast enhanced ultrasound in the diagnosis of STI seems promising but requires further investigation.[6]
When STI cannot be diagnosed based on the clinical picture and radiologic findings, histological examination is necessary. In most studies STI is histologically confirmed following radical or partial orchiectomy.[4,8,16,19,20] However, in certain cases sparing of the testis is desired and a less invasive way for obtaining a histological confirmation is needed. Perioperative frozen section examination has proven to be accurate for distinguishing benign from malignant lesions, allowing the testis to be spared. In addition, there is no evidence that oncological safety is impaired with this technique.[17] Several studies have showed the feasibility of this method of confirming histology.[1,12,21] In the case of nonpalpable or small hypoechogenic lesions, intraoperative ultrasound guided needle localization with microsurgical exploration has proven to be a safe and effective approach for microsurgical removal of the lesion and obtaining histology. This allows maximal preservation of the testicular parenchyma and its vasculature.[22,23] In this case frozen section examination was not performed, because the patient did not   want to take any risk of the tumor being missed on the frozen section. In addition, because of his age our patient was not troubled by the fact of having one testis for the rest of his life.
As previously mentioned, conservative management has been proven to be possible and safe in highly selected patients where a diagnosis of STI has been made with a high degree of certainty. According to the literature, patients clinically supected to have for STI, with negative tumor markers and Doppler ultrasound and contrast enhanced MRI indicating a STI, are suitable for conservative management with scrotal ultrasound follow-up. Several studies report the development of the ultrasound appearance of STI during follow up ranging from one day to five years.[6,7,9,10] In these studies, follow-up ultrasound demonstrated no progression, or a gradual reduction in size of the lesion, with reflectivity and vascularity essentially unchanged or diminished. This could differentiate STI from a testicular tumor.
In conclusion, differential diagnosis between STI and testicular maligancy remains difficult. STI is therefore mostly detected after (partial) orchiectomy. Some features may suggest this benign condition; a hypovascular wedge-shaped lesion, in patients with normal tumor markers. In highly selected patients,  diagnosis with a high degree of certainty allows conservative treatment with strict follow-up ultrasound. However, if the clinical picture and radiologic imaging are inconclusive or unclear, histologic confirmation cannot be avoided. In that case explorative surgery together with (microsurgical) frozen section examination should be performed, especially in patients in whom sparing of the testis is desired. In the future, further studies are needed to better diagnose this benign condition.

 

References
 
1) Kim HK, Goske MJ, Bove KE, Minovich E. Segmental testicular infarction in a young man simulating a testicular tumor. Pediatr Radiol. 2009;39:400–402
2) Fukuda S, Takahashi T, Kumori K, Takahashi Y, Yasuda K, Kasai T, Yamaguchi S. Idiopathic testicular infarction in a boy initially suspected to have acute epididymo-orchitis associated with mycoplasma infection and Henoch-Schönlein purpura. J Pediatr Urol. 2009;5:68-71
3) Barber TD, Al-Omar O, Poulik J, McLorie GA. Testicular infarction in a 12-year-old boy with Wegener’s granulomatosis. Urology 2006;67:846.e9-10
4) Ruibal M, Quintana JL, Fernández G, Zungri E. Segmental testicular infarction.
J Urol.2003;170:187-188.
5) Gianfrilli D, Isidori AM, Lenzi A. Segmental testicular ischaemia: presentation, management and follow-up. Int J Androl. 2009;32:524-31
6) Bertolotto M, Derchi LE, Sidhu PS, Serafini G, Valentino M, Grenier N, Cova MA. Acute segmental testicular infarction at contrast-enhanced ultrasound: early features and changes during follow-up. AJR Am J Roentgenol. 2011;196:834-41
7) Bilagi P, Sriprasad S, Clarke JL, Sellars ME, Muir GH, Sidhu PS. Clinical and ultrasound features of segmental testicular infarction: six-year experience from a single centre. Eur Urol. 2007;17:2810-2818
8) Adachi S, Tsutahara K, Kinoshita T, Hatano K, Kinouchi T, Kobayashi M, Inoue H, Takada T, Hara T, Yamaguchi S. Segmental testicular infarction due to cholesterol embolism: not the first case, but the first report. Pathol Int. 2008;58:745-8
9) Madaan S, Joniau S, Klockaerts K, DeWever L, Lerut E, Oyen R, Van Poppel H. Segmental testicular infarction: conservative management is feasible and safe. Eur Urol. 2008;53:441-445
10) Madaan S, Joniau S, Klockaerts K, DeWever L, Lerut E, Oyen R, Van Poppel H. Segmental testicular infarction. Conservative management is feasible and safe: part 2. Eur Urol. 2008;53:656-658
11) Guthrie JA, Fowler RC. Ultrasound diagnosis of testicular tumours presenting as epididymal disease. Clin Radiol. 1992;46:397-400
12) Calcagno C, Gastaldi F. Segmental testicular infarction following herniorrhaphy and varicocelectomy. Urol Int. 2007;79:273-275
13) Fernández-Pérez GC, Tardáguila FM, Velasco M, Rivas C, Dos Santos J, Cambronero J, Trinidad C, San Miguel P. Radiologic findings of segmental testicular infarction. AJR Am J Roentgenol. 2005;184:1587-1593
14) Venugopal S, Schoeman D, Damola A, Hamid B, Powell C. Acute scrotal pain with a twist. Ann R Coll Surg Engl. 2010;92:24-26
15) Horstman WG, Melson GL, Middleton WD, Andriole GL. Testicular tumors: findings with color Doppler US. Radiology 1992;185:733-737
16) Kodama K, Yotsuyanagi S, Fuse H, Hirano S, Kitagawa K, Masuda S. Magnetic resonance imaging to diagnose segmental testicular infarction. J Urol. 2000;163:910–911
17) Kirkham AP, Kumar P, Minhas S, Freeman AA, Ralph DJ, Muneer A, Allen C. Targeted testicular excision biopsy: when and how should we try to avoid radical orchiectomy? Clinic Radiol. 2009;64:1158-1165
18) Sharma SB, Gupta V. Segmental testicular infarction. Indian J Pediatr. 2005;72:81-82
19) Secil M, Kocyigit A, Aslan G, Kefi A, Ozdemir I, Tuna B, Yorukoglu K. Segmental testicular infarction as a complication of varicocelectomy: sonographic findings. J Clin Ultrasound. 2006;34:143-145
20) Flanagan JJ, Fowler RC. Testicular infarction mimicking tumour on scrotal ultrasound – a potential pitfall. Clin Radiol. 1995;50:49-50
21) Hidalgo J, Rodríguez A, Canalias J, Muntané MJ, Huerta MV, Carrasco N, Vesa J. Segmental testicular infarction vs testicular tumour: the usefulness of the excisional frozen biopsy. Arch Esp Urol. 2008;61:92-93
22) Hopps CV, Goldstein M. Ultrasound guided needle localization and microsurgical exploration for incidental nonpalpable testicular tumors. J Urol. 2002;168:1084-1087
23) Kravets FG, Cohen HL, Sheynkin Y, Sukkarieh T. Intraoperative sonographically guided needle localization of nonpalpable testicular tumors. AJM Am J Roentgenol. 2006;186:141-143

 

Date added to bjui.org: 18/06/2012

DOI: 10.1002/BJUIw-2012-003-web

 

Classical Hodgkin’s lymphoma presenting as vesicovaginal fistula

/by

This is a previously unreported presentation of Hodgkin’s lymphoma within the context of what is itself a rare complication of neglected pessary use. 

Authors:

Megan Murdocha;Paul Hiltonb
a) Clinical Research Associate, Newcastle University and Specialist Registrar in Obstetrics & Gynaecology, Northern Deanery
b) Consultant Gynaecologist & Urogynaecologist, Newcastle upon Tyne Hospitals NHS Foundation Trust

Corresponding Author: Paul Hilton, Consultant Gynaecologist & Urogynaecologist, Directorate of Women’s Services, Level 5, Leazes Wing Royal Victoria Infirmary, Newcastle upon Tyne , NE1 4LP, UK.   Email: [email protected]

 

Introduction

 

We report the case of a 79-year-old female who presented with acute onset urinary incontinence following the use of a shelf pessary in the management of her vaginal prolapse.  Examination revealed a large vesicovaginal fistula of unusual appearance; subsequent biopsy of the adjacent vaginal tissue confirmed classical Hodgkin’s lymphoma of mixed cellularity type.  This is a previously unreported presentation of Hodgkin’s lymphoma within the context of what is itself a rare complication of neglected pessary use.

 

Case report

 

The patient underwent abdominal hysterectomy in her forties and required a subsequent vaginal procedure for prolapse symptoms in her early seventies; as far as can be ascertained this was a conventional prolapse repair, without incorporation of an non-absorbable ‘mesh’ materials.  She developed recurrent prolapse shortly after surgery and this was managed with a shelf pessary.  Her symptoms were so well controlled that she did not attend for further follow-up, and the pessary was left in situ for 7 years without review.
Her past history included osteoporosis and hypertension; her medication at presentation was alendronate (once weekly), calcium carbonate (calcichew)  (once daily) and amlodopine (5mg daily).  She had left hip and left shoulder replacements.
She presented with sudden onset of continuous urinary incontinence having not had any urinary symptoms previously.  There were no reported bowel symptoms.  On examination under anaesthesia the shelf pessary was embedded in the anterior vaginal wall; after removal a 4x5cm vesicovaginal fistula was found extending from the vaginal vault to the level of the mid trigone.  There was third degree prolapse of the vaginal vault.  An intravenous urogram showed no evidence of ureteric obstruction.  An indwelling urethral catheter was inserted and left on free drainage for one month to encourage spontaneous closure.  This made no difference to her symptoms and she was referred to a tertiary urogynaecology unit specialising in fistula repair.  Examination under anaesthesia was repeated in order to plan the route and method of repair.  This revealed a hard necrotic area at the posterior edge of the fistula.  There was no extension into the rectum. (Figure 1a, b & c)

 

Figure 1a.  Initial view on examination showing prolapse of the bladder wall through the fistula.

 

Hayden 1a

 

1b. Posterior edge of fistula with Allis tissue forceps on the vaginal wall around the fistula edges, and a Landon blade retracting the prolapsed bladder wall.

 

Hayden 1b
1c. Close-up view as in figure 1b.
Hayden 1c

 

Provisional histology suggested changes secondary to chronic inflammation (consistent with her long-term pessary use), but also raised the possibility of lymphoma.  After discussion it was felt appropriate to proceed with surgery as planned, and vaginal vesicovaginal fistula repair combined with repair of the prolapse was undertaken by colpocleisis incorporating a Martius bulbocavernosus muscle & fat graft from the left labium majus; the ureters were stented during the procedure, and all residual visibly abnormal tissue in the area of the fistula was excised.

 

Figure 2a.  Cystoscopic appearance of fistula.

 

Hayden 2

 

Subsequent histology of the excised tissues was felt to represent an Epstein-Barr virus (EBV) -positive lymphoproliferative disease (LPD), consistent with either ‘LPD in the context of chronic inflammation in an elderly person’ or with a mixed cellularity type of classical Hodgkin’s lymphoma (MCCHL).  The clinical, radiological and histological findings were discussed at two independent specialist haematology/lymphoma MDT groups and the final agreed diagnosis, based on the finding of Reed-Sternberg cells, was of MCCHL.
After discharge from the urogynaecology unit, she was referred to her local haematologist for further imaging and clinical review.  CT images were difficult to interpret in view of the recent surgery, prior hysterectomy and a left total hip replacement.  MRI scan of the pelvis showed a small thickened area of tissue between the rectum and the left side of the bladder, i.e. in the area of the recent surgery, and above the level of the Martius fat graft (see figure 3 a & b).

 

Figure 3.  MRI images at 3 months postoperative: 3a showing thickened area to left of bladder base (arrowed).

 

Hayden 3a

 

3b. showing the Martius labial fat graft passing from left labium majus into the lower vagina (arrowed). 

 

Hayden 3b

 

Whilst it was not possible to establish with certainty whether this represented postoperative fibrosis or residual disease, it was felt appropriate to consider this as stage 1AE classical Hodgkin’s lymphoma.  Conventional treatment would have included ABVD chemotherapy (adiamycin, bleomycin, vincristine, dacarbazine) plus involved-field radiotherapy.  However, in a patient of almost 80 years of age, with at worst minimal residual disease, and in the absence of evidence of nodal or distant disease, it was decided to treat with radiotherapy alone.  The patient received external beam radiotherapy to the upper vagina in a dose of 30Gy in 15 fractions.  At subsequent review she was free from symptoms, signs or MRI evidence of disease progression; she remains under 6-monthly surveillance.  Urogynaecology review confirmed a successful fistula and prolapse repair and she has been discharged from follow up.

 

Discussion

 

In the UK, fistulae of the female genital tract are uncommon; a recent review of Hospital Episode Statistics suggest that around 120 urogenital fistulae are treated surgically each year.1  The use of mechanical devices (vaginal pessaries) in the management of pelvic organ prolapse (POP) is common.  Generally they are used for women who have not completed their family or those who do not wish to proceed to surgery, or are considered unsuitable for surgery.  Fistula as a result of pessary use has been reported, but is unusual.  A review in 2008 identified 39 major complications associated with pessary use, including eight vesicovaginal fistulas and four rectovaginal fistulas.2  Since the number of women treated by pessary for prolapse is unknown, the ‘fistula risk’ associated with this form of treatment cannot be determined.  In a recent case series of urogenital fistula in the UK, 11/348 (3.2%) were associated with the use of pessaries for the conservative management of POP.3
In 2008 there were 1730 new cases of Hodgkin’s lymphoma in the UK.  The incidence in females is 2.4 per 100,000; in women two peaks occur at the ages of 20-24 and 70-74 years.4  Extra-nodal lymphoma (with the primary disease other than in lymph nodes) may present at any site, and rare cases in the female genital tract have been reported.5, 6  It is said that 25% of malignant lymphomas arise at extra-nodal sites and in only 1% of women with extra-nodal tumours is the genital tract involved.5  This would suggest an incidence of primary genital tract Hodgkin’s of less than 1 per 100,000,000/ year .  The World Health Organisation classification divides Hodgkin’s lymphoma into several pathologic subtypes.7  In 15% the picture is described as classical Hodgkin’s lymphoma of mixed cellularity subtype, as in this case.4  The aetiology of Hodgkin’s lymphoma is unknown but studies have suggested a viral link; 50% of classical Hodgkin’s lymphomas overall, and up to 70% of MCCHL are EBV-positive.8  There is a known association between chronic inflammation and cancer and it is suggested that chronic inflammation triggered by EBV has a role in the aetiology of Hodgkin’s lymphoma.9  In the case presented, the possibility that this arose because of the presence of inflammation related to the long neglected vaginal pessary must be considered.
Conventionally it is recommended that vaginal pessaries are removed and the vagina examined for erosions on a regular basis.  This is often undertaken every 4-6 months although the optimum frequency has not been established and there is no consensus on the interval between pessary changes.10 The authors of the most recent Cochrane review of mechanical devices in the management of pelvic organ prolapse concluded that randomised controlled trials are needed to inform the best ways to manage long-term pessary use.10

 

Conclusion

 

A case of classical Hodgkin’s lymphoma presenting as a vesicovaginal fistula in a neglected vaginal pessary user is presented.  Although this is an extremely rare complication of pessary use, it emphasises the importance of regular review, including pessary removal, bimanual examination, and speculum visualisation of the vaginal walls.  With an increasing move to pessary management in primary care by General Practitioners and Practice Nurses, the development and implementation of an appropriate educational package is important.

 

References

 

1. Cromwell D, Hilton P. Patterns of care and outcomes of surgical treatment for urogenital fistula among English NHS hospitals between 2000 and 2009. 2012:(submitted).
2. Arias BE, Ridgeway B, Barber MD. Complications of neglected vaginal pessaries: case presentation and literature review. Int Urogynecol J & Pelvic Floor Dysfunct. 2008;19(8):1173-738.
3. Hilton P. Urogenital fistula in the UK – a personal case series managed over 25 years. BJU Int. 2011:(early view).
4. CancerHelp UK. Hodgkin’s Lymphoma.  2012; Available from: https://cancerhelp.cancerresearchuk.org/type/hodgkins-lymphoma/
5. Cheong IJ, Kim SH, Park CM. Primary Uterine Lymphoma: A Case Report. Korean Journal of Radiology. 2000;1(4):223-5.
6. Raggio ML, Bostrom SG, Harden EA. Hodgkin’s lymphoma of the uterus presenting as a refractory pelvic inflammatory disease. A case report. J Repro Med. 1988;33(10):827-30.
7. Swerdlow S. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer, World Health Organization. ; 2008.
8. Thomas RK, Re D, Zander T, Wolf J, Diehl V. Epidemiology and etiology of Hodgkin’s lymphoma. Annals of Oncology. 2002;13(suppl. 4):147-52.
9. Khan GG. Epstein-Barr virus, cytokines, and inflammation: A cocktail for the pathogenesis of Hodgkin’s lymphoma? Experimental Hematology. 2006;34(4):399-406.
10. Adams EJ, Thomson AJM, Maher C, Hagen S. Mechanical devices for pelvic organ prolapse in women. Cochrane Database Syst Rev. 2004;Issue 2:Art. No.: CD004010.

 

Date added to bjui.org: 07/06/2012
DOI: 10.1002/BJUIw-2012-017-web

 

Inadvertent injury to an incidental ectopic ureter in a completely duplicated collecting system during open radical perineal prostatectomy

/by

We present the diagnosis and management of a man with clinically localised prostate cancer and a complete duplication of the right collecting system associated with an asymptomatic upper pole ectopic ureter, that was inadvertently injured during open RPP.

Authors: Miguel Suhady (MS) Cabalag1, Henry Han-I (HH) Yao1, Gideon Adam (GA) Blecher1, Antonio (A) DeSousa1, Diana (D) Tran2

1 Department of Urology, Ballarat Base Hospital, Ballarat, Victoria, Australia
2 Department of Radiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia

Corresponding Author: Richard (R) McMullin,  Consultant Urologist, Ballarat Base Hospital, Drummond Street North  Ballarat VIC 3350, Ballarat, Victoria, Australia E-mail: richard.mcmullin@ballaraturology

 

Abstract
 
It is rare for embryologic abnormalities of the urinary tract to present in adulthood, especially as an incidental finding post radical perineal prostatectomy (RPP). We present the incidental diagnosis and subsequent management of a 68 year old man with clinically localised prostate cancer and a complete duplication of the right collecting system associated with an asymptomatic upper pole ectopic ureter, that was inadvertently injured during open RPP.

 

Introduction
 
With the earlier detection of clinically localised prostate cancer using prostate specific antigen (PSA) testing, it has become routine not to perform extensive staging investigations to avoid unnecessary tests. This approach may lead to rare unforeseen post-operative complications in patients with asymptomatic congenital anomalies of the urinary tract. We report the case of a 68 year old man who presented with persistent urinary extravasation from his surgical wound following RPP. Subsequent CT intravenous urogram demonstrated an incidental complete duplication of the right collecting system and an injured right upper pole ectopic ureter. To our knowledge, there are only four cases reported in the literature of ectopic ureters found incidentally in men undergoing radical prostatectomy for prostate cancer (1-4), and we describe the first case reported during RPP.

 

Case Report
 
A 68 year old asymptomatic man initially presented with an incidental elevated PSA of 4.8 ng/ml (12% free) detected on routine testing. The patient otherwise had no significant past medical history. On digital rectal examination, the prostate was mildly enlarged and firm but with no palpable nodules bilaterally. Trans-rectal ultrasound (TRUS) of the prostate with concurrent 12 core guided biopsies, revealed no suspicious areas and an estimated prostate volume of 60 cm3. Histopathology showed a 2mm focus of Gleason 6 (3+3) prostate adenocarcinoma, which was only detected following further immunohistochemical staining. An active surveillance approach with six monthly PSA tests was initially adopted given the very low volume of malignancy. Over the next 18 months, the PSA gradually rose to 8.2 ng/ml whereby a repeat TRUS guided biopsy revealed prostate adenocarcinoma with Gleason 6 (3+3) in 33% of 1 core obtained from the right lateral prostate (clinical stage T1c).
Following patient counselling, a radical nerve-sparing perineal prostatectomy was performed using a previously described technique (5). A routine pre-operative rigid cystoscopy revealed a normal urethra and bladder with two appropriately located ureteric orifices. Surgery went as planned and a 16Fr two-way silicone indwelling catheter was inserted into the bladder intra-operatively. The urethral anastomosis was subsequently checked to ensure a watertight seal and a tube drain was also inserted through a separate stab incision into the perineum. Pelvic lymphadenectomy was not performed due to the patient’s low risk pathology. The final pathology demonstrated a Gleason 7 (3+4) adenocarcinoma, localised predominantly to the right lower zone involving approximately 15% of total prostatic volume. Lymphovascular invasion was absent and the surgical margins were clear.
Early post-operative recovery was uneventful and the drain tube was removed on post-operative day (POD) 2. A routine trial of void 2 weeks post surgery resulted in a persistent urine leak from the apex of his perineal wound, which was exacerbated by urination. Of note, the patient remained pain free and afebrile throughout the post-operative period. This was initially suggestive of an anastomotic leak and therefore the indwelling urinary catheter was re-inserted. However, a cystogram did not show any extravasation of contrast (Figure 1) and the leak persisted through the apex of the wound, so the re-introduced urinary catheter was removed.
Figure 1. Post-operative retrograde cystogram showing no anastomotic leakage

 

 

Subsequent computed tomography (CT) intravenous urogram demonstrated a complete duplication of the right collecting system with an ectopic right upper pole ureter (Figure 2a and 2b), the distal end of which could not be properly visualised.

 

Figure 2a.  Coronal view of the CT intravenous urogram showing the right lower pole ureter (LPU) and the right upper pole ectopic ureter (UPEU).

 

 

Figure 2b. 3D reconstruction of the coronal CT-intravenous urogram showing the orthotopic insertion of the right lower pole ureter (LPU) into the bladder (solid arrow), the tortuous right upper pole ectopic ureter (UPEU, dotted arrow). Note an indwelling urinary catheter is in situ.

 

 

There was also a fistulous tract originating from the ectopic ureter, draining into the perineum (Figure 3). The patient subsequently developed right-sided epididymo-orchitis, which was successfully treated with intravenous gentamicin and amoxicillin.

 

Figure 3. Coronal view of the CT intravenous urogram demonstrating the right upper and lower pole renal moieties, as well as a fistulous tract (solid arrow) originating from the ectopic ureter into the perineum on the right side (dotted arrows). 

 

Management
 
The patient subsequently underwent a rigid cystoscopy and a right retrograde pyelogram, which demonstrated a non-dilated right ureter draining into a lower renal moiety, producing a ‘drooping lily’ type image of the right kidney (Figure 4).

 

Figure 4. Right retrograde pyelogram demonstrating the characteristic ‘drooping lily’ image of the lower renal moiety. 

 

 

After patient counselling, the decision was then made to perform an open right ureteric reimplantation. Intra-operatively, two ureters were identified in the retroperitoneum adjacent to the bifurcation of the right common iliac vessel. The lateral ureter was entered via a small stab incision and dye was injected. This dye was noted to be draining out of the indwelling catheter and therefore this was thought to be the normal ureter that was draining into the bladder. The medial ureter was also pierced and dye was injected, but the dye was not detected in the bladder. Thus, this was thought to be the ectopic ureter, most likely to have been injured during the RPP. Given the close proximity of the bladder to the ectopic ureter, a uretero-vesical anastomosis was performed. The distal ectopic ureter was spatulated and a cystotomy was made at a corresponding site. A 6Fr 26 cm ureteric stent was passed through the ectopic ureter over a guide wire up to the right kidney, and the distal end was placed through the cystotomy. Using four, 4-zero vicryl sutures in an interrupted fashion, the ureter was securely implanted onto the bladder with good mucosal apposition. A pelvic drain tube was placed adjacent to the newly formed uretero-vesical anastomosis. There were no peri-operative complications, the drain was removed on POD 4 and the patient was discharged home on POD 6. A flexible cystoscopy was performed approximately 4 weeks after to remove the ureteric stent. Repeat CT intravenous urogram performed 2 months post re-implantation demonstrated complete duplication of the right collecting system with double ureters in which contrast drained normally into the bladder. Importantly, it did not show any hydronephrosis bilaterally, no perineal collection nor any leak from the right renal tract (Figure 5).

 

Figure 5. Coronal view of the CT intravenous urogram post uretero-vesical anastomosis of the right upper pole ectopic ureter, showing resolution of the fistulous tract to the perineum.

 

 

Discussion
 
We report the case of a patient who was incidentally found to have a complete duplication of the right collecting system with an asymptomatic ectopic upper pole ureter that was inadvertently injured during a RPP. To our knowledge, this is the first case reported in the literature associated with such surgery.
A duplex system refers to a kidney with two pelvicalyceal systems within a single renal parenchyma, which may have either a single or bifid ureter (partial duplication), or two discrete ureters (complete duplication) (6).  Renal duplication is a relatively common congenital anomaly, with a reported prevalence of 0.3-6% (7). The majority of cases are detected during childhood, but up to 20% of patients remain asymptomatic into adulthood (8). In contrast, ectopic ureters are rare, with a reported incidence of 1 in 1900 (9). Ectopic ureters are more common in females and are usually associated with a duplicated collecting system, whereas they are typically associated with a single collecting system in men (10).The anatomic site of insertion of an ectopic ureter in a duplicated collecting system follows the Weigert-Meyer rule, whereby the upper pole ureter is more commonly ectopic and the lower pole ureter typically inserts into the trigone, or laterally and cranially to this structure. In 50-60% of patients, renal duplication is associated with vesicoureteric reflux, which may affect one or both ureters. Reflux is more common in the lower pole kidney (97%), while ureteroceles and ectopic ureters are commoner in the upper pole kidney (11).
The presentation of ectopic ureters depends on their site of insertion. Ectopic ureters inserting into the prostatic urethra typically present with urinary tract infections or lower urinary tract symptoms of urgency and frequency. Ectopic ureters inserting into a seminal vesicle, vas deferens or epididymis may present with epididymitis, chronic prostatitis, abdominal or pelvic pain, discomfort during ejaculation, constipation, or a large abdominal mass secondary to obstruction and hydronephrosis. Males with an ectopic ureter may also present with infertility (3).
In males, the majority of ectopic ureters (50%) insert into the prostatic urethra, and 33% into a seminal vesicle. The least common sites include the prostatic utricle and the vas deferens (12). Ectopic ureters in males almost never insert distal to the external sphincter, where it would present as urinary incontinence. One such case has been reported in the literature (13). Of note, this patient had no lower urinary tract symptoms prior to the RPP. It is likely that in this case, the upper pole ectopic ureter was transected during the bladder neck dissection at the level of the prostatic urethra.
There are multiple treatment options for the pathological ectopic ureter associated with a duplicated system, including ureteropyelostomy, heminphrectomy, ipsilateral ureteroureterostomy and common sheath reimplantation (14). An ureterovesical anastomosis was performed in this case due to the upper pole ectopic ureter being a distinct entity from the lower pole ureter, and because of its close proximity to the bladder.
Current guidelines do not recommend imaging of the prostate with CT or MRI for low risk disease prior to radical prostatectomy. Consequently, any asymptomatic congenital anomalies of the urinary tract will not be detected preoperatively. However, due to the rarity of such anomalies, as well as the expense and potential risk to patients, routine preoperative imaging to detect congenital abnormalities is not justifiable in this setting. In the retrospective study conducted by Costa et al, only 3 out of 254 (1.1%) surgical descriptions of nephroureterectomy samples showed anatomical variations of the collecting system, with all cases demonstrating ureteric duplications (15).
Of interest, given the established genetic association of duplex systems, the patient’s twin brother subsequently underwent a CT intravenous urogram, which did not demonstrate any evidence of a duplicated system or ectopic ureter.

 

Conclusion
 
Preoperative imaging may help detect asymptomatic congenital abnormalities of the urinary tract, enabling appropriate intraoperative management. However, given the rarity of such anomalies and the expense of imaging, extensive investigations prior to radical prostatectomy for the sole purpose of screening for congenital abnormalities is not justifiable. However, this case highlights the need to consider congenital anomalies of the urinary tract as a possible differential in peri-operative complications post radical prostatectomy.

 

References
 
1. Funahashi Y, Kamihira O, Kasugai S, Kimura K, Fukatsu A, Matsuura O. [Radical prostatectomy for prostate carcinoma with ectopic ureter ; a case report]. Nihon Hinyokika Gakkai zasshi The japanese journal of urology. 2007 2007;98(3):580-2.
2. Ghazi A, Zimmermann R, Janetschek G. Delayed detection of injury to an ectopic ureter of a duplicated collecting system following laparoscopic radical prostatectomy for early organ-confined prostate cancer. Urologia internationalis.  2011 Feb (Epub 2010 Nov;86(1):121-4.
3. Marien TP, Shapiro E, Melamed J, Taouli B, Stifelman MD, Lepor H. Management of localized prostate cancer and an incidental ureteral duplication with upper pole ectopic ureter inserting into the prostatic urethra. Reviews in urology. 2008 2008;10(4):297-303.
4. Nakai Y, Tanaka M, Yoshikawa M, Tanaka N, Hirayama A, Fujimoto K, et al. [Prostate cancer and left ectopic ureter opening to seminal vesicle with left renal agenesis: a case report]. Hinyokika kiyo Acta urologica Japonica. 2009 2009;55(1):47-50.
5. Weiss JP, Schlecker BA, Wein AJ, Hanno PM. Preservation of periprostatic autonomic nerves during total perineal prostatectomy by intrafascial dissection. Urology. 1985 1985;26(2):160-3.
6. Glassberg KI, Braren V, Duckett JW, Jacobs EC, King LR, Lebowitz RL, et al. Suggested terminology for duplex systems, ectopic ureters and ureteroceles. The Journal of urology. 1984 1984;132(6):1153-4.
7. Hartman GW, Hodson CJ. The duplex kidney and related abnormalities. Clinical radiology. 1969;20(4):387-400.
8. Privett JT, Jeans WD, Roylance J. The incidence and importance of renal duplication. Clinical radiology. 1976 1976;27(4):521-30.
9. Campbell M, Harrison J. Anomalies of the Ureter. In: Campbell M, editor. Urology. 3rd ed. Philadelphia: WB Saunders; 1970.
10. Schlussel R, Retik A. Ectopic ureter, ureterocele, and other anomalies of the ureter. In: Wein A, Kavoussi L, Novick A, editors. Campbell-Walsh Urology. 9th ed. Philadelphia: Saunders Elsevier; 2008. p. 3383-422.
11. Jelloul L, Valayer J. Ureteroureteral anastomosis in the treatment of reflux associated with ureteral duplication. The Journal of urology. 1997 1997;157(5):1863-5.
12. Ellerker AG. The extravesical ectopic ureter. The British journal of surgery. 1958 1958;45(192):344-53.
13. Ejaz T, Malone PS. Male duplex urinary incontinence. The Journal of urology. 1995 1995;153(2):470-1.
14. Chacko JK, Koyle MA, Mingin GC, Furness PD, 3rd. Ipsilateral ureteroureterostomy in the surgical management of the severely dilated ureter in ureteral duplication. The Journal of urology. 2007 2007 Oct (Epub 2007 Aug;178(4 Pt 2):1689-92.
15. Costa HC, Moreira RJ, Fukunaga P, Fernandes RC, Boni RC, Matos AC. Anatomic variations in vascular and collecting systems of kidneys from deceased donors. Transplantation proceedings. 2011 2011;43(1):61-3.

 

Date added to bjui.org: 23/05/2012
DOI: 10.1002/BJUIw-2011-145-web

 

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