Abstract
Objective:
To review the presentation and long-term oncologic outcomes of patients with regressed (“burnt out”) primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes.
Methods:
We queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990–2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method.
Results:
Fifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n=5) or first-line chemotherapy (n=34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively.
Conclusion:
Patients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT.
Keywords: Burnt out tumor, Germ cell tumors, Regressed tumor, Testicular cancer
INTRODUCTION
Regressed or burnt out testicular germ cell tumors (GCT) are a rare clinical entity, occurring in approximately 2–3% of patients with testicular masses.1,2 These tumors are characterized by an absence of viable invasive GCT despite no prior treatment, and a fibrotic scar in the testicle indicative of prior disease with or without surrounding germ cell neoplasia in situ (GCNIS).3,4 Patients may present with a palpable or incidentally discovered testicular lesion, or with symptoms or imaging suggestive of advanced disease. This finding was first described in 1927 by Prym et al in a patient presenting with advanced choriocarcinoma and was first recognized as a histologic entity in the 2016 World Health Organization Classification of testicular tumors.3 However, in the years since, our understanding of the biological trajectory of burnt out tumors has been limited to small case reports and series.5-9 The natural history and optimal management of burnt out tumors remain poorly understood.
The unknown mechanism for regression in the primary tumor along with the widely variable outcomes reported in the literature contribute to our imperfect understanding of the behavior of burnt out tumors. It has not been demonstrated that outcomes for patients with these tumors are comparable to those with viable testicular primary tumors.7,10 Therefore, we sought to describe over 30 years of experience at our institution with this rare clinical scenario. In this study, we describe the typical presentation and report long-term outcomes of patients managed with surveillance and those treated for advanced disease in the setting of a burnt out primary testicular GCT.
PATIENTS AND METHODS
Data Source and Patients
Patients treated for testicular GCT at Memorial Sloan Kettering Cancer Center (MSK) are included in a prospectively maintained clinical database that collects patient demographics, diagnosis, staging, and treatment information as well as pathology, radiology, and laboratory results. Long-term oncologic and survival outcomes are also collected as part of routine clinical care.
Following institutional review board approval (IRB #16-554), we queried our database for all radical orchiectomies performed at MSK from 1990 to 2023 and identified 156 patients whose pathology revealed burnt out or regressed tumor in the testicle without viable GCT. Patients with any viable, invasive germ cell tumor were excluded regardless of the presence of a concomitant burnt out component. All pathologic samples were reviewed at our institution by one of our dedicated genitourinary pathologists at the time of diagnosis. There was no pathology re-review performed for this study. Ninety-nine patients had received chemotherapy prior to orchiectomy and were excluded from this cohort. One patient presented with synchronous viable GCT in the contralateral testis and was also excluded from this cohort.
Measures and Outcomes
Our primary outcome of interest was 2-year recurrence-free survival (RFS) stratified by clinical stage at diagnosis (CS0/CSx vs CS II+). Secondary outcomes included treatment outcomes and overall survival. Patient-related variables included race, age at the time of orchiectomy, presenting symptoms, clinical stage, serum tumor markers (STM) at diagnosis, and International Germ Cell Cancer Collaborative Group (IGCCCG) risk group for patients with advanced disease. Treatment variables included chemotherapy regimen, number of cycles, and surgical outcomes if the patient underwent primary (pRPLND) or post-chemotherapy retroperitoneal lymph node dissection (pcRPLND).
Statistical Analysis
Patient characteristics were reported using descriptive statistics. We performed time-to-event analysis using the Kaplan-Meier method for event-free survival for all patients and stratified by clinical stage. Patients were censored using the date last seen at MSK with cancer surveillance laboratory values or imaging for disease relapse. All analyses were performed using Stata version 15.0 (StataCorp, College Station, TX).
RESULTS
Patient Characteristics and Presentation
We identified 56 patients who underwent radical orchiectomy without prior chemotherapy or synchronous contralateral viable disease, and who had a burnt out or regressed testicular tumor. Median age at orchiectomy was 40 (IQR: 32, 51). Twenty-three patients (41%) presented with symptoms attributable to, or imaging demonstrative of, advanced disease including 2 patients with incidentally discovered abdominal/retroperitoneal masses. Presenting symptoms were unavailable for 11 patients (Table 1).
Table 1.
Patient characteristics for the cohort of men with a “burnt out” (regressed) primary testicular tumor without prior systemic treatment (N = 56).
| N=56 | |
|---|---|
| Median age at index orchiectomy, years (IQR) | 40 (32, 51) |
| Race, n (%) | |
| White | 52 (93) |
| Black | 1 (1.8) |
| Asian | 1 (1.8) |
| Unknown | 2 (3.6) |
| Histology1 | |
| Seminoma | 18 |
| Nonseminoma | 12 |
| Not definable | 26 |
| Clinical stage, n (%) | |
| CSx | 12 (21) |
| CS0 | 5 (8.8) |
| CS II | 27 (47) |
| CS III | 12 (21) |
| Side of index orchiectomy, n (%) | |
| Left | 31 (55) |
| Right | 25 (45) |
| Presenting signs/symptoms2, n (%) | |
| Local | 22 (39) |
| Testicular pain | 10 (22) |
| Testicular mass | 8 (20) |
| Incidentally discovered during fertility evaluation | 4 (8.7) |
| Advanced | 23 (41) |
| Back pain | 10 (22) |
| Abdominal pain | 6 (13) |
| Flank pain | 2 (4.3) |
| Incidental imaging | 2 (4.3) |
| Neck mass | 2 (4.3) |
| Gynecomastia | 1 (2.2) |
| Nausea/vomiting | 1 (2.2) |
Sixteen patients underwent surveillance without relapse and histology remains not definable. Five patients underwent biopsy which confirmed germ cell tumor, histology unspecified, three of whom subsequently underwent pcRPLND and had no viable nonteratomatous GCT or teratoma. Five patients had elevated HCG or LDH prior to chemotherapy, and thus could represent seminoma or nonseminoma.
Presenting symptoms available for 45 patients
Seventeen patients (30%) presented without evidence of advanced disease and had a testicular scar with GCNIS (pTis, CS0, n=5) or without GCNIS (pTx, CSx, n=12). Pre-orchiectomy STM were available for 15 of these patients, and none were elevated. Thirty-nine patients (70%) had evidence of retroperitoneal disease or distant metastases: clinical stage II in 27 patients and clinical stage III in 12 patients. Pretreatment (either pre- or post-orchiectomy) serum tumor markers were available for 27 patients with advanced disease and 81% (n=22) had elevated markers prior to the initiation of chemotherapy (Table 2). Among the 34 patients with advanced disease treated with chemotherapy, 26 (67%) were IGCCCG good risk, while 8 (21%) were intermediate risk and 5 (13%) were poor risk (Table 2).
Table 2.
Treatment information for patients with advanced disease at presentation managed with first-line chemotherapy (n=34).
| N=34 | |
|---|---|
| IGCCCG risk group, n (%) | |
| Good | 21 (62) |
| Intermediate | 8 (24) |
| Poor | 5 (15) |
| Chemotherapy regimen, n (%) | |
| BEP x 3 | 4 (12) |
| BEP x 4 | 12 (35) |
| EP x 4 | 16 (47) |
| HDCT/ASCT | 1 (2.9) |
| VIP x 4 | 1 (2.9) |
| Biopsy pre-chemotherapy, n (%) | 31 (91) |
| Elevated markers at any point prior to chemotherapy1, n (%) | 22 (81) |
| AFP (N=27) | 4 (15) |
| HCG (N=26) | 15 (58) |
| LDH (N=26) | 19 (73) |
Any pre-treatment tumor markers were available in 27 patients (either pre- or post-orchiectomy but prior to initiation of chemotherapy).
IGCCCG: International Germ Cell Cancer Collaborative Group; BEP: bleomycin, etoposide, and cisplatin; EP: etoposide and cisplatin; HDCT/ASCT: high dose chemotherapy and autologous stem cell transplant; VIP: etoposide, ifosfamide, and cisplatin; AFP: alpha-fetoprotein; HCG: human chorionic gonadotropin; LDH: lactate dehydrogenase.
Management
All 17 patients without evidence of advanced disease were managed with surveillance. The 39 patients with advanced disease received upfront treatment, with 4 (10%) undergoing pRPLND and 34 (87%) receiving risk-directed first-line chemotherapy. The remaining patient underwent retroperitoneal mass resection (not full pRPLND) for presumed sarcoma and was found to have embryonal carcinoma on final pathology; he subsequently underwent orchiectomy revealing pT0 and was then managed with surveillance. All 4 patients who underwent pRPLND after orchiectomy were found to have viable seminoma in the retroperitoneum (Table 3). Two of these patients received adjuvant chemotherapy (EPx2) and two were managed with surveillance; none have recurred to date.
Table 3.
Outcomes of primary (n=4) and post-chemotherapy (n=23) RPLND.
| pRPLND (N=4) | pcRPLND (N=23) | |
|---|---|---|
| Positive nodes at RPLND1, median (IQR) | 1 (1, 4) | 0 (0, 1) |
| Nodes removed at RPLND1 (N=22), median (IQR) | 58 (37, 71) | 38 (18, 48) |
| N stage at RPLND, n (%) | ||
| pN1 | 0 | 3 (13) |
| pN2 | 4 (100) | 1 (4.3) |
| pN3 | 0 | 2 (8.7) |
| pN0 | 0 | 17 (74) |
| Pathologic size of largest node at RPLND (N=9), cm median (IQR) | 2.8 (2.5, 3.7) | 1.0 (0.9, 4.0) |
| Histology at RPLND, n {%) | ||
| Benign or fibrosis/necrosis | 0 | 17 (74) |
| Teratoma, only | 0 | 3 (13) |
| Viable tumor | 4 (100) | 3 (13) |
| Choriocarcinoma | 0 | 1 (33) |
| Pure seminoma | 4 (100%) | 1 (33) |
| Teratoma with secondary somatic type malignancy | 0 | 1 (33) |
Number of nodes removed and their positivity status available for 22 patients only.
RPLND: retroperitoneal lymph node dissection; pRPLND: primary RPLND; pcRPLND: post-chemotherapy RPLND.
Of the 34 patients who underwent induction chemotherapy, 31 (91%) underwent biopsy prior to chemotherapy to confirm the diagnosis of metastatic GCT: 13 patients were found to have seminoma, 6 had nonseminomatous GCT (NSGCT), 6 had unspecified GCT and 6 biopsies were non-diagnostic. Three patients with non-diagnostic biopsies and 2 patients without biopsy were treated due to elevated serum human chorionic gonadotropin (HCG) (n=4) or elevated serum HCG and alpha-fetoprotein (AFP) (n=1). Three patients with non-diagnostic biopsy and normalized markers were treated due to interval increasing lymphadenopathy. Six patients required second-line chemotherapy.
Twenty-three patients underwent post-chemotherapy RPLND (pcRPLND). At pcRPLND, 74% (n=17) had fibrosis/necrosis in the retroperitoneum, 13% (n=3) harbored teratoma, and 13% (n=3) harbored viable GCT, including 1 patient with teratoma with secondary somatic type malignancy (4%). All patients with viable nonteratomatous GCT on pcRPLND received adjuvant treatment (Table 3). No patients with presumed seminoma or undefinable GCT pre-treatment had teratoma or viable non-seminoma at the time of pcRPLND. One patient with presumed seminoma had residual viable seminoma at pcRPLND; he underwent salvage chemotherapy with paclitaxel, ifosfamide and cisplatin (TIP) x 4 cycles and remains classified as “no evidence of disease” (NED). Eleven patients did not undergo pcRPLND. Ten of these patients had seminoma on pre-chemotherapy biopsy and complete response to chemotherapy. The eleventh patient had seminoma on pre-chemotherapy biopsy, but an elevated AFP prior to chemotherapy. He had a complete response to chemotherapy and elected surveillance.
Patient histology was categorizable for 30 patients by biopsy, elevated STM, or RPLND histology. Eighteen of these patients had pure seminoma, while 12 had NSGCT. Twenty-six patients were unable to be categorized, including 16 treated with surveillance, 6 with biopsy-confirmed GCT but undefined histology, and 4 with non-diagnostic biopsies (Supplemental Figure 1).
Long-term Outcomes
There were 4 relapses in our cohort: 3 patients with advanced disease treated initially with chemotherapy and 1 patient in the surveillance group. The median follow-up for those who did not experience a relapse and were managed on surveillance, versus immediate treatment, was 1.7 years (IQR: 1.2, 5.2) versus 6.3 years (IQR: 2.0, 13.6), respectively. The 2-year RFS for patients managed on surveillance was 100% (95% CI: NA, NA). One patient initially treated with surveillance was lost to follow-up and re-presented 3 years after radical orchiectomy with flank pain and retroperitoneal lymphadenopathy. For those with advanced disease receiving upfront treatment, 2- and 5- year RFS was 94% (95% CI: 78, 98) and 90% (95% CI: 72, 97), respectively (Figure 1).
Figure 1.
Relapse-free survival by stage: CS0/CSx vs CS II+
There were 3 patient deaths in our cohort, 1 in the surveillance group and 2 in the treatment group. One of these deaths was due to testis cancer, occurring in a patient who had poor-risk disease at diagnosis. For the whole cohort, the overall survival rate was 98% (95% CI: 85, 100) and 91% (95% CI: 65%, 98%) at 5 and 10 years, respectively.
DISCUSSION
This study reports the long-term outcomes of 56 patients found to have a burnt out primary testicular GCT with or without advanced disease at diagnosis. To our knowledge, this is the largest cohort of such patients reported in the literature. While some have reported a poor prognosis for patients presenting with burnt out primary testicular GCT,7,10 we found that these patients face a similar treatment burden and long-term outcomes comparable to those who present with a viable primary testicular tumor. Patients presenting with advanced disease who underwent risk-directed chemotherapy had long-term RFS rates comparable to those presenting with viable disease in the testicle11; patients who presented without evidence of advanced disease had excellent long-term outcomes on surveillance. Notably though, among patients with burnt out primary tumors, we did see a high proportion of patients presenting with advanced disease relative to expected population-level stage distribution.
The median age of patients in our cohort was 40, older than the median age of all patients with testicular GCT.12 This may be due to an overrepresentation of seminoma, a delay in diagnosis, and a subset of patients whose burnt out lesion went undiagnosed for many years prior to detection. Similarly, at the population-level, roughly 20% of patients with seminoma and 30-40% of patients with nonseminoma present with advanced disease13-15 but in our cohort, 70% of patients had regional or distant metastases. This is perhaps due to the lack of a clinically apparent mass to cause symptoms, which could delay initial presentation and allow for disease progression. In our cohort, 40% of patients presented with initial symptoms, such as flank pain or abdominal pain, attributable to metastatic disease including 2 patients who presented with the incidental finding of an abdominal/retroperitoneal mass. This is greater than the reported 1–10% of patients with testicular masses who present exclusively with symptoms attributable to metastatic disease.16 Similarly, in patients with an isolated retroperitoneal mass and no obvious testicular mass, confirmation of diagnosis can be challenging. In our cohort, 1 patient without a palpable testicular mass underwent resection of a retroperitoneal mass, which was presumed to be a retroperitoneal sarcoma; however, final pathology demonstrated an embryonal carcinoma. He subsequently underwent scrotal ultrasound showing a hypoechoic lesion in the left testicle and orchiectomy demonstrating a burnt out lesion. To confirm diagnosis, 31 of 34 (94%) patients treated with chemotherapy had undergone retroperitoneal biopsy prior to initiation of treatment. The remaining 5 patients had elevated serum HCG or AFP following radical orchiectomy. This reinforces the need for a high index of suspicion for GCT in any young man presenting with retroperitoneal adenopathy, regardless of whether there is an apparent testicular primary tumor.
Equivocal scrotal ultrasound findings or the incidental discovery of a retroperitoneal mass are both common presenting signs and/or symptoms and contribute to the diagnostic challenges of managing a suspected burnt out primary testicular tumor. In these patients, when attempting to lateralize a tumor to a specific testicle prior to orchiectomy, consideration should be given to: 1) the distribution of any retroperitoneal lymphadenopathy (right sided primary tumors are more commonly found in pre-caval or interaortocaval nodes, left sided are more commonly found in pre- or para-aortic nodes); 2) a unilateral testis that may be more atrophic than the other or the prior history of cryptorchidism; and 3) subtle imaging findings such as calcifications or ill-defined hypovascular lesions.17
Two-year RFS for patients without evidence of metastatic disease on presentation was 100% (95% CI: NA, NA). The single relapse occurred roughly 3 years after radical orchiectomy in a patient lost to follow up. In our study, RFS for patients managed with surveillance compares favorably with relapse rates for patients with low-risk pure seminoma and mixed GCT managed with surveillance.18-22 The Swedish and Norwegian Testicular Cancer Project (SWENOTECA) reported an 86.5% 10-year RFS among 338 patients with CS I non-seminoma without lymphovascular invasion treated with surveillance.23 Similarly, a Danish nationwide study reported a 94% 5-year RFS in patients with CS I seminoma and no high-risk CS IA features (elevated lactate dehydrogenase [LDH] or HCG, rete testis invasion, hilar soft tissue invasion, or lymphovascular invasion).19 Surveillance is a preferred treatment modality for both CS IA seminoma and non-seminoma; and our data suggest that, likewise, surveillance is a safe management strategy for patients with regressed primary tumors and no evidence of advanced disease.
While the cause of primary tumor regression is unknown, it does not appear to portend more aggressive disease. Regressed primary malignancies have been described in multiple non-GCT malignancies including hepatocellular carcinoma and melanoma.24-27 This process is best studied in melanoma, where an immunologic etiology appears to be the most likely explanation, as regressed melanomas are characterized by T lymphocyte infiltration.28,29 The most compelling evidence for this etiology in testicular GCT is the described autoimmune response seen in GCNIS and in some seminomas.28,30 Others have suggested an ischemic etiology wherein the local tumor outgrows its blood supply, resulting in ischemic damage and regression.27,31 While it is unknown whether disease regression is more common in seminoma than in non-seminoma, all patients in our cohort who underwent pRPLND had pure seminoma in the retroperitoneum and very few had teratoma or other non-teratomatous GCT found at pcRPLND.
Overall, despite a varied burden of disease at presentation, patients with burnt out primary testicular tumors have a similar prognosis to those with viable testicular cancers. Our experience demonstrates that patients with advanced disease on presentation responded to conventional risk-directed cisplatin-based chemotherapy upon confirmation of GCT pathology with biopsy of a metastatic site. Similarly, patients without advanced disease had excellent outcomes when managed by surveillance.
Conclusion
To our knowledge, this is the largest series of burnt out GCT ever reported. Patients with burnt out or regressed primary tumors often present with advanced disease, possibly due to a lack of clinical signs or symptoms from the primary tumor. However, we found that in our patients with advanced disease who received risk-directed chemotherapy, long-term RFS rates were comparable to reported rates for those presenting with viable disease in the testicle. Among patients without metastatic disease at presentation, surveillance was associated with a low risk of relapse.
Supplementary Material
Supplemental Figure 1. Determination of disease histology for patients without viable germ cell tumor at radical orchiectomy.
Funding:
This research was funded in part through the NIH/NCI Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748).
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflicts of interest: The authors report no relevant disclosures.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
REFERENCES
- 1.Fabre E, Jira H, Izard V, et al. ‘Burned-out’ primary testicular cancer. BJU Int. 2004;94(1):74–78. doi: 10.1111/j.1464-410X.2004.04904.x [DOI] [PubMed] [Google Scholar]
- 2.Tasu J-P, Faye N, Eschwege P, Rocher L, Blery M. Imaging of burned-out testis tumor: five new cases and review of the literature. J Ultrasound Med. 2003;22(5):515–521. doi: 10.7863/jum.2003.22.5.515 [DOI] [PubMed] [Google Scholar]
- 3.Urinary and Male Genital Tumours : WHO Classification of Tumours. Vol 8. 5th ed.; 2022. [Google Scholar]
- 4.Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2022;82(5):458–468. doi: 10.1016/j.eururo.2022.06.016 [DOI] [PubMed] [Google Scholar]
- 5.Prym: Spontanheilung eines bösartigen, wahrscheinlich… - Google Scholar. Accessed December 4, 2023. https://scholar.google.com/scholar_lookup?hl=en&volume=265&publication_year=1927&pages=239-58&journal=Virchows+Arch+Pathol+Anat&author=P+Prym&title=Spontanheilung+eines+bosartigen%2C+wahrscheinlich+chorionephiteliomatosen+gewachses+im+hoden
- 6.Balalaa N, Salman M, Hassen W. Burned-Out Testicular Tumor: A Case Report. Case Rep Oncol. 2011;4(1):12–15. doi: 10.1159/000324041 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Iannantuono GM, Strigari L, Roselli M, Torino F. A scoping review on the “burned out” or “burnt out” testicular cancer: When a rare phenomenon deserves more attention. Crit Rev Oncol Hematol. 2021;165:103452. doi: 10.1016/j.critrevonc.2021.103452 [DOI] [PubMed] [Google Scholar]
- 8.Comiter CV, Renshaw AA, Benson CB, Loughlin KR. Burned-Out Primary Testicular Cancer: Sonographic and Pathological Characteristics. J Urol. 1996;156(1):85–88. doi: 10.1016/S0022-5347(01)65947-0 [DOI] [PubMed] [Google Scholar]
- 9.Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases. Am J Surg Pathol. 2006;30(7):858–865. doi: 10.1097/01.pas.0000209831.24230.56 [DOI] [PubMed] [Google Scholar]
- 10.Persano G, Crocoli A, De Pasquale MD, et al. Burned-Out Testicular Tumors in Adolescents: Clinical Aspects and Outcome. Front Pediatr. 2021;9:688021. https://www.frontiersin.org/articles/10.3389/fped.2021.688021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cheng L, Albers P, Berney DM, et al. Testicular cancer. Nat Rev Dis Primer. 2018;4(1):1–24. doi: 10.1038/s41572-018-0029-0 [DOI] [PubMed] [Google Scholar]
- 12.Cancer of the Testis - Cancer Stat Facts. SEER. Accessed September 25, 2023. https://seer.cancer.gov/statfacts/html/testis.html [Google Scholar]
- 13.SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute; 2023. Apr 19. [updated: 2023 Nov 16; cited 2023 Dec 29]. Available from: https://seer.cancer.gov/statistics-network/explorer/. Data source(s): SEER Incidence Data, November 2022 Submission (1975-2020), SEER 22 registries. [Google Scholar]
- 14.Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409–436. doi: 10.3322/caac.21731 [DOI] [PubMed] [Google Scholar]
- 15.Verhoeven RHA, Karim-Kos HE, Coebergh JWW, et al. Markedly increased incidence and improved survival of testicular cancer in the Netherlands. Acta Oncol Stockh Swed. 2014;53(3):342–350. doi: 10.3109/0284186X.2013.819992 [DOI] [PubMed] [Google Scholar]
- 16.Moul JW. Timely Diagnosis of Testicular Cancer. Urol Clin North Am. 2007;34(2):109–117. doi: 10.1016/j.ucl.2007.02.003 [DOI] [PubMed] [Google Scholar]
- 17.Desmousseaux T, Arama E, Maxwell F, et al. Ultrasound and magnetic resonance imaging of burned-out testicular tumours: the diagnostic keys based on 48 cases. Cancers (Basel). 2022;14(16): 4013. doi: 10.3390/cancers14164013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cummins S, Yau T, Huddart R, Dearnaley D, Horwich A. Surveillance in Stage I Seminoma Patients: A Long-Term Assessment. Eur Urol. 2010;57(4):673–678. doi: 10.1016/j.eururo.2009.06.006 [DOI] [PubMed] [Google Scholar]
- 19.Wagner T, Toft BG, Lauritsen J, et al. Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study. J Clin Oncol. 2024;42(1):81–89. doi: 10.1200/JCO.23.00959 [DOI] [PubMed] [Google Scholar]
- 20.Zengerling F, Kunath F, Jensen K, Ruf C, Schmidt S, Spek A. Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance—A systematic review. Urol Oncol Semin Orig Investig. 2018;36(10):448–458. doi: 10.1016/j.urolonc.2017.06.047 [DOI] [PubMed] [Google Scholar]
- 21.Daugaard G, Gundgaard MG, Mortensen MS, Agerb M, Rørth M. Surveillance for Stage I Nonseminoma Testicular Cancer: Outcomes and Long-Term Follow-Up in a Population-Based Cohort. J Clin Oncol. 2014;32(34):3817–3823. doi: 10.1200/JCO.2013.53.5831 [DOI] [PubMed] [Google Scholar]
- 22.Sturgeon JF, Moore MJ, Kakiashvili DM, et al. Non–Risk-Adapted Surveillance in Clinical Stage I Nonseminomatous Germ Cell Tumors: The Princess Margaret Hospital’s Experience. Eur Urol. 2011;59(4):556–562. doi: 10.1016/j.eururo.2010.12.010 [DOI] [PubMed] [Google Scholar]
- 23.Tandstad T, Dahl O, Cohn-Cedermark G, et al. Risk-Adapted Treatment in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: The SWENOTECA Management Program. J Clin Oncol. 2009;27(13):2122–2128. doi: 10.1200/JCO.2008.18.8953 [DOI] [PubMed] [Google Scholar]
- 24.Avril MF, Charpentier P, Margulis A, Guillaume JC. Regression of primary melanoma with metastases. Cancer. 1992;69(6):1377–1381. doi: [DOI] [PubMed] [Google Scholar]
- 25.Gromet MA, Epstein WL, Blois MS. The regressing thin malignant melanoma. A distinctive lesion with metastatic potential. Cancer. 1978;42(5):2282–2292. doi: [DOI] [PubMed] [Google Scholar]
- 26.Ribero S, Moscarella E, Ferrara G, Piana S, Argenziano G, Longo C. Regression in cutaneous melanoma: a comprehensive review from diagnosis to prognosis. J Eur Acad Dermatol Venereol. 2016;30(12):2030–2037. doi: 10.1111/jdv.13815 [DOI] [PubMed] [Google Scholar]
- 27.Takeda Y, Togashi H, Shinzawa H, et al. Spontaneous regression of hepatocellular carcinoma and review of literature. J Gastroenterol Hepatol. 2000;15(9):1079–1086. doi: 10.1046/j.1440-1746.2000.02202.x [DOI] [PubMed] [Google Scholar]
- 28.Erdag G, Schaefer JT, Smolkin ME, et al. Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma. Cancer Res. 2012;72(5):1070–1080. doi: 10.1158/0008-5472.CAN-11-3218 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ma MW, Medicherla RC, Qian M, et al. Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. Mod Pathol. 2012;25(7):1000–1010. doi: 10.1038/modpathol.2012.43 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Chovanec M, Mardiak J, Mego M. Immune mechanisms and possible immune therapy in testicular germ cell tumours. Andrology. 2019;7(4):479–486. doi: 10.1111/andr.12656 [DOI] [PubMed] [Google Scholar]
- 31.Naseem S, Azzopardi A, Shrotri N, Mufti GR. The Shrinking Seminoma – Fact or Fiction? Urol Int. 2000;65(4):208–210. doi: 10.1159/000064878 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1. Determination of disease histology for patients without viable germ cell tumor at radical orchiectomy.