Prepubertal Testicular and Paratesticular Tumors

Prepubertal Testicular and Paratesticular Tumors

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Testicular tumors account for 1-2% of all pediatric tumors, with an incidence of 0.05-2 per 100,000 children. [1] A bimodal age distribution is observed; one peak occurs in the first 2 years of life, and the second occurs in young adulthood.

Pediatric prepubertal testicular tumors are dramatically different from adult neoplasms. Germ-cell tumors account for only 60-77% of testicular tumors in children but account for 95% of testicular tumors in adults. [2] Adult germ-cell tumors with malignant potential, such as seminoma and embryonal carcinoma, are not present in prepubertal patients. Teratomas, which are uniformly benign in children, are often malignant in adults.

The 2016 update of the World Health Organization (WHO) classification of testicular germ-cell tumors divides them into two broad categories on the basis of whether they are derived from a precursor lesion: germ-cell neoplasia in situ (GCNIS). [3] Prepubertal tumors are non-GCNIS-derived, whereas postpubertal tumors are GCNIS-derived, though benign prepubertal-type teratomas may rarely develop in the postpubertal testis.

The most common germ-cell tumors are yolk-sac tumors and teratomas, which were reported by Ross to account for about 62% and 26% of testis tumors, respectively. [4, 5] Nistal et al reported frequencies of 49% for yolk-sac tumors, 13% for teratomas, 9% for seminomas and mixed germ-cell tumors, and 29% for sex-cord stromal tumors. [6]

Some series have suggested that teratomas, which most believe are vastly underreported because of their benign nature, may account for almost 50% of prepubertal testicular tumors. [7] However, in tumor registries, yolk-sac tumors have been more common than teratomas, though it is possible that this may reflect a reporting bias. [4, 8, 9]

Gonadal stromal tumors are generally considered significantly less common than germ-cell tumors and primarily include juvenile granulosa-cell tumors, Leydig-cell tumors, and Sertoli-cell tumors.

The vast majority (85%) of yolk-sac tumors in children present as clinical stage I disease, compared with only 35% in adults. [10]  Alpha-fetoprotein (AFP) can be used as a reliable tumor marker because levels are increased in more than 90% of yolk-sac tumors. Therefore, patients can be safely managed with observation after orchiectomy followed by chemotherapy for recurrent tumors. [11]  Retroperitoneal lymph node dissection is reserved for children with persistent retroperitoneal lymphadenopathy or increased serum tumor markers after orchiectomy and chemotherapy.

Prepubertal teratomas account for fewer than 30% of testicular germ-cell tumors in children and are uniformly benign. [4]  Histology is often pure with diploid DNA content containing all three embryologic germ layers (ectoderm, mesoderm, and endoderm). Testis-sparing surgery with frozen section is a reasonable consideration for this and other benign prepubertal tumors. [12, 13] No follow-up is recommended for prepubertal teratomas, whereas postpubertal patients should be monitored into adulthood.

Epidermoid cysts are benign tumors of epithelial origin and account for 10-15% of cases. [1, 14]  They are often firm and well-defined, with a central hypoechoic region or mixed internal echogenicity surrounded by an echogenic rim on ultrasonography. Following tumor enucleation, these tumors do not require follow-up.

Seminomas and mixed germ-cell tumors are extremely rare in prepubertal children. Most authorities believe that seminomas should be managed as in adults and mixed germ-cell tumors should be treated according to the most malignant subtype present.

Sertoli-cell tumors are the most common gonadal stromal tumors in prepubertal children. They tend to appear as painless masses in boys younger than 6 months and produce no endocrinologic effects; however, 14% of patients present with gynecomastia. [10]  All reported lesions in children younger than 5 years have been benign. Therefore, children younger than 5 years are adequately treated with orchiectomy and do not require metastatic evaluation. Older children should undergo chest radiography and abdominal computed tomography (CT) to rule out metastases. Metastases are treated with a combination of radiotherapy, chemotherapy, and retroperitoneal lymph node dissection.

Large-cell calcifying Sertoli-cell tumor is a variant with large amounts of cytoplasm and calcification. One third of patients with this tumor have associated genetic abnormalities; however, these tumors are universally benign.

Leydig-cell tumors are the second most common gonadal stromal tumors in children and are also benign. These tumors most often occur in boys aged 5-10 years, and the synthesis of testosterone may produce precocious puberty, gynecomastia, and elevated levels of 17-ketosteroids. Leydig-cell tumors must be differentiated from hyperplastic nodules that develop in boys with poorly controlled congenital adrenal hyperplasia (CAH).

Juvenile granulosa-cell tumors account for approximately 3% of all neonatal testicular tumors and commonly appear as cystic, painless testicular masses. [11, 15, 16]  They almost always appear in the first year of life, and most appear by age 6 months. They can be associated with anomalies of the Y chromosome, mosaicism, and ambiguous genitalia. These tumors are hormonally inactive and benign.

Gonadoblastoma occurs in association with disorders of sex development. About 80% of cases involve phenotypic females with intra-abdominal testes or streak gonads. [17]  The putative gonadoblastoma gene is on the Y chromosome, and the tumor almost always develops in a child with a Y chromosome. The streak gonads in patients with mixed gonadal dysgenesis often develop gonadoblastomas. Incidence peaks at puberty, and early gonadectomy is recommended in patients at risk for gonadoblastoma. Metastatic spread occurs in 10% of patients. [18]  These tumors may elevate serum levels of beta human chorionic gonadotropin (β-HCG).

Cystic dysplasia of the testis is a benign lesion that is often associated with ipsilateral renal agenesis or dysplasia. This association, along with a characteristic ultrasonographic appearance (ie, hypoechoic lesions), permits preoperative diagnosis and possible treatment with testicular-sparing surgery. [4]

Leukemia and lymphoma are the most common secondary malignancies to affect the testis. [19]  These tumors can present bilaterally, and, because the blood-testis barrier protects the intratesticular cells, the testis may be the site of residual tumor in children after chemotherapy. Metastatic disease to the testes should be considered in a child presenting with bilateral testicular tumors.

Paratesticular structures can give rise to various benign (lipoma, leiomyoma, hemangioma, or fibroma) and malignant tumors; however, these are extremely rare. Rhabdomyosarcoma is the most common malignant tumor (17%) and may arise from the distal spermatic cord and appear as a scrotal mass or hydrocele. [10]  These tumors have a bimodal distribution and occur in boys aged 3-4 months and in teenagers. Up to 70% of cases involve the retroperitoneal lymph nodes at presentation.

These tumors are highly aggressive and spread via the blood or lymphatics or through direct extension to the lungs, cortical bone, or bone marrow in 20% of patients at the time of diagnosis. Radical inguinal orchiectomy followed by retroperitoneal lymph node dissection is recommended for all children older than 10 years and for those younger than 10 years with retroperitoneal disease. Patients with positive lymph nodes are treated with multimodal therapy (chemotherapy and radiation).

The cause of pediatric testicular tumors is unknown. An association with prenatal exposure to diethylstilbestrol (DES) has been postulated but not demonstrated.

Testicular tumors account for approximately 1-2% of all pediatric solid tumors. [1] The incidence is 0.05-2 per 100,000 children. Although benign tumors are more common in prepubertal patients than in postpubertal patients, yolk-sac tumors have been more commonly reported in some series and tumor registries. The true incidence of benign tumors, such as teratomas, may be less than what is reported because of reporting bias.

The worldwide incidence of prepubertal testicular and paratesticular tumors is similar to that in the United States.

The incidence of pediatric testicular tumors peaks in children aged 2-4 years. Most yolk-sac tumors occur in children younger than 2 years.

Testicular tumors occur in boys and men.

Testicular gem cell tumors appear to have a 1.4-fold greater incidence in Asian/Pacific Islanders than in white or black children. There seems to be no discernible difference in the incidence of testicular tumors between black and white boys aged 0-14 years. [20]

The prognosis for patients with benign testicular lesions is excellent. Even for patients with metastatic yolk-sac tumor, survival with chemotherapy is approximately 90%. [16]

Patients with rhabdomyosarcoma have an overall survival rate of more than 70% when treated with multimodal therapy. Poor prognostic indicators include alveolar histology, age older than 7 years, unresectable retroperitoneal disease, and distant metastatic disease.

One death occurs per every 10 million cases per year.

A large series by Maizlin et al evaluated 479 prepubertal patients (≤12 years; median age at diagnosis, 3 years) with testicular tumors from the National Cancer Data Base (1998-2012). [9]  Yolk-sac tumors were the most common histology. Of the 479 patients, 465 underwent resection (radical orchiecomy in 75%); chemotherapy was used in 28% of cases and radiotherapy in 7%. Mortality was 3% at a mean follow-up of 5.6 years, and it was not significantly affected by tumor histology or extent of surgical resection.

For any child with history of testicular malignancy, self-testicular examination is recommended at start of puberty and should be performed monthly thereafter.

For patient education resources, see the Men’s Health Center and the Cancer Center, as well as Testicular Cancer and Testicular Self-Exam.

Metcalfe PD, Farivar-Mohseni H, Farhat W, McLorie G, Khoury A, Bägli DJ. Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol. 2003 Dec. 170 (6 Pt 1):2412-5; discussion 2415-6. [Medline].

Cooper CS, Snyder HM III. Pediatric genitourinary cancer. Nachtsheim DA, ed. Urological Oncology. Georgetown, TX: Landes Bioscience; 2005.

Williamson SR, Delahunt B, Magi-Galluzzi C, Algaba F, Egevad L, Ulbright TM, et al. The World Health Organization 2016 classification of testicular germ cell tumours: a review and update from the International Society of Urological Pathology Testis Consultation Panel. Histopathology. 2017 Feb. 70 (3):335-346. [Medline].

Ross JH, Kay R. Prepubertal testis tumors. Rev Urol. 2004 Winter. 6 (1):11-8. [Medline].

Cornejo KM, Frazier L, Lee RS, Kozakewich HP, Young RH. Yolk Sac Tumor of the Testis in Infants and Children: A Clinicopathologic Analysis of 33 Cases. Am J Surg Pathol. 2015 Aug. 39 (8):1121-31. [Medline].

Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M. Perspectives in Pediatric Pathology, Chapter 25. Testicular and Paratesticular Tumors in the Pediatric Age Group. Pediatr Dev Pathol. 2016 Nov/Dec. 19 (6):471-492. [Medline].

Akiyama S, Ito K, Kim WJ, Tanaka Y, Yamazaki Y. Prepubertal testicular tumors: a single-center experience of 44years. J Pediatr Surg. 2016 Aug. 51 (8):1351-4. [Medline].

Thomas JC, Ross JH, Kay R. Stromal testis tumors in children: a report from the prepubertal testis tumor registry. J Urol. 2001 Dec. 166 (6):2338-40. [Medline].

Maizlin II, Dellinger M, Gow KW, Goldin AB, Goldfarb M, Nuchtern JG, et al. Testicular tumors in prepubescent patients. J Pediatr Surg. 2017 Oct 8. [Medline].

Agarwal PK, Palmer JS. Testicular and paratesticular neoplasms in prepubertal males. J Urol. 2006 Sep. 176 (3):875-81. [Medline].

Ross JH, Rybicki L, Kay R. Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the Prepubertal Testis Tumor Registry. J Urol. 2002 Oct. 168 (4 Pt 2):1675-8; discussion 1678-9. [Medline].

Woo LL, Ross JH. The role of testis-sparing surgery in children and adolescents with testicular tumors. Urol Oncol. 2016 Feb. 34 (2):76-83. [Medline].

Borghesi M, Brunocilla E, Schiavina R, Gentile G, Dababneh H, Della Mora L, et al. Role of testis sparing surgery in the conservative management of small testicular masses: oncological and functional perspectives. Actas Urol Esp. 2015 Jan-Feb. 39 (1):57-62. [Medline].

Pohl HG, Shukla AR, Metcalf PD, Cilento BG, Retik AB, Bagli DJ, et al. Prepubertal testis tumors: actual prevalence rate of histological types. J Urol. 2004 Dec. 172 (6 Pt 1):2370-2. [Medline].

Shukla AR, Huff DS, Canning DA, Filmer RB, Snyder HM 3rd, Carpintieri D, et al. Juvenile granulosa cell tumor of the testis:: contemporary clinical management and pathological diagnosis. J Urol. 2004 May. 171 (5):1900-2. [Medline].

Kao CS, Cornejo KM, Ulbright TM, Young RH. Juvenile granulosa cell tumors of the testis: a clinicopathologic study of 70 cases with emphasis on its wide morphologic spectrum. Am J Surg Pathol. 2015 Sep. 39 (9):1159-69. [Medline].

Stephenson AJ, Gilligan TD. Neoplasms of the testis. Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia: Elsevier; 2016. Vol 1: 784-814.

Müller J, Ritzén EM, Ivarsson SA, Rajpert-De Meyts E, Norjavaara E, Skakkebaek NE. Management of males with 45,X/46,XY gonadal dysgenesis. Horm Res. 1999. 52 (1):11-4. [Medline].

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Walsh TJ, Davies BJ, Croughan MS, Carroll PR, Turek PJ. Racial differences among boys with testicular germ cell tumors in the United States. J Urol. 2008 May. 179 (5):1961-5. [Medline].

Tallen G, Hernáiz Driever P, Degenhardt P, Henze G, Riebel T. High reliability of scrotal ultrasonography in the management of childhood primary testicular neoplasms. Klin Padiatr. 2011 May. 223 (3):131-7. [Medline].

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Cost NG, Lubahn JD, Adibi M, Romman A, Wickiser JE, Raj GV, et al. Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors. J Urol. 2014 May. 191 (5 Suppl):1485-90. [Medline].

Hisamatsu E, Takagi S, Nakagawa Y, Sugita Y, Yoshino K, Ueoka K, et al. Prepubertal testicular tumors: a 20-year experience with 40 cases. Int J Urol. 2010 Nov. 17 (11):956-9. [Medline].

Bujons A, Sfulcini JC, Pascual M, Feu OA, Garat JM, Villavicencio H. Prepubertal testicular tumours and efficacy of testicular preserving surgery. BJU Int. 2011 Jun. 107 (11):1812-6. [Medline].

Christopher S Cooper, MD, FACS, FAAP Professor with Tenure and Vice Chair, Department of Urology, Professor, Department of Pediatrics, Associate Dean for Student Affairs and Curriculum, Children’s Hospital of Iowa and University of Iowa, Roy J and Lucille A Carver College of Medicine

Christopher S Cooper, MD, FACS, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Medical Association, Phi Beta Kappa, Society for Pediatric Urology, Society for Fetal Urology, International Children’s Continence Society, American College of Surgeons, American Urological Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Harry P Koo, MD Chairman of Urology Division, Director of Pediatric Urology, Professor of Surgery, Virginia Commonwealth University School of Medicine, Medical College of Virginia; Director of Urology, Children’s Hospital of Richmond

Harry P Koo, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Urological Association

Disclosure: Nothing to disclose.

Marc Cendron, MD Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children’s Hospital Boston

Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, New Hampshire Medical Society, Society for Pediatric Urology, Society for Fetal Urology, Johns Hopkins Medical and Surgical Association, European Society for Paediatric Urology

Disclosure: Nothing to disclose.

Bartley G Cilento, Jr, MD Instructor, Department of Surgery, Division of Urology, Children’s Hospital of Boston and Harvard Medical School

Bartley G Cilento, Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Brian L Gallagher, MD Staff Urologist, Department of Urology, Iowa Clinic

Disclosure: Nothing to disclose.

Prepubertal Testicular and Paratesticular Tumors

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