Reconstructive and Paediatric Urology
Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants
Mr Supul Hennayake, Consultant Paediatric Urologist, Department of Paediatric Urology, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, UK. e-mail: email@example.com, firstname.lastname@example.org
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Approximately 200 cases of persistent Müllerian duct syndrome have been reported over the last 50 years and most authors suggest leaving the Müllerian remnant in situ because of the difficulty in dissection and the presumed absence of risk of malignancy. However, with increasing reports of Müllerian malignancies emerging, we report our 10-year experience of managing patients with persistent Müllerian duct syndrome, with removal of müllerian remnants.
This case series shows that there is an increased risk of Müllerian malignancy that was previously unknown. With the laparoscopic approach, orchidopexy with simultaneous removal of Müllerian remnants could be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. This is a new technique that has not been previously performed. Considering the current evidence of malignancy in the Müllerian remnant, surgeons would need to discuss with families about removal of remnants or long-term monitoring.
- • To describe the presentation and management of eight patients with persistent Müllerian duct syndrome (PMDS) seen over a 10-year period at our tertiary centre.
- • To review the literature of Müllerian malignancies reported in PMDS.
PATIENTS AND METHODS
- • The hospital records of eight patients with PMDS were retrospectively reviewed between 2001 and 2011.
- • Extensive PubMed searches for PMDS and Müllerian malignancy were performed.
- • Eleven cases with PMDS and malignancy of the Müllerian remnants were identified.
- • From our own PMDS series: five males presented with bilateral undescended testes and three had unilateral undescended testis.
- • We found that the Müllerian remnants could be removed by laparoscopy and three patients had simultaneous laparoscopic removal of the Müllerian structures and laparoscopic orchidopexy.
- • The principle aim of orchidopexy with simultaneous laparoscopic removal of the Müllerian structures can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future.
- • Surgeons should consider excision of the Müllerian remnants where possible.
persistent Müllerian duct syndrome
Persistent Müllerian duct syndrome (PMDS) is a rare genetic disorder of internal male sexual development. These males have a 46XY karyotype with normal external male genitalia but with internal Müllerian duct structures; including a uterus, cervix, Fallopian tubes and upper two thirds of vagina .
PMDS can result from a defect in either the genes coding for the anti-Müllerian hormone (AMH) or in the AMH receptor . They are distinguished by analysing the AMH levels. AMH induces Müllerian duct regression at 7 weeks of gestation. Subsequent to this, the testes move transabdominally to the deep inguinal rings and into the scrotum . The presence of the Fallopian ducts and their attachments to the testis prevents the testis from descending normally. The undescended testis (UDT) could be impalpable or palpable in the groin.
The most common presentation is impalpable UDT on one side and either a palpable UDT or an inguinal hernia on the other side. Patients may also present with bilateral palpable UDT and, rarely. with bilateral impalpable UDT  or with transverse testicular ectopia . PMDS is usually diagnosed during orchidopexy or inguinal herniorrhaphy .
Approximately 200 cases of PMDS have been reported over the last 50 years and most authors suggest leaving the Müllerian remnant in situ because of difficulty in dissection and a presumed absence of malignancy risk. However, with increasing reports of Müllerian malignancies emerging, we report our 10-year experience of managing patients with PMDS with removal of Müllerian remnants.
Retrospective review of case notes and literature was very helpful in determining the main principles of management and in establishing a surgical strategy as to how to proceed after unexpected diagnosis of PMDS at groin exploration or at laparoscopy.
METHOD AND RESULTS
The patients were identified from the prospectively maintained urology and endocrine databases at our tertiary centre and complete review of case notes and specialized investigations were achieved.
Case 1: AH 18-month-old boy was referred with impalpable UDT on the right and palpable UDT on the left. Laparoscopy revealed PMDS. He had a 46XY karyotype and AMH was undetectable, confirming AMH deficiency. He had a laparoscopic left orchidopexy with complete removal of the Müllerian structures and 6 months later underwent laparoscopic right orchidopexy. Both testes were down in the scrotum and healthy at 6 months follow-up.
Case 2: AUR His 9-year-old brother had previously undergone open one-stage Fowler–Stephens orchidopexy for bilateral impalpable UDT at 12 months of age. His testes became impalpable postoperatively and he was known to the endocrine service with a diagnosis of ‘vanishing testes syndrome’. He was re-evaluated subsequent to the index case's diagnosis and PMDS was found on laparoscopy. His left testis was found at the inguinal ring, tethered to the Müllerian ducts, necessitating repeat orchidopexy after removal of the Müllerian structures. The right testis was atretic in the groin and was removed. At 6 months follow-up the left testis was normal in the scrotum. He was also confirmed as AMH deficient with 46XY karyotype.
Case 3: The uncle of case 1 and 2 also had bilateral UDT. The left testis was palpable and the right testis was impalpable, and he was never operated on in childhood. He went through puberty appropriately but was not able to father children. He was diagnosed as having a Müllerian remnant when operated on for a seminoma of his intra-abdominal testis aged 40 years. This patient was not managed by us.
Case 4 MR: One-year-old boy presented with a large reducible left inguinal hernia and right impalpable UDT. Exploration of the left groin revealed Müllerian remnants. Left orchidopexy was performed after freeing the testis and vas from the Fallopian duct. A healthy left testis was felt in the scrotum 3 months after the operation. The child is awaiting laparoscopy for removal of Müllerian structures and right orchidopexy. He also has distal hypospadias.
Case 5 MYI: An 8-month-old boy was referred for bilateral UDT. The left testis was palpable and came into the scrotum easily and the right testis was impalpable. Bilateral orchidopexy and laparoscopic excision of Müllerian structures were performed. He was also found to have 21-hydroxylase-deficiency congenital adrenal hyperplasia. The karyotype was 46XY. At the 5-year follow-up both testes were healthy and normal in the scrotum.
Case 6 JJ: A 4-year-old boy born with bilateral UDT and penoscrotal hypospadias, had a previous left groin exploration which revealed a 2-mm long testicular nubbin. Laparoscopy of the right intra-abdominal testis then revealed PMDS. He required a Fowler–Stephens stage I procedure because the right testis was quite high. At the second operation, right orchidopexy and hysterectomy were performed. Histology confirmed complete removal of the uterus and at 6 months follow-up the right testis was healthy in the scrotum.
Case 7 HC: Born with proximal hypospadias and palpable right UDT. Groin exploration revealed a 0.5-mL small right gonad with a structure similar to a Fallopian tube close to it and these were excised. Histology showed a streak gonad with some ovarian tissue and a Fallopian tube. The biopsy of normally descended left testis showed normal testicular tissue. Subsequent endocrine assessment revealed normal male karyotype with two cell lines; most, 57/59, with a very small Y chromosome and the others, 2/59. normal. Both Y chromosomes had the SRY gene. This patient is considered as having mixed gonadal dysgenesis with persistent Müllerian ducts. The child is awaiting laparoscopy for removal of residual Müllerian structures which were noted on MRI.
Case 8 JA: Born with proximal hypospadias and impalpable right UDT. A diagnosis of mixed gonadal dysgenesis with persistence of Müllerian structures was made and these were removed by open transvesical–transtrigonal surgery at 1 year of age. The dysgenetic right gonad was removed at the same time. The left gonad was in the scrotum and a biopsy showed this to be a dysgenetic testis. The karyotype was 46XY. The left testis was removed after completion of normal puberty and histology showed evidence of intratubular germ cell neoplasia.
The laparoscopy was performed via an umbilical port using zero and 30-degree scopes with two instruments introduced from ports placed on either side. For older larger children, a 10-mm telescope and 5-mm instruments were used. For smaller children, a 5-mm telescope and 3-mm instruments were used. A short table was used, in smaller children, so that the surgeon could perform the operation from the head end comfortably. In older children, the surgeon stayed on the right side of the table. The child was placed in the Trendelenburg position with buttocks at the foot end of the table with legs in stirrups, for the second surgeon to perform cystoscopy. Two monitors were placed on the left side of the patient: for cystoscopy, close to the head end, and for laparoscopy close to the foot end.
The requirements for successful surgery were as follows:
- • pre-operative bowel preparation and anaesthetic management to achieve an empty rectum and non-distended bowels
- • an empty bladder retracted up to the anterior abdomen with a stay suture or with a retractor from a fourth port (a urethral or suprapubic catheter was used and the bladder was emptied with a syringe)
- • a Hegar dilator in the rectum for clear identification and for retraction of the rectum towards the sacrum or sideways
- • a urethral dilator or a cystoscope in the Müllerian remnant to aid with the identification of this and appropriate traction
- • rotation of the 30-degree scope to look anteriorly towards the urethra to show the entry point of the Müllerian remnant to the posterior urethra.
Scissors were used to open the peritoneum lateral to the vessels and medial to the vas deferens and to mobilize the vessels as described for standard laparoscopic orchidopexy. The peritoneum was opened behind the bladder. A fine monopolar diathermy hook was the main instrument used for dissection between the uterus and vasa, getting into the planes using traction. A pulsed-bipolar cutter (Plasmakinetic; Gyrus, Tuttlingen, Germany) was used to transect the upper vagina as low down as possible and a large catheter was placed in the urethra for 1 week. In two patients, large uteri were hitched up using external stay sutures. The testes were brought down to the scrotum via the inguinal canal, or just lateral to the median umbilical ligament, to reach the superficial inguinal ring directly by making a groin incision in one instance and by passing another 5-mm port from the scrotum at other times. In the Fowler–Stephens stage 2 procedure, the vasal vessels were clearly seen and preserved at the second-stage operation.
PMDS is an autosomal recessive inherited disorder. AMH produced by testicular Sertoli cells at 7 weeks of gestation causes the Müllerian ducts to disappear by epithelial–mesenchymal transformation . Subsequent to the atrophy of the Müllerian ducts induced by AMH, the testes move transabdominally to the deep inguinal rings by guidance of the gubernaculum and continue to descend into the scrotum . Defects with AMH or the receptor result in PMDS. Patients with PMDS are externally normally virilized because it is dihydrotestosterone that induces this and this is not linked with AMH . As PMDS is an autosomal recessive condition, AMH mutations occur with an increasing rate of consanguinity . This has been highlighted in the case series, with five cases being consanguineous. The two cases with siblings involved had a homozygous mutation preventing AMH secretion. There is only one other report of this mutation in the world and that is from a Yugoslavian patient in 2004 . We are awaiting genetic analysis from the other cases.
We found approximately 200 case reports on PMDS in the literature. The most common presenting symptoms were inguinal hernia, undescended testis, testis tumour, and abdominal mass.
There was a pre-operative suspicion of PMDS in only one patient (Case 2) as he had laparoscopic assessment after the diagnosis of PMDS in his younger brother. In the other seven patients the diagnosis was made at surgery. Unilateral and even bilateral undescended testes without PMDS are a common presentation compared with PMDS. Most surgeons may not see any patient with this condition during their surgical career, or may come across one unexpectedly. It is important to be aware of this rare condition and perform laparoscopy whenever there is an impalpable testis.
The main question is how to progress when PMDS is suspected. Müllerian structures may be found during groin exploration for an inguinal hernia or for a palpable undescended testis or at laparoscopy for an impalpable testis. It would be most helpful if a surgeon with more experience were available to confirm the diagnosis. If a clinical diagnosis is not possible, it would be best to abandon the procedure after taking intra-operative photographs with or without gonadal biopsies. When a firm diagnosis is made with experience, the intended procedure could be carried out under the same anaesthetic after informing the parents.
In this series, unusual findings were noted at inguinal herniotomy in one patient and during laparoscopy for impalpable testis in three patients. The presence of a uterus, Fallopian tubes and testes associated with a normally developed penis were sufficient to make a working diagnosis in all three patients. They subsequently all had chromosomal and AMH studies.
In the child with the hernia on the left and impalpable testis on the right (Case 4), the general paediatric surgeon noted the abnormal structures and requested confirmation and advice on how to proceed. The ideal management for this patient should have been laparoscopy in the first instance considering that the right testis was impalpable. After a firm clinical diagnosis it was decided to perform a formal inguinal herniotomy and left orchidopexy ensuring that the Müllerian structures were replaced in the peritoneal cavity and to organize laparoscopic right orchidopexy and excision of Müllerian structures as a second procedure. It is important to replace the Müllerian structures in the peritoneal cavity in such a way that they will be readily found at laparoscopy. On the other hand, if the uterus and the Fallopian tube(s) are clearly seen in the hernial sac, meticulous dissection to remove them would be appropriate with careful preservation of the vasa, which descend on either side of the uterus. The child may have a cystoscopy and laparoscopy under the same anaesthetic.
In three patients the diagnosis was made at laparoscopy. The testes were dealt with in the same way because they were simple impalpable testes – standard laparoscopic orchidopexy when the testes were close to the deep inguinal ring with long testicular vessels and Fowler–Stephens two-stage orchidopexy when the testis was higher and the vessels were shorter (in one patient). In these three patients removal of the Müllerian structures facilitated orchidopexy by allowing the vas to move laterally.
Two cases had undergone previous orchidopexies and PMDS was not diagnosed at the time. In case 6, groin exploration was performed for a small palpable left testis which was felt next to the pubic tubercle. The operation notes for these two patients did not mention the presence of Fallopian tubes or uterus. These patients underwent surgery before the common use of laparoscopy. It is possible to miss a PMDS at groin orchidopexy because the peritoneum is not opened routinely during the procedure.
When PMDS is found at surgery, it is possible to go ahead with the planned procedure after a firm clinical diagnosis. The decision to leave the Müllerian remnants tends to be based on the surgical team involved with the priority being orchidopexy to preserve fertility and to prevent testicular malignancy, which is more common than Müllerian malignancy.
Approximately 200 cases of PMDS have been reported over the last 50 years and it has been linked with familial association, infertility and testicular malignancy. These are mostly single case reports or familial cases and most authors suggest leaving the Müllerian remnant in situ because of the difficulty of dissection and the presumed lack of risk of malignancy. However, a thorough search of the literature over the last 40 years uncovered 11 patients developing malignancy, arising from the Müllerian remnants and not from the testes, between 4 and 68 years of age [8–18]
There is agreement that the main surgical considerations are preserving fertility and preventing malignant change in the testes. It is known that long-term cryptorchidism can lead to infertility and ideally orchidopexy should be performed before 2 years of age to preserve fertility. In PMDS, the testes seem to be histologically normal. The incidence of malignant change in these testes is 5–18%, which is the same as the rate of malignancy in abdominal testes in a man without PMDS . Case 3 had both PMDS and an intra-abdominal seminoma. Reports have documented embryonal carcinoma, seminoma, yolk sac tumour and teratoma in PMDS .
We found 11 cases in the literature of Müllerian malignancy in PMDS presenting between 4 and 68 years of age (Table 1). In four of the 11 cases their PMDS was missed at previous urological procedures. These missed remnants then led to Müllerian malignancy. Two of these patients subsequently died as the result of metastatic spread. Altogether, metastatic spread occurred in three cases: two with adenocarcinoma and one with adenosarcoma. One patient had local recurrence of adenocarcinoma 4 years after primary resection. There was no mention of postoperative complications in the others once the malignancy was fully resected. However, in one patient, the follow up period has been mentioned as 16 weeks only.
Table 1. Case series of malignancies arising from the Müllerian remnant
| 1||1968||44||Recurrent UTIs, Back pain, Urethral discharge||At age 18, pt had hypospadias repair, bilateral inguinal exploration for cryptorchidism and left orchidopexy. PMDS not seen.||Squamous cell carcinoma ||• Inoperable tumour|
|• Metastatic spread|
| 2||1976||68||Lower abdominal pain, Irritative bladder symptoms||Not known. No information regarding cryptorchidism given.||Papillary cystadenocarcinoma ||• Resection of tumour|
|• Radiotherapy and oestrogen therapy|
|• No evidence of recurrence at age 82|
| 3||1981||33||Haematuria, Right flank pain||Several years of haematuria: Cystoscopy, retrograde studies. PMDS not seen. Pt had unremarkable genitalia, testicles and vas deferens.||Clear cell carcinoma ||• Resection of tumour|
|• No metastases|
|• No further information given regarding recurrence|
| 4||1990||4||UTI, Haematuria||Nil. External genitalia were normal.||Squamous cell carcinoma ||• Resection of tumour|
|• No metastases|
|• No further information regarding follow-up|
| 5||1992||50||Haematuria||Not known. No information regarding cryptorchidism given.||Adenocarcinoma ||• Resection of tumour|
|• Recurrence of tumour 4 years post-op.|
|• Radiotherapy given|
|• No further information|
| 6||1996||36||Lower abdominal pain, Fever||Radical surgery for hypospadias. PMDS not seen. External genitalia normal, testes present on both sides.||Squamous cell carcinoma ||• Metastatic spread|
|• Resection of tumour and bilateral cutaneous ureterostomy|
|• No further information given|
| 7||2002||67||Autopsy||Not known. Both testes palpable on examination.||Clear cell adenocarcinoma ||• Pt died in traffic accident|
|• Adenocarcinoma found incidentally|
|• Metastasized to retroperitoneal lymph nodes and lungs|
| 8||2005||14||Haematuria, Increasing lower abdominal protuberance||Left nephrectomy at 2 months for multicystic kidney. Right orchiectomy for UDT at age 8, simultaneous left side inguinal orchidopexy for inguinal testicle. PMDS not seen.||Adenosarcoma ||• Tumour resected|
|• 2 months post-op. developed lung, bone and abdominal metastasis|
|• Pt died|
| 9||2005||39||Abdominal pain, Haematuria, Urinary retention, Bilateral cryptorchidism||Nil||Endocervical adenocarcinoma ||• Tumour partially resected|
|• Pt developed liver metastasis|
|• Died 1.5 years after first operation|
|10||2006||44||Haemospermia, Haematuria, Infertility for 15 years||Nil||Papillary cystadenocarcinoma ||Not known|
|11||2006||15||Lower abdominal protrusion, Urinary retention||Nil. Both testes were descended and regular in size and consistency on examination.||Clear cell adenocarcinoma ||• Resection of tumour|
|• Pt had no recurrence at 16 weeks post-op.|
Simply considering the published literature, there are 11 cases of Müllerian malignancies with PMDS and approximately 200 reports of PMDS. However, PMDS may not be diagnosed at all and not every PMDS or Müllerian malignancy is reported. Furthermore, Müllerian malignancy with PMDS may not be diagnosed as such. Assuming cancer occurrence is binomially distributed, we may formulate that we are 90% confident that between 3.1% and 8.4% of males with PMDS will develop a Müllerian malignancy. Therefore, it seems prudent to remove the Müllerian structures at the time of a surgical procedure being performed, where possible. It seems there might be an intrinsic tendency for Müllerian remnants to manifest into cancers regardless of hormonal stimuli .
It is known that the Müllerian remnants can cause tethering and adequate mobilization of a testis during orchidopexy may be impossible without surgically removing or dividing the uterine remnant . Another paper, from India, reported longitudinal division of the Müllerian remnant to release the tethering of the vas for successful orchidopexy . The authors were wary of possible malignancy in the Müllerian remnant and suggested long-term follow-up with MRI. We found that simultaneous orchidopexy and removal of the Müllerian remnant was possible with the laparoscopic approach as described in this report. The magnification provided with laparoscopy, techniques to obtain adequate visualization of the area, appropriate traction to reach the planes and meticulous dissection enabled careful separation of the vasa from the uterus. The practice in our institution has always been removal of the Müllerian remnants and David Gough performed this through the transtrigonal approach . We use the laparoscopic approach because it much less invasive and gives better access to the depths in the pelvis.
The likelihood of fertility in PMDS patients is still unknown, considering that the epididymis does not appear completely normal and the uterus and the vasa open into the prostatic urethra close to each other. Berkmen  in 1997 reported that in PMDS there is an absence of spermatozoa in semen analysis; however, this report does not mention the age at orchidopexy of the patient. There is a case report of PMDS with normal fertility before orchidopexy and this patient had a normally descended scrotal testis from birth . The patient was married and fathered two children. A clinical examination of the groin showed an empty left scrotum with normally descended right testis. Subsequent surgery revealed the presence of Müllerian remnants.
It is possible that the reported infertility in PMDS has more to do with the structural abnormalities caused by the Müllerian remnants, the result of long-term cryptorchidism or damage caused to the vas deferens during orchidopexy. Even if there is no normal passage from testis to urethra, with the viable testis brought down to the scrotum at an early age, there is always the possibility of intracytoplasmic sperm injection.
Most tumours occur after puberty, therefore long-term follow-up should be mandatory for patients with PMDS [20,22,24]. The testis should be palpated and examined for any inconsistencies. If the testes are not palpable, or the Müllerian remnants are still intact, future monitoring should be performed with either an ultrasound or MRI scan. Considering the current evidence of malignancy in the Müllerian remnant, the counselling of patients with regards to removal of this may need to be considered.
PMDS is an important differential diagnosis in males with bilateral UDT. A positive family history of cryptorchidism, male infertility and any consanguinity should be elicited in the history. An ultrasound scan may be helpful preoperatively to visualize any Müllerian remnants, however this is operator dependent with the potential for false-negative results. Laparoscopy is the gold standard for diagnosis. If Müllerian remnants are found and the patient is prepubertal, AMH levels should be checked to find the aetiology of the PMDS to help with counselling.
This case series shows that using the laparoscopic approach orchidopexy with simultaneous hysterectomy can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. Considering the current evidence of malignancy arising from Müllerian remnants, the surgical team would need to discuss with the patient's family about removal or long-term monitoring.
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