Abstract
Background
Sertoli cell tumors (SCTs) of the testes are rare, and the literature provides only weak evidence concerning their clinical course and management. The objective of this study was to summarize evidence on SCTs’ clinical presentation, clinicopathological risk factors for malignancy, treatment options, and oncological outcomes.
Materials and Methods
Data sources included Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and Web of Science. Published case reports, case series, and cohorts were included. Data on clinicopathological variables, treatment of local or metastatic disease, site of metastasis, or survival were extracted from each study considered in this paper, and associations between clinicopathological variables and metastatic disease were analyzed. Whenever feasible, data on individual patients were collected.
Results
Of the 435 patients included, only one (<1%) showed local recurrence after testis‐sparing surgery (TSS). Three patients underwent adjuvant retroperitoneal lymphadenectomy. Fifty patients presented with metastases, located in the retroperitoneal lymph nodes (76%), lungs (36%), and bones (16%); median time to recurrence was 12 months. Risk factors for metastatic disease included age, tumor size, necrosis, tumor extension to the spermatic cord, angiolymphatic invasion, and mitotic index. Patients with metastases had a median life expectancy of 20 months. In six patients, metastasectomy resulted in complete remission.
Conclusion
Our findings suggest that few local recurrences result after TSS, and no adjuvant therapy can be regarded as a standard of care. Several risk factors are predictive of metastatic disease. Surgery leads to remission in metastatic disease, whereas systemic treatment alone does not result in long‐term remission.
Implications for Practice
Testicular Sertoli cell tumors usually present without metastatic disease and show low local recurrence rates after testis‐sparing surgery; no adjuvant therapy option can be regarded as a standard of care. Patients with risk factors should undergo staging investigations. Those with metastatic disease have poor prognoses, and metastasectomy may be offered in selected cases.
Keywords: Testicular neoplasm, Sex cord‐gonadal stromal tumor, Sertoli cell tumor, Lymph node excision
Short abstract
Considering the rarity of Sertoli cell tumors, there are unanswered questions about optimal treatment for patients with localized or metastatic disease. This review of the literature presents the available information on clinical presentation, treatment options, and patient outcomes, as well as clinicopathological risk factors associated with metastatic disease.
Background
Sex cord‐stromal tumors of the testis represent 4% of all testicular tumors 1, 2, and Sertoli cell tumors (SCTs) in particular account for only 1% of all testicular tumors 3. Most SCTs, such as sclerosing SCTs, are classified as “not otherwise specified” (NOS) 2. Histological variants include intratubular large cell hyalinizing Sertoli cell neoplasia, which can be linked to Peutz‐Jeghers syndrome, and large cell calcifying SCTs, which occur sporadically or in connection with Carney complex.
Given SCTs’ rarity, there are several unanswered questions regarding the optimal treatment of patients with localized or metastatic disease. First, it is unknown if testis‐sparing surgery (TSS) is a safe treatment option or if radical orchiectomy should be preferred. Second, the only known risk factors currently used to discriminate between benign and malignant SCTs are based on a study including only 28 patients 3. Third, there are no clear recommendations on how to assess, follow‐up, or treat patients with SCTs, and in particular, it is unclear how to treat patients with metastatic SCTs.
The present literature review aims to synthesize available information on SCTs, including clinical presentation, clinicopathological risk factors associated with metastatic disease, treatment options for benign and malignant variants, and patient outcomes for metastatic disease.
Materials and Methods
Data Acquisition and Search Strategy
This systematic review was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) statement 4, 5. The review protocol was published on the PROSPERO registry (http://www.crd.york.ac.uk/PROSPERO; registration number CRD42018110112).
The literature search included articles published before May 5, 2018, and retrieved from the most significant electronic databases (MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, and Web of Science). A clinical medical librarian applied a broad approach to identify relevant articles, using several combinations, synonyms, and search terms based on “Sertoli cell tumor,” “sex cord tumor,” “stromal tumor,” and “interstitial cell tumor.” Non‐English studies were excluded unless the corresponding abstracts were available in English or the full texts were available in French, Spanish, Italian, or German. In addition, relevant publications’ reference lists were manually screened to identify further studies. The search strategy is detailed in supplemental online Appendix 1.
Duplicate articles were filtered using EndNote's “close match function” and manual deduplication. Two authors (J.G., K.S.) screened titles and abstracts independently to select publications that fulfilled the eligibility criteria and came to a consensus about the inclusion of those studies. If data from a single study appeared in multiple publications, they were counted only once. Disagreements were discussed and resolved by consensus or by third‐party arbitration (C.D.F.). All case reports, clinical case series, and other reports describing patients with SCTs of the testes were included.
Types of Outcome Measures Included
Studies reporting on clinicopathological variables, treatments of local or metastatic disease, site of metastasis, or disease‐free, cancer‐specific, and overall survival were eligible for review. In order to capture all relevant literature, no interventions, controls, or outcomes were predefined in the search strategy.
Data Extraction
A data extraction sheet was developed based on the Cochrane Consumers and Communication Review Group's template, and it was adapted after a pilot testing phase on 20 randomly selected eligible studies. Data on study design, patient characteristics, clinicopathological risk factors, treatment, and follow‐up were collected. One researcher (K.S.) extracted the data, which were then reviewed by a second researcher (J.G.). Disagreements were discussed and resolved by consensus or third‐party arbitration (C.D.F.). Whenever possible, data on individual patients were extracted.
Statistical Analysis
Univariable logistic regression analyses were performed to identify variables associated with metastatic disease. Receiver operating curve (ROC) analyses of continuous variables were performed to identify optimal cutoff points. Statistical analyses were performed using SPSS Statistics version 25.0 (IBM Corp., Armonk, NY). Results for continuous normally distributed variables were expressed as means ± SD, continuous nonnormally distributed variables were expressed as median and interquartile ranges (IQRs), and categorical variables were expressed as percentages. All p values <.05 were considered statistically significant. All statistical tests were two‐sided.
Results
Studies
After deduplication, 3,542 publications met initial search criteria, and 307 publications were eligible for a full‐text review once titles and abstracts had been checked. After said review, 191 studies involving 435 patients were ultimately included (Fig. 1; supplemental online Table 1).
Figure 1.
Flow chart of the study selection process.Abbreviation: GIT, gastro intestinal tumors.
Demographics, Clinical Symptoms, and Laboratory Findings
The most common histological variant of SCTs was NOS (325/435, 75%), followed by large cell calcifying SCTs (99/435, 23%) and intratubular large cell hyalinizing Sertoli cell neoplasia (10/435, 2%). Median age at diagnosis of patients with SCTs was 29 years (IQR 16–44 years, range 0.8–86 years). Of the 320 patients for whom information on clinical presentation was available, a majority presented with a testicular mass (187/320, 58%) or enlargement (98/320, 31%), gynecomastia (48/320, 15%), or scrotal pain (35/320, 11%). Incidental findings during ultrasound examinations were less frequent (7/320, 2%), as was diagnosis during workup for symptoms like hydrocele (6/320, 2%), abdominal pain (5/320, 2%), infertility (2/320, 0.6%), or varicocele (1/320, 0.3%). Alpha‐1‐fetoprotein, lactate dehydrogenase, and human chorionic gonadotropin hormone were reported to be elevated in 4 of 277 cases (1.4%), 4 of 277 cases (1.4%), and 2 of 277 cases (0.7%), respectively.
Local Treatment and Pathological Findings
Information on local treatment of SCTs was available for 355 patients, most of whom underwent orchiectomy (307/355, 87%). Testis‐sparing surgery was performed in 46 of 355 cases (13%). Orchiectomy was delayed in two 9‐year‐old patients with bilateral SCTs to allow for sperm maturation 6.
During follow‐up, 3 months after undergoing TSS, one patient (1/46, 2%) was found to have a local recurrence, was treated with secondary orchiectomy, and remained disease‐free for 1 year thereafter. Contralateral recurrence was observed in 4 of 355 patients (1%). The median tumor mass size was 20 mm (IQR 12.5–39.0 mm). Pathological findings were reported in 277 cases, and they included calcification (69/277, 25%), high mitotic rate (55/277, 20%), angiolymphatic invasion (44/277, 16%), necrosis (34/277, 12%), atypia (30/277, 11%), and intratubular growth (18/277, 6%). Vimentin was positive in 86 of 277 cases (31%) and inhibin in 45 of 277 cases (16%). S100 was positive in 27 of 277 patients (10%).
Adjuvant Therapies
Three patients with localized SCTs underwent adjuvant retroperitoneal lymph node dissection (RPLND) revealing cancer‐free lymph nodes. These patients showed no evidence of disease during their follow‐ups after 3, 12, and 41 months, respectively 7, 8, 9. Seven patients received additional treatment with an aromatase inhibitor (testolactone or anastrazole) before or after orchiectomy and TSS, to reduce gynecomastia and body growth velocity 10, 11, 12, 13, 14, 15. No other adjuvant chemo‐ or radiotherapy treatments were reported.
Metastatic Disease at Initial Staging and Recurrence
Metastatic disease was reported in 50 of 435 patients, of whom 20 of 50 (40%) were diagnosed at initial staging and 15 of 50 (30%) had metastatic relapse during follow‐up. No information regarding the exact timing of diagnosis was available for 15 patients with metastatic disease. Metastatic sites included the retroperitoneal lymph nodes (RPLNs; 16), lungs (8), bones (4), inguinal lymph nodes (3), liver (1), brain (1), and kidneys (1). Follow‐up data were available in 233 of 435 patients (54%). The median follow‐up time was 24 months (IQR 10.5–48 months). Metastatic relapse was reported after a median of 12 months (IQR 5–38 months) in 15 patients (6%) at the following locations: RPLN (11), lungs (7), liver (2), bones (1), and axillary lymph nodes (1; Fig. 2).
Figure 2.
Anatomical locations of metastases in 50 patients of which the timing of metastatic disease was described in 28 of 50 patients. Whereas 13 of 28 patients had metastatic disease at initial staging, 15 of 28 patients developed metastatic disease during follow‐up.
Risk Factors for Metastatic Disease
For the continuous variables “age” and “tumor diameter,” ROC analyses revealed ideal cutoff points at 27.5 years and 24 mm, respectively. In univariable regression analyses, the following variables were associated with metastatic disease at initial staging or follow‐up (Table 1): age > 27.5 years (odds ratio [OR] 11.5, 95% confidence interval [CI] 4.4–30.6, p < .01), tumor diameter > 24 mm (OR 15.8, 95% CI 4.5–55.7, p < .01), presence of necrosis (OR 102, 95% CI 11.2–982.3, p < .01), extension to the spermatic cord (OR 20, 95% CI 1.5–260.8, p < .02), angiolymphatic invasion (OR 13.8, 95% CI 2.9–66.1, p < .01), and a high mitotic index (OR 37.1, 95% CI 7.8–175.3, p < .01). There was no significant difference between SCTs NOS and other histological variants (large cell calcifying SCTs [OR: 0.6, 95% CI 0.3–1.2, p = .17] and intratubular large cell hyalinizing Sertoli cell neoplasia [no metastases]).
Table 1.
Univariable regression analyses of clinicopathological variables predicting metastatic disease
| Variable | Univariable, OR (95% CI) | p value |
|---|---|---|
| Histological variant | ||
| SCT not otherwise specified | Reference | .17 |
| LCCSCT | 0.6 (0.3–1.2) | |
| Age | ||
| <27.5 years | Reference | |
| ≥27.5 years | 11.5 (4.4–30.6) | <.01 |
| Tumor size | ||
| <23.9 mm | Reference | |
| ≥24.0 mm | 15.8 (4.5–55.7) | <.01 |
| Necrosis | ||
| Absent | Reference | |
| Present | 102 (11.2–982.3) | <.01 |
| Extension to spermatic cord | ||
| Absent | Reference | |
| Present | 20 (1.5–260.8) | .02 |
| Angiolymphatic invasion | ||
| Absent | Reference | |
| Present | 13.8 (2.9–66.1) | <.01 |
| High mitotic index | ||
| Absent | Reference | |
| Present | 37.1 (7.8–175.3) | <.01 |
| Infiltrating margins | ||
| Absent | Reference | |
| Present | 3.3 (0.2–70.9) | .44 |
| Extracapsular growth | ||
| Absent | Reference | |
| Present | 1.3 (0.1–13.6) | .85 |
Abbreviations: CI, confidence interval; OR, odds ratio; LCCSCT, large cell calcifying SCT; SCT, Sertoli cell tumor.
Treatment of Metastatic Disease and Outcome
Because of the lack of therapy guidelines, different treatment modalities have been described in the literature. Data regarding treatment of metastatic disease were available for 28 patients, and response to treatment was reported for 27 of them (supplemental online Table 2). Surgery was performed on 12 patients; five showed complete response—four after RPLND 16, 17, 18, 19 and one after lung resection 20 —although follow‐up was limited. One of these patients received adjuvant radiotherapy 19, and another received adjuvant chemotherapy 21. One patient received neoadjuvant chemotherapy and died of sepsis during treatment; the autopsy, however, revealed complete remission in the specimen 20. All patients treated with chemotherapy and/or radiotherapy without surgery showed progressive disease, and the overall median survival of patients with metastatic disease was 20 months (IQR: 6–30 months).
Discussion
This study contains the most comprehensive summary and meta‐analysis of available literature regarding testicular SCTs and provides insight into post‐TSS recurrence rates. Furthermore, it identifies different risk factors that may help determine whether staging and follow‐up imaging or adjuvant therapies should be considered for certain patients. Additionally, the data compiled on adjuvant therapy, metastatic spread, and treatment of systemic disease may prove useful in guiding treatment decisions for patients with metastatic disease.
The <1% local recurrence rate of SCTs supports the use of TSS in patients, but only after they have been appropriately informed about the risk of recurrence and the need for a subsequent completion orchiectomy should histological risk factors exist.
The <1% local recurrence rate of SCTs supports the use of TSS in patients, but only after they have been appropriately informed about the risk of recurrence and the need for a subsequent completion orchiectomy should histological risk factors exist. If TSS is to be used, regular testicular ultrasound should be considered.
A pathological workup is required to determine the presence of risk factors for metastatic disease and differentiate between benign and malignant SCTs. The current World Health Organization classification lists the following risk factors for malignant disease: tumor size >5 cm, presence of hemorrhage, necrosis, lymphovascular invasion, and pleomorphism 2. In addition, the present systematic review has identified tumor extension to the spermatic cord and a high mitotic index as potential risk factors for metastatic disease and has proposed a different cutoff value for tumor size (24 mm). However, because of the substantial variability in pathology reports regarding which potential risk factors should be considered, no multivariable analyses were performed; only univariable analyses were reported. Risk assessment after local therapy has been conducted might help clinical decision making, and the following scenarios may apply: (a) In patients with no risk factors for metastatic disease, staging and follow‐up with imaging may be discussed, and post‐TSS patients may simply undergo ultrasound surveillance of the testis; (b) in patients with risk factors for metastatic disease, staging and regular follow‐up with cross‐sectional imaging of the chest, abdomen, and pelvis may be considered 22.
Advocates of adjuvant RPLND argue that early surgery may cure some patients with micrometastatic disease limited to the retroperitoneum because the latter is the most common site of recurrence. However, according to the literature, experience with and evidence for adjuvant therapies is limited. Moreover, it remains unclear whether SCTs follow a discreet, stepwise progression involving a specific primary landing site, and there are no data on whether adjuvant RPLND reduces the risk of recurrence or lengthens survival. Patients with metastatic disease have poor prognoses, and standard treatment recommendations do not exist. In oligometastatic cases, the surgical resection of metastases should be discussed with patients, as some have been reportedly cured after surgery. No standard chemo‐ or radiotherapy regimen is known for SCTs (as opposed to testicular germ‐cell tumors), but it may be offered as a palliative treatment option. Given the limited life expectancy of patients with metastastic disease, as well as limited experience with systemic cancer therapies versus germ‐cell cancer therapies, experimental targeted approaches or immunotherapy could be considered. However, exploratory findings show only limited, targetable genomic alterations and low tumor mutational burden, arguing against checkpoint inhibition 23.
Sertoli cell tumors are rare, and the published literature consists only of retrospective studies, so the present meta‐analysis was prone to bias. Moreover, clinicopathological risk factors were often not completely reported. Thus, multivariable analyses were not performed. Search criteria were designed and reviewed by both clinicians and librarians, and they were predefined in a peer‐reviewed protocol. However, it is possible that not all potentially relevant studies were identified because of undetected imprecision in the search strategy, which constituted another potential source of bias. Because of the absence of prospective trials, and in order to evaluate this study's model, the Orphan Testis Histologies (OATH) registry has been recently created by the authors; collaborators are encouraged to contribute data relating to patients with rare testis cancer histologies (http://bit.ly/OATH-registry).
Conclusion
In the absence of prospective studies, the current comprehensive analysis of reported SCT cases is unique. It may help physicians differentiate between benign and malignant SCTs and select the most appropriate treatment for affected patients.
Author Contributions
Conception/design: Thomas Hermanns, Christian Daniel Fankhauser
Provision of study material or patients: Josias Grogg, Kym Schneider
Collection and/or assembly of data: Josias Grogg, Kym Schneider
Data analysis and interpretation: Peter Karl Bode, Anja Lorch, Joerg Beyer, Christian Daniel Fankhauser
Manuscript writing: Josias Grogg, Kym Schneider, Christian Daniel Fankhauser
Final approval of manuscript: Josias Grogg, Kym Schneider, Peter Karl Bode, Benedikt Kranzbühler, Daniel Eberli, Tullio Sulser, Anja Lorch, Joerg Beyer, Thomas Hermanns, Christian Daniel Fankhauser
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1: Supplemental Information
Acknowledgments
C.D.F. was supported by the following foundations: University Hospital of Zurich, medAlumni Zurich, Stiftung für urologische Forschung, Marlis Geiser‐Lemken Stiftung, Fonds zur Förderung des akademischen Nachwuchses (FAN), Ernst Göhner Stiftung, SAKK/Dr. Paul Janssen Fellowship, and Arnold U. und Susanne Huggenberger‐Bischoff Stiftung.
Disclosures of potential conflicts of interest may be found at the end of this article.
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Supplementary Materials
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1: Supplemental Information