Rapidly Progressive Metastatic Sertoli Cell Tumor Associated With an Adenomatous Polyposis Coli Mutation: A Case Report and Literature Review

ABSTRACT

Introduction

Sertoli cell tumors are rare testicular sex cord‐stromal tumors, and clinically malignant behavior is uncommon. We report a rapidly progressive metastatic Sertoli cell tumor associated with an APC mutation.

Case Presentation

A 27‐year‐old man with familial adenomatous polyposis (FAP) presented with painless right scrotal enlargement. Computed tomography revealed a right testicular tumor and multiple pulmonary nodules suspicious for metastases. Right high inguinal orchiectomy was performed. Histopathological and immunohistochemical findings, including nuclear β‐catenin staining, supported Sertoli cell tumor. Despite bleomycin, etoposide, and cisplatin chemotherapy initially achieving stable disease, metastases progressed after three cycles. Comprehensive genomic profiling identified a pathogenic APC variant likely germline due to his FAP; however, no actionable therapeutic target was identified. Widespread systemic metastases developed. The patient died 11 months post‐orchiectomy.

Conclusion

This case highlights the aggressive potential of APC‐associated Sertoli cell tumors, characterized by metastatic presentation, limited response to chemotherapy, and a rapidly fatal course.

Keynote Message

Sertoli cell tumors are rare testicular tumors that usually follow a benign course, but a small proportion behave aggressively. We describe a young man with FAP whose Sertoli cell tumor had already spread to the lungs at diagnosis and did not respond durably to chemotherapy. Genomic testing identified an APC pathogenic variant consistent with his underlying FAP, but no targetable treatment option was found. This case suggests that APC‐driven activation of the Wnt/β‐catenin pathway may contribute to aggressive tumor behavior and underscores the need for novel therapies in metastatic Sertoli cell tumors.

Abbreviations

AFP

α‐fetoprotein

APC

adenomatous polyposis coli (gene)

BEP

bleomycin, etoposide, and cisplatin

CGP

comprehensive genomic profiling

CT

computed tomography

FAP

familial adenomatous polyposis

LDH

lactate dehydrogenase

NOS

not otherwise specified

SCT

Sertoli cell tumor

TSCST

testicular sex cord‐stromal tumor

VAF

variant allele frequency

β‐hCG

β‐human chorionic gonadotropin

1. Introduction

Sertoli cell tumors (SCTs) are rare testicular sex cord‐stromal tumors (TSCSTs), comprising approximately 1% of all testicular neoplasms. Most follow a benign clinical course; malignant SCTs are rare and lack established treatment strategies. Germline adenomatous polyposis coli (APC) alterations have recently been implicated in the development of SCT through activation of the Wnt/β‐catenin signaling pathway [1]. We report a case of metastatic SCT with an APC pathogenic variant in a young man with familial adenomatous polyposis (FAP).

2. Case Presentation

A 27‐year‐old man with a maternal family history of FAP presented with a 1‐month history of painless right scrotal enlargement. Serum germ cell tumor markers, including lactate dehydrogenase (LDH), β‐human chorionic gonadotropin (β‐hCG), and α‐fetoprotein (AFP), were within normal ranges. Contrast‐enhanced computed tomography (CT) demonstrated a right testicular tumor measuring 6 cm with multiple bilateral pulmonary nodules (Figure 1).

FIGURE 1.

Multiple pulmonary metastases.

Right high inguinal orchiectomy was performed. Histopathologically, the tumor showed cord‐like, microcystic, and reticular growth patterns. Immunohistochemically, germ cell tumor markers (AFP, c‐kit, SALL4, SOX2, OCT4, and PLAP) were negative, whereas inhibin‐α showed focal positivity, Melan‐A was positive, and β‐catenin showed strong nuclear staining in approximately 95% of the tumor cells, with a diffuse distribution (Figure 2A–D). Marked nuclear atypia, a high mitotic rate (24 mitoses per 10 high‐power fields [HPFs]; 2.4 mm²; 40× objective, field diameter 0.55 mm), corresponding to 10 mitoses/mm², lymphovascular invasion, and tumor necrosis were also identified. The Ki‐67 labeling index was approximately 40%, indicating high proliferative activity (Figure 3). These findings were consistent with a diagnosis of malignant SCT, classified as the not otherwise specified (NOS) subtype. Because no standard therapy has been established for metastatic SCT, bleomycin, etoposide, and cisplatin (BEP) chemotherapy was initiated empirically. Imaging after two cycles demonstrated stable disease in the pulmonary metastases; however, progression was evident on restaging after the third cycle. Comprehensive genomic profiling (CGP) was performed using FoundationOne CDx (Foundation Medicine Inc., Cambridge, MA, USA) on formalin‐fixed, paraffin‐embedded (FFPE) tumor tissue from the right testis, without matched normal blood. No actionable therapeutic target was identified.

FIGURE 2.

Histopathological findings. Hematoxylin and eosin staining (A) demonstrates proliferation of tumor cells with cord‐like and reticular architectures. Immunohistochemical analysis shows focal positivity for inhibin‐α (B), positivity for Melan‐A (C), and strong nuclear staining of β‐catenin (D). Inset demonstrates a higher magnification view of nuclear translocation. Scale bars = 200 μm.

FIGURE 3.

Histopathological features demonstrating malignancy. Hematoxylin and eosin staining (left) reveals lymphovascular invasion with central tumor necrosis. Immunohistochemical staining (right) revealed a highly elevated Ki‐67 labeling index of approximately 40%. Scale bars = 200 μm.

Follow‐up imaging demonstrated widespread disease progression involving the lungs (Figure 4). Following discussion with the patient and his family regarding the administration of second‐line chemotherapy, best supportive care was selected. The patient died of disease 11 months after orchiectomy.

FIGURE 4.

Follow‐up imaging demonstrating widespread progression of metastatic lesions.

3. Discussion

SCTs are rare TSCSTs, accounting for approximately 1% of all testicular tumors [2, 3]. SCTs are pathologically classified into three subtypes: large cell calcifying, intratubular large cell hyalinizing, and NOS [4]. Histological diagnosis is sometimes challenging because these tumors can mimic seminoma. Immunohistochemical markers such as Melan‐A and inhibin‐α are commonly positive in TSCSTs [5, 6]. β‐Catenin showed nuclear staining in approximately 95% of the tumor cells, in a diffuse distribution. Although this finding was formerly considered highly suggestive of SCT‐NOS, nuclear β‐catenin is now also recognized in other TSCSTs as a manifestation of subclonal Wnt/β‐catenin activation, but in a smaller proportion of cells: expression in Leydig cell tumors is focal or multifocal and never exceeds 50%, while approximately 70% of nuclei were positive in a CTNNB1‐mutated adult granulosa cell tumor [7, 8, 9]. The diffuse pattern seen here is therefore most consistent with SCT‐NOS. Malignant SCTs account for approximately 5%–10% of all SCTs [10, 11]. Proposed risk factors for malignancy include tumor size > 5 cm, necrosis, marked nuclear atypia, lymphovascular invasion, and elevated mitotic activity [12]. However, histological findings alone cannot reliably predict clinical behavior, and metastasis remains the most important indicator of malignancy. Cisplatin‐based chemotherapy and radiotherapy have been attempted, although reported efficacy is limited [5]. A meta‐analysis of 435 SCT patients reported an 11% metastatic rate at presentation with a median life expectancy of 20 months and no long‐term remission from systemic therapy alone [5]. In our case, the tumor was classified as the NOS subtype, with clinicopathological features of malignancy. Consistent with the limited efficacy of systemic therapy reported in metastatic SCT, BEP chemotherapy failed to achieve any durable response.

CGP revealed an APC variant NM_000038.4:c.3779_3782del (p.Q1260Lfs*4) with a VAF of 84.9%. Given his FAP, this variant was considered highly likely to be germline in origin, although its germline status could not be definitively confirmed because matched normal blood was not analyzed. Previous reports have suggested that germline APC alterations may predispose to SCT development [13] through constitutive activation of the Wnt/β‐catenin signaling pathway, which may contribute to tumorigenesis and aggressive biological behavior [1]. No second somatic APC alteration or explicit loss of heterozygosity was identified by CGP, leaving direct molecular evidence for a two‐hit mechanism unconfirmed in our case. Given that tumor‐only CGP cannot definitively confirm germline origin, further genomic studies are warranted to clarify the molecular biology and therapeutic targets of APC‐associated SCTs.

4. Conclusion

We report a rare case of metastatic APC‐associated SCT in a young man with FAP. APC‐related Wnt/β‐catenin pathway activation may have contributed to its aggressive biological behavior and limited response to chemotherapy, although further studies are required to establish this association.

Funding

The authors have no funding to report.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images, with guarantees of confidentiality.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.