Extratesticular Extension of Germ Cell Tumors Preferentially Occurs at the Hilum

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1 Anatomic Pathology / EXTRATESTICULAR EXTENSION OF GERM CELL TUMORS Extratesticular Extension of Germ Cell Tumors Preferentially Occurs at the Hilum Sarah M. Dry, MD, and Andrew A. Renshaw, MD Key Words: Testis; Germ cell tumors; Seminomas; Nonseminomatous germ cell tumors; Pathologic staging; Tunica albuginea; Rete testes; Testicular hilum Germ cell tumors that extend beyond the testis are associated with a higher risk of metastasis. However, it is not known whether extratesticular invasion occurs at a preferential site. We reviewed all primary testicular germ cell tumors resected at the Brigham and Women's Hospital, Boston, MA, between July, 987, and July, 997. Of total cases, (6.%) cases showed extratesticular extension. Thirty additional cases (.%), which had lymphatic or vascular invasion only, without interstitial involvement of extratesticular structures, were excluded. Extratesticular extension most likely occurred only at the hilum in (9%) cases; additional cases (9.5%) with tumor in the epididymis did not contain sections of hilum; however, the tunica albuginea was well sampled in these cases, and no separate site of tunica invasion was found. Multiple sections of the tunica albuginea were present in all cases, and penetration of the tunica albuginea was not identified in any case. Extratesticular extension was identified on gross examination of the orchiectomy specimen in only 8 of 8 (%) cases. Extratesticular extension of germ cell tumors preferentially occurs at the hilum, and frequently the extension at this site is grossly inapparent. Histologic examination of the hilum should be performed in all cases of testicular germ cell tumors. Testicular germ cell tumors are the most common solid tumor of men aged 0 to 5 years. During 997, an estimated 7,00 new cases and 50 deaths of testicular cancer occurred. Today, most men with germ cell tumors will be cured of the disease; however, treatment options and prognosis depend on pathologic features. Clinically important distinctions include histologic type (seminoma vs nonseminoma), the presence or absence of lymphovascular invasion, and tumor extension beyond the testis. Local extension of the primary tumor into extratesticular structures, including the epididymis, the spermatic cord, the tunica vaginalis, and the scrotum, is associated with a higher likelihood of relapse and retroperitoneal lymph node metastasis.-9 Despite the fact that extratesticular invasion is a clinically important histologic finding, to our knowledge, there have been no published studies of whether such invasion occurs at a preferential site. Germ cell tumors may invade through the tunica albuginea to involve the tunica vaginalis or scrotum or, alternatively, could invade outside of the testis parenchyma by extending up the testicular hilum into the epididymis and spermatic cord. While the fibrous tunica albuginea is continuous throughout the majority of the testis, this continuity is lost at the testicular hilum. In addition, the hilum contains the rete testis, which subsequently drain into the efferent ductules and epididymis. We wondered whether the anatomy of the testicular hilum would more readily permit extratesticular extension of germ cell tumors than at other sites within the testis. To study this, we reviewed our experience with testicular germ cell tumors, with special focus on the testicular hilum, to determine whether extratesticular extension occurs preferentially at this site. Materials and Methods All surgical pathology reports of primary testicular germ cell tumors resected at the Brigham and Women's Hospital 5 Am J Clin Pathol 999;:5-58 Downloaded from by guest on 7 November 08 Abstract

2 Anatomic Pathology / ORIGINAL ARTICLE Results On review of the histopathologic features, the tumors could be divided into categories: direct extension of less than cm in maximum width (measured from the slide) through the hilum into extratesticular structures (n = ); direct extension of more than cm in maximum width through the hilum into extratesticular structures (n = ); and involvement of extratesticular structures without a definite measurable site of extension from the intratesticular tissue into the extratesticular structures (n = 8), which we termed unmeasurable. Of the cases, (9%) extensively involved the hilum, including 9 tumors that invaded stroma between arborizing channels of the rete testis and tumors that did not invade through but were present within 0. cm adjacent to the rete testis. In the latter cases, both of which were in the unmeasurable category, sections of rete testis were not present. Both cases showed tumor invasion into epididymis or spermatic cord structures without evidence of tumor extension beyond the tunica at any other site, despite extensive sampling of the tunica (5 and sections of tunica submitted). Importantly, none of the cases showed invasion through the tunica albuginea at any other location. Our ability to detect extension through the hilum was related to the number of sections submitted ITable II. In 5 cases, at least section demonstrated direct tumor extension from intratesticular tissues, through the hilum, into extratesticular tissues; this included 0 of cases from the less-than--cm group, of cases from the more-than--cm group, and of 8 cases from the unmeasurable group. Significantly fewer sections of hilum were obtained in cases in which the site of extratesticular extension was unmeasurable (P =.09, Fisher exact test) compared with the combined less-than--cm and morethan--cm groups. In contrast, the difference in the number of sections of tunica albuginea present (Table ) was not statistically significant between the less-than--cm and more-than--cm groups combined and the unmeasurable group. This suggests that it is unlikely that we preferentially missed a nonhilar site of extratesticular invasion in the unmeasurable group. Of the germ cell tumors examined, 0 (%) were pure seminomas, and (56%) were NSGCT ITable. Five tumors (%) contained yolk sac or teratoma elements, (%) were pure embryonal carcinomas, and the remaining 5 (%) were a combination of embryonal carcinoma and seminoma. No elements of choriocarcinoma were present in any tumor. The primary tumors ranged from. to 8.0 cm. There were no statistically significant differences among groups in tumor size or histologic features (Table ). The tumor cells were present as cords or strands (seminomas and tumors with embryonal elements) llmage II or as discrete nodules (NSCGT only) llmage infiltrating through the hilum and into the epididymis, spermatic cord, or soft tissues surrounding the pampiniform plexus. Four ITable II Sectioning of Germ Cell Tumors Maximum Width of Tumor Invading Extratesticular Tissue < cm No. of cases Sections of tunica Sections of hilum > cm Unmeasurable " * Statistically significant (P =.09) in comparison with the combined <- and >)cm groups. Am J Clin Pathol 999; : Downloaded from by guest on 7 November 08 between July, 987, and July, 997, were reviewed. Of cases, (6.%) were at least stage T in the 99 American Joint Committee for Cancer staging system0; in this system, stage T requires extension at least beyond the tunica albuginea or into the epididymis. All histologic slides from these cases were reviewed by both of us. Tumors that were confined within the testis parenchyma but showed lymphovascular invasion within extratesticular vessels (n = 0 [.%]) were excluded from analysis. In addition, all slides from all primary testicular tumors resected at the Brigham and Women's Hospital during and were reviewed. Gross descriptions were available for all tumors resected since 990. The histopathologic type (seminoma, embryonal carcinoma, teratoma, or yolk sac tumor) was determined by examination of H&E-stained slides. Tumors were grouped into pure seminomas or nonseminomatous germ cell tumors (NSGCT), which were any tumor or combination of tumors other than pure seminoma. For this study, the testicular hilum was defined as the site at which the rete testis emerges from the testis and the adjacent 0.5 cm diameter of surrounding tissue, not including seminiferous tubules. The rete testis was identifiable by its architectural pattern of arborizing channels lined by a single epithelial layer of flat, cuboidal, or columnar cells; blunt papillae with fibrovascular cores were present and at times numerous within the rete testis, as previously described. Statistical analysis was done using the Fisher exact test for categoric variables and the Kruskal-Wallis test for continuous variables.

3 Dry and Renshaw / EXTRATESTICULAR EXTENSION OF GERM CELL TUMORS Table Hilar Extension of Testicular Germ Cell Tumors: Tumor Types* Maximum Width of Tumor Invading Extratesticular Tissue < cm () Unmeasurable (50) (E/YS, E, E) (E/YS/T) 0 (E/S, E/S/YS) 0 (E/S, E/YS) (E/S) (60) NS = nonseminomatous; YS = yolk sac; T = teratoma; E = embryonal; S = seminoma. * Data are given as numbers of cases unless otherwise indicated. Differences in gross extension and tumor types between groups are not statistically significant. Image I I Seminoma diffusely invading through the rete Image Nonseminomatous germ cell tumors tended to testis (rete indicated by arrow) in cords and strands of cells invade through the rete testis (rete indicated by arrow) in (H&E, x). discrete nodules (H&E, x). tumors (7%), seminomas, and NSGCT (embryonal carcinoma and seminoma) contained pagetoid spread of germ cell tumor within the rete testis, with individual or clusters of tumor cells undermining the rete epithelium Image, a pattern previously reported in germ cell tumor.-6 Extratesticular extension of tumors at the hilum was not observed to occur preferentially at or along a particular hilar anatomic structure. Gross examination revealed no indication of extratesticular extension in 0 of 8 (56%) tumors (Table ). Gross evidence of extratesticular extension was more difficult to detect in the less-than--cm group (%) than in the morethan--cm (50%) or unmeasurable (60%) groups and did not correlate with the percentage of tumors having a gross description (8% in the <l-cm group, 00% in the >l-cm group, and 6% in the unmeasurable group). There was no 56 Am J Clin Pathol 999; :5-58 Downloaded from by guest on 7 November 08 Pure seminomas' NS germ cell tumors With YS or T component Primary tumor size (cm) no. of cases with gross description No. (%) with gross extension* Tumor type in no gross extension* Pure seminomas NS germ cell tumors Tumor type in positive gross extension* Pure seminomas NS germ cell tumors > cm

4 Anatomic Pathology / ORIGINAL ARTICLE the rete testis (H&E, x5). statistically significant difference between the groups in visible gross extension and tumor type (Table ) or in visible gross extension and epididymal involvement. From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Address reprint requests to Dr Dry: Department of Pathology and Laboratory Medicine, Room A-79, Center for the Health Sciences, University of California, Los Angeles, Los Angeles, CA Discussion We reviewed primary testicular germ cell tumors resected at the Brigham and Women's Hospital during a 0year period, with special focus on the testicular hilum, to determine whether extratesticular extension occurs preferentially at a specific site. Our results strongly suggest that extratesticular invasion of germ cell tumors occurs predominantly at the testicular hilum. In fact, of the cases in our files, we could not identify a single case with a separate site of invasion through the tunica albuginea. Extensive involvement of the hilum occurred in (9%) cases, and sections showing definite extension of intratesticular tumor through the hilum into extratesticular tissues were present in 5 of these cases. Two additional cases did not contain sections of hilum; however, the tunica albuginea was well sampled in these cases and no separate site of tunica invasion was found. No significant differences in sampling of the tunica albuginea were present, so we do not believe sampling error led to our inability to detect a nonhilar site of extratesticular extension. We believe this is the first study to demonstrate that extratesticular extension of germ cell tumors preferentially occurs at a specific site. Gross extension outside the testis was apparent in only 8 of 8 (%) cases, and was of small volume (< cm maximum diameter) in 8%. Importantly, there was no significant difference in epididymal involvement between Downloaded from by guest on 7 November 08 Image Four seminomas showed pagetoid spread within the groups with and without gross extratesticular extension. Furthermore, as we found no significant differences in grossly apparent extension between seminomas and NSGCTs, this cannot be used to identify tumors that require hilar sampling. These results emphasize the importance of adequate sampling of the hilum and extratesticular structures in all cases of testicular germ cell tumors. We reviewed all cases of primary testicular tumors resected at our institution during a 0-year period and found that in 9% (/), extratesticular extension most likely occurred only at the hilum. In no case did we identify invasion through the tunica albuginea at a site separate from the hilum. In approximately half of our cases, extratesticular extension was not grossly apparent and had a maximum width of < cm. Germ cell tumors preferentially invade through the tunica albuginea at the hilum, and frequently the extension at this site is grossly inapparent. Histologic examination of the hilum should be performed in all cases of testicular germ cell tumors. References. Bosl G, Bajorin D, Sheinfeld J, et al. Cancer of the testis. In: DeVita V Jr, Hellman S, Rosenberg S, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, PA: LippincottRaven; 997: Parker S, Tong T, Bolden S, et al. Cancer statistics, 997. CA: Cancer] Clin. 997;7:5-7.. Freedman LS, Jones WG, Peckham MJ, et al. Histopathology in the prediction of relapse of patients with stage I testicular teratoma treated by orchidectomy alone. Lancet. 987;: Fung CY, Kalish LA, Brodsky GL, et al. Stage nonseminomatous germ cell testicular tumor: prediction of metastatic potential by primary histopathology. J Clin Oncol. 988;6: Hoskin P, Dilly S, Easton D, et al. Prognostic factors in stage I non-seminomatous germ-cell testicular tumors managed by orchiectomy and surveillance: implications for adjuvant chemotherapy. J Clin Oncol. 986;: Klepp O, Olsson AM, Henrikson H, et al. Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. J Clin Oncol. 990;8: Raghavan D, Peckham MJ, Heyderman E, et al. Prognostic factors in clinical stage I non-seminomatous genii-cell tumours of the testis. Br J Cancer. 98;5: Rodriguez PN, Hafez GR, Messing EM. Nonseminomatous germ cell tumor of the testicle: does extensive staging of the primary tumor predict the likelihood of metastatic disease? J Urol. 986;6: AmJCIinPathol 999;:

5 Dry and Renshaw / EXTRATESTICULAR EXTENSION OF GERM CELL TUMORS 9. Sesterhenn IA, Weiss RB, Mostofi FK, et al. Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma. J Clin Oncol. 99;0: Beahrs O, Henson D, Hutter R, Kennedy B, (American Joint Committee on Cancer) eds. Manual for Staging of Cancer. th ed. Philadelphia, PA: Lippincott; 99.. Ulbright TM, Gersell DJ, Due W, et al. Rete testis hyperplasia with hyaline globule formation. Am J Surg Pathol. 99;5: Due W, Loy V. Evidence of interepithelial seminoma spread into the rete testis by immunostaining of paraffin sections with antibodies against cytokeratin and vimentin. Urol Res. 988;6: Lee AHS, Smart CJ, Mead GM, et al. Painful shrinking testis and pagetoid spread of germ cell neoplasia in the rete testis. Br J Urol. 99;7: Lee AH, Theaker JM. Pagetoid spread into rete testis by testicular tumours. Histopathobgy. 99;: Mostofi FK, Price Jr EB. Tumors of the Male Genital System. nd ed. Washington, DC: Armed Forces Institute of Pathology; 97. Atlas of Tumor Pathology; vol Perry A, Wiley EL, Albores-Saavedra J. Pagetoid spread of intratubular germ cell neoplasia into rete testis. Hum Pathol. 99;5:5-9. Downloaded from by guest on 7 November Am J Clin Pathol 999; :5-58