Case of the month from the Department of Medical Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Australia: recurrent metastatic spermatocytic tumour successfully treated with salvage systemic chemotherapy

Abstract

Spermatocytic tumours are a rare subtype of testicular neoplasm and represent less than 1% of all testicular neoplasms. They generally display indolent biology and therefore commonly present as large testicular masses. Despite this, and in contrast to invasive germ cell tumours, spermatocytic tumours are rarely pT2 (i.e., rarely involve the tunica vaginalis or display lymphovascular invasion) and are almost exclusively confined to the testicle [1], such that orchidectomy is usually curative. It is estimated that <10% of cases metastasise, unless sarcomatoid differentiation is present [2]. However, metastatic spermatocytic tumours, when they occur, portend a poor prognosis, and there is a relative paucity of evidence informing management in the metastatic setting.

Metastectomy rarely yields long-term survival, and complete responses to chemotherapy and radiotherapy are rare [2]. There is no standard first-line approach, however, extrapolating from treatment paradigms from seminoma and non-seminoma, bleomycin, etoposide and cisplatin (BEP) represents a commonly used regimen, with variable responses demonstrated [2]. Second-line chemotherapeutic strategies are even less well studied. We describe a case of relapsed, metastatic spermatocytic tumour that had a favourable response to second-line chemotherapy after prior first-line BEP chemotherapy.

A 45-year-old presented to an external centre with a large left testicular mass in 2021 and underwent radical left orchidectomy revealing a 1.25-kg, pT2, extensively necrotic, germ cell tumour with associated lymphovascular invasion. Serum tumour biomarkers were normal. Immunohistochemistry showed reactivity of tumour cells for CD117, whilst they were negative for PLAP cytokeratin AE1/AE3, CD30, beta-HCG (bHCG), glypican 3 and alpha fetoprotein (AFP). The tumour was considered a mixed germ cell tumour with probable seminoma and embryonal carcinoma elements, acknowledging that only 2% viable tumour was identified in the large mass, making a definitive diagnosis challenging. Systemic staging was clear and the patient entered active surveillance.

Four months later, the patient developed metastasis to the ipsilateral para-aortic lymph nodes (largest 23 × 30 × 31 mm) but elected not to undergo chemotherapy. Surveillance imaging after 3 months confirmed progression of the ipsilateral para-aortic lymph nodes (increased to 59 × 59 × 57 mm) but no new sites of disease, and he went on to receive three cycles of BEP chemotherapy for International Germ Cell Cancer Collaborative Group good-risk recurrent germ cell tumour. CT after chemotherapy demonstrated a good partial response (mass now 18 × 34 × 39 mm), and no apparent [¹⁸F]fluorodeoxyglucose (FDG) activity was seen on positron emission tomography (PET)/CT imaging. Unfortunately, the patient was lost to follow-up shortly thereafter. He subsequently developed symptomatic disease progression 18 months later and was referred to our service for management.

At the time of progression, the patient had a large retroperitoneal mass (120 × 140 × 160 mm) resulting in left nephroureteric obstruction. Serum tumour biomarker evaluation revealed elevated lactate dehydrogenase of 663 (upper limit of normal [ULN] 250 U/L), bHCG of 2.9 (ULN 2.6 IU/L); AFP was undetectable (<2.2 μg/L). An FDG-PET/CT demonstrated a heterogeneous abdominal mass, with a maximum standardised uptake value (SUV_max) of 6.9, and volume of 1494 mL (Fig. 1A). No other sites of metastatic disease were identified. Retroperitoneal biopsy confirmed a malignant germ cell tumour, with weak staining for CD117 (c-kit) and SALL4, and negative staining for OCT3/4, CD30, PLAP, AFP and bHCG, consistent with metastatic spermatocytic tumour (Fig. 2). No sarcomatoid features were observed. The archival orchidectomy specimen was reviewed and considered morphologically identical to the metastatic biopsy. Targeted next-generation sequencing (Oncomine Precision Assay) of the metastasis identified a TP53 R273H variant, however, no alteration in FGFR3, HRAS or NRAS was detected. Fluorescence in situ hybridisation (FISH) showed no evidence of isochromosome 12p but additional copies of KRAS (12p12.1) and D12Z3 (chromosome 12 centromere) were seen.

The patient underwent ureteric stenting, followed by four cycles of salvage paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy. An interval FDG-PET/CT after two cycles demonstrated metabolic response to therapy with reduction in SUV_max from 6.9 to 2.3, and formal restaging CT and FDG-PET/CT at completion of therapy demonstrated reduction in size of the retroperitoneal lesion to 49 × 27 mm, and no residual FDG avidity (Fig. 1B). A further FDG-PET/CT performed 6 months after completion of chemotherapy revealed a new 13 × 11 mm left retroperitoneal nodal focus of FDG avidity (SUV_max 9.6 [Fig. 1C; green arrow]) with no other evidence of disease, and the patient's serum tumour biomarkers remained normal. The patient's case was discussed in a urology multidisciplinary meeting, where close surveillance was recommended, and on most recent surveillance at 8 months post-chemotherapy his disease remains stable. It is anticipated he may require resection of the residual mass in the future. In the interim, the patient has returned to work and is symptom-free with serum tumour biomarkers remaining within the normal range.

Spermatocytic tumours represent approximately 1% of all testicular tumours and most commonly occur in individuals in their 5th and 6th decades [1]. Whilst metastasis from sarcomatoid variants of spermatocytic tumours are well described, metastasis from conventional spermatocytic tumours is extremely rare. However, there remains a spectrum of clinical behaviour. The case we describe represents an unusual presentation of a metastatic spermatocytic tumour, demonstrating aggressive biology in the absence of sarcomatoid features, yet an excellent response to second-line, platinum-based chemotherapy.

Spermatocytic tumours evolve from mature germ cell progenitors and display a distinct genomic landscape compared to seminoma and non-seminoma, which derive from primordial germ cells and arise through germ cell neoplasia in situ [3]. Isochromosome 12p (i12p), crucial in the development of invasive tumour in seminoma and non-seminoma, is rarely described in early-stage spermatocytic tumours except in aggressive subtypes such as anaplastic or sarcomatoid change [3]. In contrast to its absence in early-stage disease, i12p has been reported in two cases of metastatic spermatocytic tumours without sarcomatoid change [4], suggesting it may play a role in the metastatic potential of spermatocytic tumours. Notably, i12p was negative in the case we describe, however, the observed amplification of KRAS (on 12p) may contribute to metastatic potential in a similar mechanism. Vascular invasion was also noted in four of the five metastatic cases in a small series [4], also present in the orchidectomy specimen our case, and may contribute to metastatic potential.

Aside from i12p, early GTPase and protein kinase alterations may be key to the development of many spermatocytic tumours, offering them a survival advantage whilst rendering an environment for additional oncogenic variants to develop. Alterations in NRAS, HRAS and BRAF are common, although generally seen in indolent cases [3]. Aneuploidy is also frequently observed [3]. In contrast, TP53 mutations are less common and associated with sarcomatoid transformation and an aggressive clinical phenotype in published studies [3]. Notably, although no sarcomatoid changes were observed in our case, the early recurrence and need for second-line treatment may be explained by the TP53 mutation. In retrospect, the absence of OCT3/4 and PLAP and positivity for CK117 should have raised the possibility of an alternate initial diagnosis in our case, however, significant necrosis of >90% in the orchidectomy specimen made this challenging.

The relevance of the molecular landscape with regard to treatment has not been elucidated by the existing literature, and there is no established consensus on optimal first-line or subsequent therapy. In a contemporary systematic review of this issue, BEP was the most common initial treatment strategy, with alternative chemotherapeutic, radiotherapy or surgical strategies also trialled [2]. In the second line, no consistent approach was identified and the use of TIP has, to our knowledge, only been described once in the literature, and in an individual with extensive rhabdomyosarcomatous differentiation who also experienced a favourable response [5]. In general, multimodal approaches with chemotherapy, surgery and/or radiotherapy are favoured for individuals with sarcomatoid differentiation owing to their aggressive biology, however, prospective data supporting this approach are similarly lacking.

Given the rarity of metastatic spread of spermatocytic tumours without sarcomatous differentiation, the described case reinforces the importance of post-orchiectomy surveillance in all cases, particularly in those with lymphovascular invasion, sarcomatoid change or 12p amplification on FISH. The aggressive biology, yet favourable treatment response in the case we describe is not adequately explained by available molecular factors, and highlights the need for collaboration and further interrogation of the molecular landscape of rare tumours.

There is sparse evidence to support treatment selection for metastatic spermatocytic tumour. Owing to the rarity of this neoplasm, there continues to be a strong reliance on case reports and series, with inherent issues around publication bias; however, in the absence of prospective studies, these data remain important to drive care. We report a case of a recurrent metastatic spermatocytic tumour successfully treated with salvage TIP chemotherapy. Further characterisation of molecular features of this rare neoplasm may be important to transform care.

None declared.