Twenty-Six-Year-Old Primigravid Woman With a Cystic Mass

CASE SCENARIO Twenty-Six-Year-Old Primigravid Woman With a Cystic Mass Ellen Shapiro, MD, FACS, FAAP Department of Urology, New York University School of Medicine, New York, NY [Rev Urol. 2005;7(1):58-62] © 2005 MedReviews, LLC CASE REPORT 26-year-old primigravid woman underwent routine ultrasound examination at 22 weeks of gestation. An anechoic cystic structure measuring 15 mm was seen between the left kidney and spleen (Figure 1A, left and right). The kidneys appeared normal and measured 23 mm bilaterally. The amniotic fluid volume was normal. No structural abnormalities were detected and there was a 3-vessel cord. At 28 weeks, the mass had increased in size to 24 mm and was developing some solid components. By 35 weeks, the mass was echogenic and heterogeneous and had increased to 37 mm × 34 mm × 30 mm (Figure 1B). A A B Figure 1. Fetal ultrasound. (A) In the left image, a 15 mm mass is seen between the left kidney and the spleen at 22 weeks gestation. The right image is a Doppler study demonstrating a normal left renal artery. (B) At 35 weeks gestation, an echogenic, heterogeneous mass measuring 37 mm is seen. MANAGEMENT OPTIONS The next appropriate step in the management of this patient would be: ❑ 1. Observe ❑ 2. Early delivery by C-section ❑ 3. Amniocentesis for vanillylmandelic acid and homovanillic acid levels ❑ 4. Percutaneous biopsy of mass ❑ 5. Postnatal left adrenalectomy Vote online at www.medreviews.com; fax your response to MedReviews at (212) 971-4047; or e-mail your selection to dgern@medreviews.com. 58ººººVOL. 7 NO. 1ºº2005ººººREVIEWS IN UROLOGY Case Scenario Discussion of Last Issue’s Case Scenario IN THE LAST ISSUE, DRS. ZEITLIN AND he urologist needs to be aware of what tests to perform in the workup of the infertile patient. In the last few years, as molecular biology has moved from the laboratory to the bedside, it is becoming apparent that many men with a zero sperm count (azoospermia) or a low sperm count (oligospermia) may have genetic abnormalities causing their infertility, and, more importantly, these abnormalities could be passed on to their offspring. Because the Y chromosome is inherited from the father, it stands to reason that genetic defects located on the Y chromosome could be transmitted during fertilization from father to son. Many of these genetic defects are naturally self-limiting, that is, only the affected man is unable to achieve fertilization normally and cannot pass on the genetic defects. The advent of intracytoplasmic sperm injection (ICSI) with in vitro fertilization (IVF) bypasses this natural selection process and allows these genetic defects to be transmitted. Because many of these genetic abnormalities affecting spermatogenesis have both diagnostic and prognostic significance and are increasingly being recognized at the molecular level, it is imperative that urologists become familiar with the tests used to identify such patients. T THE RAJFER PRESENTED THIS CASE REPORT: A 31-year-old Israeli man presented with azoospermia on 2 separate semen analyses showing normal semen volumes of 5 to 6 cc. His endocrine and sexual histories were normal, although he had not tried to achieve a pregnancy. He had no history of undescended testes, genitourinary surgery, or cancer, and no known prior exposure to radiation, chemotherapy, or environmental toxins. Of note, he was born without a lower left leg, ankle, and foot. The patient had a cousin who required a testicular sperm extraction in conjunction with ICSI in order to achieve a pregnancy via IVF. On examination, except for the prosthesis on his left lower extremity, he appeared normal with normal male hair distribution and no gynecomastia. His testes were descended bilaterally and firm to palpation. The right and left testes were 10 and 8 cc in volume, respectively, and both epididymides and vasa deferentia were palpably normal. The serum luteinizing hormone was 12.3
IU/mL, follicle stimulating hormone (FSH) was 12.3
IU/mL, and testosterone was 400 ng/dL. A third semen analysis using a spun pellet confirmed the azoospermia. What is the next test that should be performed to determine whether the patient has sperm in his testes? Should it be a testis biopsy? Is there another less invasive test that may be diagnostic? FOLLOWING QUESTION REGARDING PATIENT MANAGEMENT OPTIONS WAS ASKED: Which test should be performed next for this patient (once you know what his FSH and sperm count are)? 1. Diagnostic testis biopsy 2. Karyotype and Y chromosome microdeletion test 3. TRUS and possible SV aspiration 4. Treatment with hCG and FSH VOL. 7 NO. 1ºº2005ººººREVIEWS IN UROLOGYºººº59 Case Scenario continued AUTHORS’ DISCUSSION The first question that must be answered in a patient with azoospermia is whether sperm production is present and there is simply an obstruction to the ductal system (obstructive azoospermia), or whether sperm production is affected (nonobstructive azoospermia). In obstructive azoospermia (OA), testicular volume is normal and the testes usually feel firm on palpation, whereas in nonobstructive azoospermia (NOA), testicular volume may be diminished and testes may feel soft to palpation. Because spermatogenesis is regulated partly by FSH, it is measured as part of the work-up of the azoospermic patient. Although a normal FSH is usually not diagnostic in differentiating obstructive from nonobstructive azoospermia, an elevated FSH suggests the presence of NOA. Therefore, based on the physical examination (small, soft testes) and serum FSH (elevated), it appears this patient has NOA. Compared to NOA, OA is relatively easy to treat. Depending on the age of the female partner and the desire of the male to undergo reconstructive surgery, sperm in patients with OA can always be obtained in these men in order to achieve a pregnancy. The sperm can be obtained by either reconstructing the ductal system, if indicated, or extracting the sperm from the testis/epididymis to perform ICSI with IVF. The dilemma for patients who have NOA is whether there even are sperm present within the testes. If it is determined in the workup that an NOA patient does not have sperm in the testes, the physician could give the couple options for achieving a pregnancy other than using the male partner’s sperm, which would save the couple both time and money. Sperm production in the testes can range from the complete absence of sperm (Sertoli-cell-only) to normal spermatogenesis, to varying rates of spermatogenesis, for example, hypospermatogenesis, maturation arrest, and so forth. The genetic regulation of spermatogenesis has not been completely delineated, but a number of genes are known to play a role in this process. It has been known for many years that the testis-determining gene is located on the Y chromosome and it appears that this chromosome, in particular, with a possible contribution from some of the autosomes, is involved in the process of spermatogenesis. The standard karyotype can accurately discern abnormalities of chromosome number and deletions of significant amounts of genetic material. Tiepolo and Zuffardi1 initially described large deletions of the long arm of the Y chromosome at Yq11 that were found in 6 azoospermic men and discussed the importance of this region with respect to spermatogenesis, and this has been confirmed by others.2-4 60ººººVOL. 7 NO. 1ºº2005ººººREVIEWS IN UROLOGY Reijo and colleagues5 described de novo deletions in 12 of 89 (13%) azoospermic men and pinpointed the abnormality to the same distal Yq11 region of the long arm of the Y chromosome, which they termed the DAZ gene (deleted in azoospermia). This deletion in the azoospermic factor (AZF) region of the DAZ gene results in histologic findings on testicular biopsy ranging from a Sertoli-cell-only pattern to spermatogenic arrest with occasional mature, condensed spermatids. Furthermore, in this group, differences in histology from tubule to adjacent tubule, specifically the presence of sperm, were a “seeing is believing” concept of spermatogenesis occurring in different regions of the testis within zones and incorporating a number of adjacent tubules. These authors speculated that at least 1 in 10,000 newborn male babies carries a de novo deletion of the DAZ gene. Insight into the prognostic significance of the presence of a deletion in the AZF region comes from the study by Vogt and colleagues6 who evaluated 370 patients with both azoospermia and severe oligoasthenospermia (< 2 million sperm/cc) who had an XY karyotype. They described three regions of Yq11, including proximal (AZFa), middle (AZFb), and distal (AZFc) and noted that the region that Reijo and colleagues5,7-8 described was the AZFc region. In addition, the AZFc-deleted patients would sometimes have sperm in their ejaculates, as opposed to patients with type AZFa or AZFb deletions. Furthermore, it was proposed that any of these deletions could be transmitted to male offspring via IVF. When Girardi and colleagues9 studied both oligospermic (< 5 million sperm/cc) and azoospermic patients for deletions, they found that 7% and 5% of these two groups, respectively, had submicroscopic deletions of the Y chromosome. From this study as well as the data of Vogt and colleagues6 and Pryor and colleagues,10 it was recommended that all severely oligospermic patients and all azoospermic patients be genetically screened for these microdeletions. When Brandell and colleagues11 assessed the implications of such a microdeletion of the Y chromosome identified in 9 out of 80 (11%) of their infertile patients, they found that 2 patients with AZFb deletions had sperm in their testes, but none with AZF deletions. These observations were followed up by Hopps and colleagues12 who reported on the outcomes of attempts at sperm extraction in a series of 78 men with microdeletions of the AZFa, b, and c regions. No patient with an AZFa (n = 3), AZFb (n = 11), AZFb+c (n = 16), or AZFa+b+c (n = 6) deletion had sperm at the time of testicular sperm extraction. All of these 36 patients were azoospermic. Forty-two of the 78 men (either azoospermic Case Scenario A Figure 1. Abnormal mosaic male karyotype revealing a 46,X,idic(Y) (q11.2)[15]/45,X[5] chromosome complement. Two cell lines are present. One is monosomic for the X chromosome (A) and the other cell line contains one normal chromosome X and an isodicentric Y chromosome with breakage and reunion at band q11.2 and subsequent loss of segment Yq11.2 to qter and gain of Ypter to q11.2 (B) (Images courtesy of Alfigen.) B or severely oligospermic) had an isolated AZFc deletion and 56% with isolated AZFc deletions had sperm either in their ejaculate or in their testes that could be used for ICSI and IVF. Oates and colleagues13 thoroughly characterized the histology of the testes in 37 of 42 azoospermic and oligospermic males with the AZFc deletion. Thirty (71%) of the 42 patients who were completely evaluated had some degree of spermatogenesis. Thirteen pregnancies (47% from ejaculated sperm and 14% from testicular extraction) have produced 18 offspring in this group. Of the 10 male offspring who were tested, all have the same AZFc deletion. All offspring were healthy except one who had pulmonary atresia and right ventricular hypoplasia and died shortly after birth. These observations confirm the rule of genetics, which is that the Y chromosome of male offspring is inherited from the father. Based on the aforementioned review of the literature, in 2002 the American Urologic Association (AUA) published recommendations in a paper entitled “Best Practice Policies for Male Infertility.”14 They recommended that all patients with azoospermia and testicular atrophy should be offered testing for abnormalities of the chromosomes, that is, a karyotype and a Y chromosome microdeletion test. They added that men with NOA and severe oligospermia should be informed that they may have chromosomal abnormalities or Y chromosome microdeletions and testing should be offered before using the sperm for ICSI. Further genetic counseling may be offered when a genetic abnormality is suspected in either partner and should be provided when a genetic abnormality is detected. Conclusions Genetic testing in our patient, specifically a karyotype and Y chromosome microdeletion test, revealed the following: 46,X,idic(Y)(q11.2)[15]/45,X[5] and a complete AZF a+b+c deletion, respectively (Figure 1). This abnormal karyotype (45,XO/46,XY) with the “normal” portion of the mosaic having the loss of the Y region that included the AZFa, AZFb, and AZFc regions suggested that he would not have sperm in his testicular tissue. He was advised that he should not proceed to testicular sperm aspiration. The patient successfully lobbied against this advice and underwent a testicular microdissection, which did not reveal the presence of sperm, as we had predicted to him and his wife, because of the absence of the region of the Y chromosome responsible for spermatogenesis. Knowledge of the karyotype and Y chromosome microdeletion tests in the workup of the azoospermic and severely oligospermic patient will save many patients unnecessary testicular biopsies and microdissections. In summary, we recommend that patients with azoospermia or sperm counts less than 5 million /cc have a karyotype and a Y chromosome microdeletion test performed. The results will help in the evaluation and management of the patient’s quest for conception. VOL. 7 NO. 1ºº2005ººººREVIEWS IN UROLOGYºººº61 Case Scenario continued References 1. 2. 3. 4. 5. 6. 7. Tiepolo L, Zuffardi O. Localization of factors controlling spermatogenesis in the nonfluorescent portion of the human Y chromosome long arm. Hum Genet. 1976;34:119-124. Reteif AE, Van Zyl JA, Menkveld R, et al. Chromosome studies in 496 infertile males with a sperm count below 20 million /ml. Hum Genet. 1984;66: 162-164. De Braekeleer M, Dao TN. Cytogenetic studies in male infertility: a review. Hum Reprod. 1991;6:245-250. Quilter CR, Svennevik EC, Serhal P, et al. Cytogenetic and Y chromosome microdeletion screening of a random group of infertile males. Fert and Ster. 2003; 79:301-307. Reijo R, Lee TY, Salo P, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 1995;10:383-393. Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet. 1996;5:933-943. Mulhall JP, Reijo R, Alagappan R, et al. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular 62ººººVOL. 7 NO. 1ºº2005ººººREVIEWS IN UROLOGY spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod. 1997; 12:503-508. 8. Reijo R, Alagappan RK, Patrizio P, et al. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet. 1996;347: 1290-1293. 9. Girardi SK, Mielnik A, Schlegel PN. Submicroscopic deletions in the Y chromosome of infertile men. Hum Reprod. 1997;12:1635-1641. 10. Pryor JL, Kent-First M, Muallem A, et al. Microdeletions in the Y chromosome of infertile men. N Engl J Med. 1997; 336:534-539. 11. Brandell RA, Mielnik A, Liotta D, et al. AZFb deletions predict the absence of spermatozoa with testicular sperm extraction: preliminary report of a prognostic genetic test. Hum Reprod. 1998;13:2812-2815. 12. Hopps CV, Mielnik A, Goldstein M, et al. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod. 2003;18:1660-1665. 13. Oates RD, Silber S, Brown LG, et al. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod. 2002; 17:2813-2824. 14. Jarow JP, Sharlip ID, Belker AM, et al. Best practice policies for male infertility. J Urol. 2002;167:2138-2144.