Malignant Germ Cell Tumors Linked to Higher Stage at Presentation, Adverse Pathologic Features in Older Men

The intrinsic complexities related to testicular cancer make it one of the most challenging genitourinary cancers to treat. It can be difficult to counsel patients on what they can expect regarding prognosis and treatment planning. Consequently, there is a tremendous need to investigate the relationship between patient-related factors, clinical and pathologic features, and more or less aggressive disease. A recent study published in the Annals of Diagnostic Pathology investigated the association between age at presentation of malignant germ cell tumors (GCTs) and adverse pathologic features and disease staging.¹

It is well known that testicular GCTs impact men in their second and third decades of life. There is rising incidence of the disease,² and the age at which patients are diagnosed is also increasing.³ The study authors noted that “more than 95% of all reported testicular malignancies in the United States are [GCTs] with seminomas, accounting for half of all cases.”⁴ While testicular GCTs are more common in young adults, the majority of testicular tumors in older men are not germ cell in origin but rather include lymphomas, spermatocytic tumors, stromal tumors, or secondary malignancies. In fact, according to the authors, “only 5% of testicular [GCTs] are diagnosed at age 50 years or older”. When men older than 50 do have GCTs, they tend to be primary testicular tumors and, less commonly, retroperitoneal tumors.⁵ At the same time, primary retroperitoneal GCTs are 5 times more frequent in men over the age of 50 compared with younger men.

Not only is the incidence different between older and younger men, but so is response to treatment, the authors wrote. Men older then 50 are more likely to have chemotherapy-related complications, side effects, and relapse compared with their younger peers.

That there are pathologic factors associated with worse prognosis is also well documented. Lymphovascular invasion is associated with higher risk of metastasis, while tumor size and rete testis invasion are strong predictors of relapse in patients with seminomatous disease.⁶ The authors of this study sought to “provide insight into the incidence, histopathologic features, and biologic behavior of malignant [GCTs], with an emphasis on testicular [GCTs], among men aged ≥50 years … and highlight unique features that distinguish this demographic from the typical clinical presentation of testicular [GCTs].”

The authors identified men ≥50 at their institution who had been diagnosed with a malignant GCT and investigated clinical and histopathologic features of their disease. Patients with spermatocytic tumors were excluded from the study. The median age of the study’s 47 patients was 56 years, and the median tumor size was 4.6 cm. Eighty-three percent of patients presented with a testicular mass, while 15% presented with retroperitoneal lymphadenopathy. One patient was diagnosed with inguinal lymphadenopathy.

On pathology, 55% of patients were found to have seminomatous disease, 28% had mixed GCT, 4% had teratoma, and 11% had regressed testicular GCTs. The authors noted that 1 patient had only germ cell neoplasia in situ and fibrosis on testicular pathology. Of the patients with mixed GCT, embryonal carcinoma was the most common component identified (77%), followed by seminoma (62%), yolk sac tumor (62%), and germ cell neoplasia in situ (57%).

A total of 77% of patients were found to have aggressive pathologic features, including 47% with lymphovascular invasion, 23% with retroperitoneal/lymph node involvement, and 47% who presented at a higher stage at time of diagnosis. Twenty percent of patients were found to have distant metastatic disease. One metastatic mixed GCT involving the retroperitoneum was unusual and showed aggressive histology, including high-grade sarcomatoid yolk sac tumor with somatic transformation of intestinal type adenocarcinoma and a focus resembling a malignant giant cell tumor of bone or soft tissue.

A total of 89% of patients had follow-up ranging from 1 month to more than 8 years. Of those patients, 79% were alive with no evidence of disease recurrence, 14% died of disease, and 7% died of non-malignancy-related factors. All patients who died of disease had a poor response to cisplatin-based chemotherapy and had disease progression prior to death, according to the authors.

This study demonstrated that the presentation of seminomatous disease correlated with patient age. The findings showed that the most predominant pattern of patients with mixed GCT is embryonal carcinoma, which is consistent with previously reported studies⁷ and supports that there is a shift from pure nonseminomatous disease to seminomatous and mixed GCTs. The patients in this study had a high incidence of aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement, and higher stage at presentation. These findings may promote the use of ancillary analysis such as immunohistochemical staining and fluorescent in situ hybridization to provide an accurate diagnosis, the authors wrote.

This study also emphasized the need to further investigate disease in this patient population. These patients have been shown to have poorer survival compared with their younger counterparts, an outcome that is likely multifactorial and related to system-based as well as patient-related factors, including a patient’s ability to tolerate chemotherapy.

The authors concluded their findings “expand and corroborate the previously reported data on malignant [GCTs] in older men. Unique presentation characteristics include the tendency for higher stage at presentation with adverse pathologic features and a more aggressive subsequent clinical course. GCTs in this age group can represent a challenging entity from [both] a diagnostic and management standpoint and should be given special consideration due to their poor clinical outcomes.”

David Ambinder, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Almutairi F, Geisler D, Rammal R, et al. Malignant germ cell tumors in men aged 50 years and over are associated with adverse pathologic features and higher stage at presentation. Ann Diagn Pathol. 2023;62:152070. doi:10.1016/j.anndiagpath.2022.152070
2. NCCN Clinical Practice Guidelines in Oncology. Testicular cancer. Version 1.2023. National Comprehensive Cancer Network. January 26, 2023. Accessed August 28, 2023. https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf
3. Yamashita S, Koyama J, Goto T, et al. Trends in age and histology of testicular cancer from 1980–2019: a single-center study. Tohoku J Exp Med. 2020;252(3):219-224. doi:10.1620/tjem.252.219
4. Ghazarian AA, Trabert B, Devesa SS, McGlynn KA. Recent trends in the incidence of testicular germ cell tumors in the United States. Andrology. 2015;3(1):13-18. doi:10.1111/andr.288
5. Feldman DR, Voss MH, Jacobsen EP, et al. Clinical features, presentation, and tolerance of platinum-based chemotherapy in germ cell tumor patients 50 years of age and older. 2013;119(14):2574-2581. doi:10.1002/cncr.28025
6. Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol. 2002;20(22):4448-4452. doi:10.1200/JCO.2002.01.038
7. Berney DM, Warren AY, Verma M, et al. Malignant germ cell tumours in the elderly: a histopathological review of 50 cases in men aged 60 years or over. Mod Pathol. 2008;21(1):54-59. doi:10.1038/modpathol.3800978