IJSXXX10.1177/1066896914548794International Journal of Surgical PathologySun et al

Case Report

Metachronous Bilateral Testicular Seminoma Developing After an Interval of 31 Years: Case Report and Review of the Literature

International Journal of Surgical Pathology 2015, Vol. 23(2) 156­–160 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914548794 ijs.sagepub.com

Belinda L. Sun, MD, PhD1, Russell Pearl, MD1, Roohollah Sharifi, MD1, and Grace Guzman, MD1

Abstract Men diagnosed with testicular germ cell tumors are at higher risk for development of a second germ cell tumor in the contralateral testis. Metachronous bilateral testicular germ cell tumors usually occur within 5 years. Here, we report a case of a 63-year-old man previously diagnosed with testicular seminoma and treated with a left orchiectomy followed by radiation, developing contralateral testicular seminoma after an interval of 31 years. The patient was asymptomatic and found to have an enlarged, nontender right testis on routine urological examination. Further workup did not reveal evidence of metastatic disease or lymphadenopathy. The surgery specimen revealed a 4.2 × 3.1 × 1.8 cm distinct mass without tumor involvement of tunica albuginea or the tunica vaginalis. Microscopy showed classic seminoma with venous/lymphatic tumor invasion. The current case underscores the importance of recommending lifelong follow-up for patients with testicular germ cell tumors. Keywords metachronous bilateral testicular germ cell tumor, seminoma


Materials and Methods

Men diagnosed with testicular germ cell tumor are at higher risk for development of a second cancer in the contralateral testes. The incidence of bilateral testicular germ cell tumor is approximately 1.82% of patients with testicular germ cell tumors.1 Bilateral testicular tumors can occur at different times, referred to as “metachronous,” or simultaneously, called “synchronous.” The prevalence of metachronous bilateral testicular germ cell tumors is 2 times higher than synchronous tumors.1 Metachronous bilateral testicular germ cell tumors usually occur within 5 years. In most large US series of bilateral germ testicular cell tumor, the longest interval of metachronous bilateral testicular germ cell tumor is approximately 20 years (Table 1). Here, we report a case of a 63-year-old man diagnosed with testicular seminoma within the left testes at age of 32 years, who later developed testicular seminoma within the contralateral testes after an interval of 31 years. The current case shows that contralateral testicular seminoma may occur at an advanced age, underscoring the importance of recommending life-long follow-up for these patients.

Case Report The patient is a 63-year-old man with a medical history of left sided testicular seminoma, infrarenal aortic dissection, kidney stones, gastroesophageal reflex disease, and hypertension, who was found to have a right testicular mass on routine urological examination. The patient denied scrotal swelling, discomfort, and weight loss. He denied a history of testicle mal-descent or infertility, and there was no family history of testicular cancer. The patient had left orchiectomy followed by radiation therapy 31 years ago for stage I testicular seminoma and aortic endograft placement for infrarenal aortic dissection 5 years ago. Physical 1

University of Illinois Hospital and Health Sciences System, Chicago, IL, USA Corresponding Author: Grace Guzman, Department of Pathology and Laboratory Medicine, University of Illinois Hospital and Health Sciences System, 840 South Wood Street, MC 847, Chicago, IL 60612, USA. Email: [email protected]


Sun et al Table 1.  Meta-Analysis of Testicular Germinal Cell Tumor (TGCT) Studies in the United States. Bilateral TGCT, n (%) No. of Bilateral Study Period Patients TGCT, n (%)

References 2

Patel et al (1990)   Holzbeierlein et al (2003)3 Che et al (2002)4 Fosså et al (2005)5 Total

1935-1944 1977-1986 1950-2001 1978-1999 1973-2001

295 500 3984 2431 29 515 36 725


3 (1) 16 (3.2) 58 (1.4) 24 (1) 462 (1.6) 562 (1.5)

Interval of Metachonous Seminoma,a Nonseminoma,b n (%) n (%) Synchronous TGCT (Months)

1 (33) 12 (75) 48 (83) 20 (83) 287 (62) 368 (65)

2 (66) 4 (25) 10 (17) 4 (16) 175 (38) 195 (35)

36 12-180 9-252 180 3-223 3-252

1 (100) 8 (66) 39 (81) 14 (70) 191 (67) 253 (68)

0 (0) 4 (34) 9 (16) 6 (30) 96 (33) 115 (31)


Seminoma presented in one or both sides of bilateral metachonous testicular germinal cell tumors. Nonseminoma presented in bilateral metachronous testicular germinal cell tumors.


examination was pertinent for an enlarged, nontender right testicle. An ultrasound revealed a 3.2-cm well-circumscribed, hypoechoic, heterogeneous mass. The left testicle was absent. Pertinent labs included normal level of α-fetoprotein (AFP) 3.2 µg/L, slightly elevated level of β-human chorionic gonadotropin (β-hCG) 3 IU/L, and all other laboratory tests were within normal limits. Computed tomography of the chest, abdomen, and pelvis were negative for evidence of metastatic disease or lymphadenopathy. The patient underwent radical right orchiectomy. He was followed up according to standard follow-up protocol and is currently disease free.

Histology and Immunohistochemistry The surgical specimen was formalin fixed, thoroughly sampled, embedded in paraffin, cut in 6-µm thick sections (Leica Semiautomated Microtome RM2245, Leica Microsystems, Wetzlar, Germany), and stained with hematoxylin and eosin. Immunohistochemistry was performed on 6-µm thick paraffin-embedded sections using an automated stainer Ventana Ultra instruments (Ventana Medical Systems, Tucson, AZ). The commercially available antibodies were used for immunohistochemical staining for placental alkaline phosphatase (clone NB10, Ventana Medical Systems, Tucson, AZ), AFP (polyclonal antibody, CellMarque, Rocklin, CA), hCG (polyclonal antibody, CellMarque, Rocklin, CA), CD30 (clonone Ber-H2, Ventana Medical Systems, Tucson, AZ).

Results The specimen was a 4.8 × 3.2 × 2.7 cm, 46 g, testicle tissue with attached patent free spermatic cord measuring 7.5 cm in length and 2 cm in diameter. The tunica vaginalis is freely movable and smooth without interruption. Serial sections reveals a light yellow, firm, distinct mass measuring 4.2 × 3.1 × 1.8 cm located at subcapsular and medial portion of the testicle tissue. Epididymis was cystic and

1.5 × 1.2 × 0.8 cm in measurement. Tunica albuginea was smooth and glistening. The mass was surrounded by normal testicle parenchyma, not grossly invading tunica albuginea and the tunica vaginalis. Low-power microscopy showed distinct hypercellular mass with the tumor cells forming nests outlined by fibrous septae infiltrated by lymphocytic cells. There was no necrosis or hemorrhage. The tumor cells were limited to the testis with a pushing border and without extension into the rete testis. Microscopically, in high power, the tumor cells had abundant clear cytoplasm, sharply outlined cell membrane, a large centrally located nucleus, and clumped chromatin pattern. The nucleolus showed prominence, amphophilic staining pattern, apparent multiplicity, elongated shape, and irregular contours. The number of mitoses was variable among foci and ranged 0 to 4 per 10 high-power field. The tumor cells were separated by fibrous bands that were infiltrated by lymphocytes, plasma cells, and histiocytes (Figure 1A). Venous/lymphatic tumor invasion was present (Figure 1B). Tunica albuginea, epididymis, rete testis, spermatic cord, and spermatic cord margin were negative for malignant tumor cells. Focal seminiferous tubule fibrosis and Leydig cell hyperplasia were noted. Immunohistochemically, the tumor cells exhibit reactivity for placental alkaline phosphatase (PLAP; Figure 1C), and are negative for CD30 and AFP. Immunohistochemical stain for hCG showed few isolated cells staining positive (Figure 1D). In addition, the patient was found having right spermatic cord lipoma measuring 8.0 × 3.2 × 1.5 cm. The tumor consists of bright yellow fat separated by fine fibrous trabeculae. Microscopically, the tumor cells present as mature adipose tissue with no cellular atypia.

Discussion Testicular cancer accounts for approximately 1% of all cancers in males. The American Cancer Society estimates


International Journal of Surgical Pathology 23(2)

Figure 1.  Seminoma. (A) The tumor cells are uniform with abundant clear cytoplasm, centrally located nucleus and clumped chromatin. The tumor cells are separated by fibrous band with infiltration of lymphocytes (hematoxylin and eosin, 200×). (B) Tumor cells invade lymphovascular vessels (arrows) (hematoxylin and eosin, 100×). (C) Immunohistochemical stain for PLAP is strongly positive in tumor cells (200×). (D) A few cells are positive for hCG (200×).

about 8820 new cases of testicular cancer and about 380 deaths from testicular cancer in the United States in 2013.6 The majority of these cancers (>95%) are derived from germ cells, including seminoma and nonseminoma germ cell testicular tumors. The incidence of testicular germ cell tumors has geographical variations with the highest reported in Denmark. It has gradually increased in most populations of European origin and in the United States as well over the past decades.7,8 Patients diagnosed with testicular tumors, especially germ cell tumors, have higher risk of developing contralateral testicular tumors. A systematic literature review showed that the prevalence of bilateral testicular germ cell tumors is 1.82% of 50 376 men with testicular germ cell tumors from all reported populations during 1991 to 2011. Overall, 69.2% of these men with bilateral testicular germ cell tumors presented with metachronous tumors and 30.8% had synchronous tumors.1 According to our review of several large series of

testicular germ cell tumor study conducted in the United States, the incidence of bilateral testicular germ cell tumors in the United States is about 1.5%, in which 65% had metachronous tumors and 35% had synchronous tumors (Table 1). Seminoma is the most common histological type of bilateral testicular cancer, similar to that of unilateral testicular cancer. Seminomas were more prevalent among patients with bilateral germ cell disease than patients with unilateral disease. Approximately 68% of cases with bilateral metachonous testicular germ cell tumors present with seminoma (Table 1). A majority (about 50 %) of metachronous bilateral testicular germ cell tumors occur within 5 years. When the second tumor is seminoma, the median interval between tumors intends to be longer (~10 years) compared with that when the histology of the second tumor is nonseminomatous germ cell tumor. In the largest US series study of bilateral testicular germ cell tumor, 23% of the cohort has


Sun et al interval greater than 10 years after the original diagnosis.3 However, the contralateral testicular tumor may occur much later in life. Since the first case report on bilateral metachronous testicular germ cell tumor in 1942, there have been 25 cases reported with contralateral testicular tumors occurring after 20 years or more of the original testicular tumor. In these 25 cases, 4 cases occurred after 30 years of the original testicular tumors with the longest interval of 40 years.9,10 The present case is the fifth case with metachronous bilateral testicular germ cell tumors occurring with an interval of more than 30 years. A retrospective review showed that the incidence of bilateral testicular cancers in the postchemotherapy era was 3 times higher than that in the prechemotherapy era. The increased incident of bilateral testicular tumors is possibly related to the longer survival of patients by the successful treatment of the original testicular tumors.2 The case presented here emphasizes that, in rare cases, the interval between the development of bilateral testicular germ cell tumors may extend more than 30 years. With increased survival rates in patients with testicular tumors, the need for lifelong follow-up is underscored. Overall, the patients with bilateral testicular germ cell tumors have outcomes similar to patients with unilateral testicular tumors when matched for stage. The 5-year survival rates for men with synchronous and metachronous bilateral testicular tumor were 88% and 95%, respectively,1 suggesting that metachronous tumors have favorable survival outcome than synchronous tumors. More than 70% of patients with bilateral testicular cancer presented with stage I disease at the diagnosis of the second tumor. This is most likely because of close follow-up as well as increased patient awareness. Most second tumors were discovered by physician examination or patient selftesticular examination. Pathological prognostic risk factors for occult testicular germ cell tumors (for stage I) include histopathological type, and for seminoma, tumor size (≥4 cm) and invasion of the rete testis. The persistence of elevated serum tumor markers 3 weeks after orchiectomy may indicate the presence of residual disease, and its normalization does not necessarily mean absence of tumor. Imaging by abdominopelvic computed tomography scan and thoracic computed tomography scan/X-ray thorax and physical examination are used to assess retroperitoneal and mediastinal nodes, and viscera and supraclavicular nodes. Currently, there are no clear guidelines for treatment of bilateral testicular tumors. Patients with bilateral testicular tumor have overall excellent outcomes if treated in a timely and appropriate manner based on histology and stage. Treatment for the second tumor is based on tumor stage and histology. The incidence of contralateral

testicular cancer was shown not to be significantly changed by the radiation therapy for the initial testicular cancer.11 The etiology of bilateral testicular germ cell tumor remains unknown although both genetic and environmental causes have been implicated. Currently, epidemiological risk factors of developing testicular germ cell tumors are found, including history of cryptorchidism, Klinefelter syndrome, presence of contralateral tumor, infertility, and familial history of testis cancer in firstgrade relatives.12 Notably, elevated risk among family members13 and associations with inherited genotypes14 suggest genetic causes. On the other hand, the steady increases in incidence rates of testicular cancer in the industrialized countries, which nearly doubled between 1975 and 2007,1 can be explained only by environmental factors.15 However, the identified genotypical risk variants account for only 4% to 6% of familial risk,16 and environmental factors that would explain increasing rates are uncertain. The etiological factors responsible for bilateral testicular germ cell tumors, especially for metachronous bilateral testicular germ cell tumors, remain unidentified. In summary, the current case presents a patient with metachronous bilateral testicular seminoma that developed in an interval of 31 years. To the best of our knowledge, our review of the medical literature indicates that this patient is the fifth case that presented with contralateral testicular germ cell tumor developing after an interval of more than 30 years. This case underscores the importance of lifelong follow-up of patients with testicular germ cell tumor. These individuals have a high risk of developing contralateral testicular germ cell tumor, especially seminoma, and tend to have second tumor later in their life, necessitating lifelong follow-up. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for the research, authorship, and publication of this article was provided by the Department of Pathology at the University of Illinois, College of Medicine.

References 1. Zequi Sde C, da Costa WH, Santana TB, Favaretto RL, Sacomani CA, Guimaraes GC. Bilateral testicular germ

160 cell tumours: a systematic review. BJU Int. 2012;110:11021109. 2. Patel SR, Richardson RL, Kvols L. Synchronous and metachronous bilateral testicular tumors mayo clinic experience. Cancer. 1990;65:1-4. 3. Holzbeierlein JM, Sogani PC, Sheinfeld J. Histology and clinical outcomes in patients with bilateral testicular germ cell tumors: the Memorial Sloan Kettering Cancer Center experience 1950 to 2001. J Urol. 2003;169:2122-2125. 4. Che M, Tamboli P, Ro JY, et al. Bilateral testicular germ cell tumors: twenty-year experience at M. D. Anderson Cancer Center. Cancer. 2002;95:1228-1233. 5. Fosså SD, Chen J, Schonfeld SJ, et al. Risk of contralateral testicular cancer: a population-based study of 29,515 U.S. men. J Natl Cancer Inst. 2005;97:1056-1066. 6. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013. http://www. cancer.org/acs/groups/content/@epidemiologysurveilance/ documents/document/acspc-036845.pdf. Accessed August 13, 2014. 7. McGlynn KA, Devesa SS, Sigurdson AJ, Brown LM, Tsao L, Tarone RE. Trends in the incidence of testicular germ cell tumors in the United States. Cancer. 2003;97:63-70. 8. Bergström R, Adami HO, Möhner M, et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J Natl Cancer Inst. 1996;88:727-733.

International Journal of Surgical Pathology 23(2) 9. Dieckmann KP, Boeckmann W, Brosig W, Jonas D, Bauer HW. Bilateral testicular germ cell tumors. Report of nine cases and review of the literature. Cancer. 1986;57:1254-1258. 10. Hamilton JB, Gilbert JB. Studies in malignant tumors of the testis. IV. Bilateral testicular cancer. Incidence, nature, and bearing upon management of the patient with a single testicular cancer. Cancer Res. 1942;2:125-129. 11. Jones DA, Ester EC, Leavitt D, et al. Adjuvant radiotherapy for synchronous bilateral testicular seminoma: a case report and a review of the pertinent literature. Case Rep Urol. 2013;2013:241073. 12. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004:220-227. 13. Peto J, Houlston RS. Genetics and the common cancers. Eur J Cancer. 2001;37(suppl 8):88S-96S. 14. Rapley EA, Turnbull C, Al Olama AA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet. 2009;41:807-810. 15. Manecksha RP, Fitzpatrick JM. Epidemiology of testicular cancer. BJU Int. 2009;104:1329-1333. 16. Turnbull C1, Rapley EA, Seal S, et al; UK Testicular Cancer Collaboration. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010;42:604-607.

Metachronous bilateral testicular seminoma developing after an interval of 31 years: case report and review of the literature.

Men diagnosed with testicular germ cell tumors are at higher risk for development of a second germ cell tumor in the contralateral testis. Metachronou...
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