First Do No Harm: A Cautious, Risk-adapted Approach to Testicular Cancer Patients

Case Review First Do No Harm: A Cautious, Risk-adapted Approach to Testicular Cancer Patients Hersh M. Trivedi, BS,1 Nirmish Singla, MD, MSCS,1 John Lafin, PhD,1 David Fetzer, MD,2 Payal Kapur, MD,3 Aditya Bagrodia, MD1 1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; 2Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX; 3Department of Pathology, University wof Texas Southwestern Medical Center, Dallas, TX Current guidelines regarding treatment for germ-cell tumors (GCTs) emphasizes cautious progression focusing on stage-specific treatments. Presented herein is the case of a 30-year-old man who, through monitoring of serum alpha-fetoprotein (AFP) levels and surveillance imaging, avoided excessive treatment. This case demonstrates how an experienced clinician, familiar with natural history of GCTs, can appropriately classify level of risk and allow a patient to preserve natural fertility. Furthermore, we highlight the potential for miRNA analysis in staging and management of GCTs. This case serves to underscore the importance of acting with caution in the pursuit of the best outcome for our patients. [Rev Urol. 2020;22(2):85–89] © 2020 MedReviews®, LLC KEY WORDS Germ-cell tumor • Serum tumor markers • Testis cancer • microRNA A 30-year-old white man presented with painless enlargement of the left testicle to approximately the size of a grapefruit over several months with no other associated systemic symptoms. Scrotal ultrasound revealed an enlarged heterogeneous solid mass with fluid components replacing the left testicle, with internal blood flow, consistent with a primary testicular neoplasm (Figure 1). Notably, the right testicle contained punctate echogenic foci (scatter microcalcifications) and a hypoechoic, geographic area that raised concerns for a contralateral malignancy (Figure 2). He endorsed a history of trauma and swelling in the right testicle 4 years prior. Serum markers revealed marked elevation of alpha-fetoprotein (AFP) to 46,887 ng/mL and normal beta-human chorionic gonadotropin (b-hCG) and lactate dehydrogenase (LDH) levels. Radiologic staging with CT scans of the chest, abdomen, and pelvis revealed prominence of his para-aortic retroperitoneal lymph nodes (largest of which was 8 × 8 mm), without evidence of distant metastases (Figure 3). Sperm banking revealed normal semen Vol. 22 No. 2 • 2020 • Reviews in Urology • 85 Early-stage Testicular Cancer continued Figure 1. Left testis: Ultrasound images of scrotum show near-complete replacement of left testis by a heterogeneous, solid, and cystic mass (left, sagittal), with internal color Doppler flow (center). Side-by-side ultrasound image (right) shows marked enlargement of left testis compared with right. Figure 2. Ultrasound images of the scrotum show the right testis in sagittal (left) and transverse (center) orientation with a poorly defined, hypoechoic, somewhat wedge-shaped area (arrows), oriented along the mediastinum testis (open arrow). A few microcalcifications are noted (arrowheads). Minimal internal color Doppler flow is shown (right). Figure 3. Notable for prominence of paraaortic retroperitoneal lymph nodes, the largest of which is 8 × 8 mm, without evidence of distant metastases. No enlarged lymph nodes by CT size criteria. 86 • Vol. 22 No. 2 • 2020 • Reviews in Urology parameters, and serum testosterone levels were within normal range. Left inguinal orchiectomy revealed an 11.5-cm pure yolk-sac tumor with focal lymphovascular invasion (pT2). The tumor was unifocal and limited to the testis, showing no signs of spermatic cord invasion (Figure 4). Following surgery, serial AFP measurements were monitored and normalized by 14 weeks after surgery per expected half-life decay (Figure 5). The accepted half-life of AFP is 5 to 7 days with upper limits of normal ranging from 8 to 25 ng/mL depending on specific populations.1 After normalization of AFP, repeat scrotal ultrasound identified slight increase in the size of the right polar mass. An MRI of the scrotum was pursued considering the concerning sonographic findings in the remaining solitary testicle. The MRI was suspicious due to a wedge-shaped focus of peripheral enhancement around a Figure 4. Yolk-sac tumor with microcystic and reticular patterns. Early-stage Testicular Cancer 6000 AFP Levels (ng/mL) 5000 4000 3000 2000 1000 0 1 2 3 4 5 6 7 8 9 10 Time Relative to Left Orchiectomy (# of Weeks) 11 12 Figure 5. Number of weeks postorchiectomy compared with serum alpha-fetoprotein (AFP) levels (ng/mL). hypointense region, suggestive of potential malignancy (Figure 6). Due to concern for malignancy in the right testicle, a microRNA (miRNA) 371 assay was done in a research context, with a negative result. The decision was made to pursue an inguinal biopsy/partial orchiectomy with expert pathology available for frozen-section examination, which revealed necrosis and atrophy without intratubular germ-cell neoplasia in situ, and his solitary testicle was secured in place (Figure 7). On final pathology, germ-cell neoplasia in situ (GCNIS) was seen adjacent to the completely excised scar. The patient elected for serial examination (as opposed to prophylactic radiotherapy) for fertility preservation. The patient remains off androgen supplementation, has no evidence of invasive tumor formation on serial physical examination and ultrasound, and his wife delivered a naturally conceived, healthy boy during followup. He remains on surveillance protocol. Discussion We report the case of a patient with markedly elevated pre-orchiectomy serum tumor markers, who was ultimately found to have Stage I Figure 6. MRI revealed a vague, poorly defined region of relative hypointensity signal on sagittal T2-weighted image (left, arrow) with corresponding wedge-shaped area of peripheral enhancement and central hypoenhanced on postcontrast T1-weighted images in sagittal (center) and axial (right) orientations Figure 7. The regressed germ-cell tumor (GCT) forms a poorly circumscribed scar with entrapped sclerotic seminiferous tubules and increased vessels (scar 1). There is germ-cell neoplasia in situ in the adjacent parenchyma (germ-cell neoplasia in situ [GCNIS]) that is confirmed by the positive immunostain for OCT 3/4 (GCNIS OC3). Vol. 22 No. 2 • 2020 • Reviews in Urology • 87 Early-stage Testicular Cancer continued disease. This unique case is an excellent reminder of the many nuanced scenarios in GCT management. First, the case highlights the importance of serial tumor marker evaluation until nadir is reached, as per American Urological Association (AUA) and European Association of Urology (EAU) testicular cancer guidelines.1,2 Serum tumor markers (STM) are a mandatory part of GCT management; however, if interpreted incorrectly can lead to substantial under- or overtreatment. In our patient, physicians unfamiliar with subtleties of GCT management may have been tempted to administer systemic chemotherapy based on elevated preoperative STMs. Postorchiectomy, our expectation of AFP downtrend based on half-life alone would be that the AFP levels drop to normal limits within 11 to 12 half-lives, or roughly 8 to 11 weeks. Our patient’s AFP levels reached a nadir within a similar time course, further underlying the specificity of serum AFP markers for GCT.1 Importantly, if the AFP was not followed to nadir, the patient would have been categorized as intermediate or poor-risk and received intermediate/poor risk-directed therapy, which would have been egregious overtreatment with associated potential for treatment-related toxicity. This case highlights how following STM to nadir informs treatment decisions and can avoid systemic chemotherapy or further surgical intervention.3 The second major teaching point for this case is active surveillance in the context of specific cellular type of GCT and borderline retroperitoneal lymph nodes. Generally, nonseminomatous GCT (NSGCT) are compared with seminomas, with pure seminomas having better prognostic factors overall (because of later age, earlier presenting stage, and slower growth rates). Within the broad umbrella of NSGCT, yolk-sac tumors tend to be more differentiated and thus less inherently malignant versus embryonal carcinoma.1,3 Pure seminomas, with active surveillance, tend to reach 100% survival with relapses being cured by salvage therapy. In NSGCT, relapse most often occurs in the first 2 years and is more likely in those patients with lymphovascular invasion (34%–54% vs 14%–26%, respectively).1 In general, serum tumor markers are more indicative of failure on active surveillance than size of lesion, especially with radical orchiectomy, and most relapses are detected in retroperitoneal lymph nodes by imaging and concurrent serum tumor markers.1 Thus, the AUA guidelines point to more active surveillance within the first 2 years as detailed below.1 Currently, follow-up is at roughly 2 years with all subsequent surveillance imaging and laboratory results having been benign. Per AUA guidelines, patients with Stage I NSGCT, surveillance postorchiectomy consists of physical examination and serum tumor markers (AFP, hCG ± LDH) Main Points • Serum tumor markers (STM) are a mandatory part of germ-cell tumor (GCT) management; however, if interpreted incorrectly can lead to substantial under- or overtreatment. This unique case is an excellent reminder of the many nuanced scenarios in GCT management and highlights the importance of STM evaluation until nadir is reached, as per American Urological Association (AUA) and European Association of Urology (EAU) testicular cancer guidelines. • Pure seminomas, with active surveillance, tend to reach 100% survival with relapses being cured by salvage therapy. In nonseminomatous GCT (NSGCT), relapse most often occurs in the first 2 years and is more likely in those patients with lymphovascular invasion. STM are more indicative of failure on active surveillance than size of lesion, especially with radical orchiectomy, and most relapses are detected in retroperitoneal lymph nodes by imaging and concurrent serum tumor markers. Thus, the AUA guidelines point to more active surveillance within the first 2 years. • A deliberate approach should be taken with repeat serial ultrasonography, MRI, and miRNA (in a research context, not for clinical decision making) prior to invasive examination in the management of equivocal, marker-negative testicular lesions. AUA guidelines suggest short-interval repeat doppler sonography and physical examination for equivocal, marker-negative masses. This theme of moving cautiously in areas of clinical uncertainty is prevalent throughout the AUA guidelines. The EAU guidelines recommend enucleation of indeterminate small testicular masses to obtain pathologic certainty for certain patients. • Serum miRNAs are emerging as ideal biomarkers for diagnosing and monitoring GCT. 88 • Vol. 22 No. 2 • 2020 • Reviews in Urology Early-stage Testicular Cancer every 2 to 3 months in the first and second years, every 4 to 6 months in the third year, and once a year for the fourth and fifth years. Similarly, imaging surveillance in this patient population (consisting of chest radiograph and imaging of the abdomen ± pelvis) should be obtained every 4 to 6 months in the first year, and then once in Year 2, Year 3, and then one-time followup in the next 2 years. There is a less than 1% risk of late relapse after 5 years, thus the AUA recommends follow-up surveillance after this initial surveillance algorithm based on clinical concerns.2 The concept of being sure, being patient, and being safe as it applies to optimal management of Stage I GCT patients is accentuated in this case.4 The third main teaching point is exemplified in the management of equivocal, marker-negative testicular lesions. In this case, a deliberate approach was taken with repeat serial ultrasonography, MRI, and miRNA (in a research context, not for clinical decision making) prior to invasive examination. Importantly, the AUA guidelines suggest short-interval repeat doppler sonography and physical examination for equivocal, markernegative masses.1 This theme of moving cautiously in areas of clinical uncertainty is prevalent throughout the AUA guidelines. The EAU guidelines recommend enucleation of indeterminate small testicular masses to obtain pathologic certainty for certain patients.2 In this case, because the patient had adequate semen and androgen parameters, shared decision making was performed to respect patient priorities of fertility preservation and avoidance of life-long androgen replacement. Although he remains at risk of developing an invasive GCT due to presumed residual GCNIS, goals of fathering children through natural conception techniques were actualized. CIS is present in approximately 90% of patients with GCTs. Natural history studies indicated that 50% of GCNIS will ultimately develop into invasive tumors. Per guidelines, the patient was counseled on prophylactic radiotherapy versus serial examination. He wished to prioritize fertility preservation and is on an active surveillance program. This case also highlights how despite preplanning of dedicated genitourinary pathologist availability at time of partial orchiectomy, intraoperative identification of GCNIS remains exceedingly difficult. Finally, this case identifies prospects and limitations of miRNAs in the management of GCT patients. Serum miRNAs are emerging as ideal biomarkers for diagnosing and monitoring GCT.5–7 In particular, specific mature miRNAs from the miR-371-373 and miR-302/367 clusters are released into the circulation by testicular cancer tissue and exhibit higher sensitivity and specificity for GCT compared with traditional STMs.5,6 In our case, absence of detectable miR-371 in the patient’s serum supported the absence of occult viable GCT elements, but was uninformative with respect to the presence of GCNIS within the solitary right testicle. These findings accentuate that performance characteristics of serum miRNAs require more complete understanding prior to widespread clinical implementation. We advise that casual polymerase chain reaction examination of GCTassociated miRNAs for clinical decision making be avoided until these assays are validated and standardize in a clinical-grade fashion. cancer outcomes while minimizing treatment-related morbidity. In our patient, it is repeatedly illustrated that expertise and familiarity with GCTs is required from the time a patient seeks consultation for suspected or confirmed testicular cancer through potentially life-long survivorship. Our case makes it apparent that every step of the process requires careful attention to detail and experience with managing relatively rare clinical scenarios. Several key points from the AUA and EAU guidelines are exemplified in this case, which can broadly be summarized as moving carefully and deliberately, to confirm that appropriate, stagespecific principles are followed. In our case, monitoring of tumor markers, retroperitoneal lymph nodes, and equivocal scrotal mass highlight these concepts. Testicular cancer patients are often in the primes of their lives and must contend with consequences of treatment-related decisions for many years. Expertise and experience for accurate diagnose and management and patient preferences prioritization are owed to these young cancer survivors. References 1. 2. 3. 4. 5. 6. Conclusions Our case highlights the nuanced care of early-stage GCT patients as we aim to maintain excellent 7. Stephenson A, Eggener SE, Bass EB, et al. Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline (2019). American Urological Association website. https://www.auanet.org/guidelines/testicularcancer-guideline. Accessed July 1, 2020. Albers P, Albrecht W, Algaba F, et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol. 2015;68:1054–1068. Tsuchida Y, Saito S, Ishida M, et al. Yolk sac tumor (endodermal sinus tumor) and alpha-fetoprotein. A report of three cases. Cancer. 1973;32:917–921. Kollmannsberger CK, Nappi L, Nichols C. Management of Stage II germ cell tumors: be sure, be patient, be safe. J Clin Oncol. 2019;37:1856–1862. Murray MJ, Halsall DJ, Hook CE, et al. Identification of microRNAs from the miR-371~373 and miR-302 clusters as potential serum biomarkers of malignant germ cell tumors. Am J Clin Pathol. 2011;135:119–125. Dieckmann K-P, Radtke A, Geczi L. et al. Serum levels of microRNA-371a-3p (M371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study. J Clin Oncol. 2019;37:1412–1423. Singla N, Lafin JT, Bagrodia A. MicroRNAs: turning the tide in testicular cancer. Eur Urol. 2019;76: 541–542. Vol. 22 No. 2 • 2020 • Reviews in Urology • 89