Spermatocytic tumor coexisting with a contralateral inguinoscrotal undifferentiated sarcoma: a case report

Abstract

Background

Spermatocytic tumors represent uncommon neoplasms of the testes and are mostly indolent with favorable prognosis in the non-metastatic stage. Rarely, they can undergo sarcomatous transformation, significantly worsening prognosis. This case highlights a patient harboring a testicular spermatocytic tumor and a concomitant sarcoma of the contralateral inguinoscrotal soft tissue, not related to the spermatocytic tumor.

Case presentation

A 77-year-old male patient presented with a left scrotal mass and a suspected right inguinoscrotal hernia. Laboratory values showed a slightly elevated alpha-1-fetoprotein, while beta-human chorionic gonadotropin and lactate dehydrogenase were within normal limits. Ultrasound imaging revealed a diffusely enlarged, inhomogeneous left testis, highly suspicious for testicular malignancy. Staging revealed no lymphatic or distant metastases. The patient underwent left radical orchiectomy. Histological analysis revealed a spermatocytic tumor of the left testis. Intraoperatively, a gelatinous mass in the contralateral right inguinoscrotal area was discovered and biopsied. The mass on the right was identified as a sarcomatous tumor. Subsequent management entailed radiotherapy, followed by radical resection and scrotectomy with preperitoneal mesh reinforcement. Pathologic workup including molecular genetic testing showed different immunohistochemical and molecular profiles in both tumors. This led to the final diagnosis of a coexisting undifferentiated sarcoma.

Discussion and conclusions

Despite being uncommon and generally less aggressive compared to other testicular malignancies, spermatocytic tumors necessitate vigilance for potential sarcomatous transformation. In this case, a sarcomatous transformation of a spermatocytic tumor was excluded and diagnostics instead revealed an even rarer case of a coexisting undifferentiated sarcoma of the contralateral inguinoscrotal soft tissue. To our knowledge, this is the first reported case of a spermatocytic tumor with a coexisting, unrelated sarcoma. The rarity of these entities underlines the importance of multidisciplinary team meetings for accurate diagnosis and optimal treatment-related decisions.

Introduction

Spermatocytic tumors (ST) are rare germ cell tumors confined to the testis. They were previously categorized as ‘spermatocytic seminoma’ due to their morphological similarities to classic seminomas. However, in the World Health Organization (WHO) classification of 2016 terminology has been changed to ‘spermatocytic tumor’ in order to reflect more accurately their distinctive clinical behavior, morphology, immunohistochemical profile and molecular background [1,2,3]. Unlike seminomas, ST are not associated with germ cell neoplasia in situ (GCNIS), usually lack molecular 12p alterations and typically exhibit a unique chromosome 9 amplification related to the DMRT1 gene [4]. While seminomas originate from primordial germ cells expressing stem cell-specific genes, ST originate from a more advanced stage of germ cell development. They arise from primary spermatocytes undergoing prophase meiosis [5]. Most ST show an indolent behavior.

Precise diagnosis of a ST using frozen sections is challenging for the pathologist. Therefore, testis-sparing surgical techniques are limited [4]. Furthermore, radical orchiectomy is the treatment of choice and is usually sufficient as ST rarely metastasize [4, 6, 7].

A rare but important exception are ST with sarcomatous transformation, which require more extensive therapy and follow-up, as they are associated with an aggressive clinical course and a high mortality rate [8, 9].

Case report

Patient information

A 77-year-old male patient presented with a painless right inguinal swelling over two weeks, initially suspected to indicate inguinoscrotal hernia, and a painless solid mass in his left scrotum, discovered by the physician during clinical examination. There was no positive family history of tumor disease. The patient's medical history revealed prostatic bladder dysfunction, treated by transurethral prostate resection a few months prior, as well as an unremarkable prostate cancer screening.

Clinical findings

Physical examination revealed firm nodular structures on an enlarged, non-tender left testis. No inguinoscrotal hernia was palpable on the left side. A mobile, partially reducible inguinoscrotal mass with a smooth surface was palpated on the right side, showing no erythema and no tenderness. No suspicious lymph nodes were detected during examination. B-symptoms were absent.

Diagnostic assessment

Laboratory values

Testicular cancer markers indicated slightly elevated alpha-1-fetoprotein (AFP) 10 IU/mL (reference < 8 IU/mL), beta-human chorionic gonadotropin (bHCG) 1 mU/mL (reference < 5 mU/mL) and lactate dehydrogenase (LDH) 158 U/L (reference < 220 U/L) within normal levels.

Imaging

Ultrasound revealed a diffusely enlarged left testis with heterogeneous parenchyma, highly suspicious for testicular cancer (Fig. 1a). On the right side, a hypoechoic mass measuring up to 14 cm was delineated, potentially indicative of an inguinoscrotal hernia. The right testis appeared homogeneous with regular perfusion. Contrast-enhanced computed tomography (CT) of the thorax and abdomen was performed for staging purposes. The CT revealed no evidence of local or distant metastases. The right-sided groin mass was not suspected to be malignant and the diagnosis of an inguinoscrotal hernia remained the most likely. Therefore, no further diagnostic investigation was initiated.

Fig. 1

Comparison of ultrasound and gross pathology. a Ultrasound of the left testis. An inhomogeneous, hypoechoic, solid mass measuring up to 5 cm in greatest diameter in the left testis raises suspicion of malignancy. b Cut section of the left testis. The testicular parenchyma is almost completely replaced by a solid, partially nodular, tan-white tumor of 5 × 3.1 × 3.1 cm and soft consistency

Initial therapeutic intervention

As clinical findings were indicative of malignancy in the left testis, a left radical orchiectomy as well as an open biopsy of the right testis was performed. Intraoperatively, the content of the suspected right inguinoscrotal hernia showed a suspicious gelatinous morphology and was biopsied. There were no other abnormalities and no complications during surgery. All tissue samples were submitted to pathology.

Macroscopic findings

The left radical orchiectomy specimen showed an enlarged testis with a smooth and intact surface. The section surface showed a solid, partially nodular testicular tumor (Fig. 1b). In the periphery of the tumor, focal hemorrhage was found. The tunica albuginea was not breached. Specimen margins and extensive samples of the tumor were submitted for histology. The biopsies of the right inguinoscrotal mass were made up by several fragments of homogeneous, tan-colored tissue of soft, gelatinous consistency, measuring 3.5 × 3.5 × 2 cm.

Microscopy

Left orchiectomy and biopsy of the right testis

The left testis tumor showed a partially diffuse, partially nodular growth of discohesive and polymorphous tumor cells. The vast majority of tumor cells were of intermediate size with round nuclei, infrequently showing filamentous (so-called "spireme-like") chromatin (Fig. 2a) with occasional large, mono- and multinucleated cells and rare small lymphocyte-like cells dispersed in between, typical for spermatocytic tumors. There was no significant population of inflammatory cells. Mitotic figures, including atypical ones, were readily found. No infiltration of lymphatic vessels, blood vessels or nerve sheaths were detected. The rete testis and specimen margins showed no tumor.

Fig. 2

Microscopic photographs of the spermatocytic tumor in the left testis (Hematoxylin and eosin (HE) morphology and immunohistochemical profile). a Sheets of intermediate-sized tumor cells with occasional filamentous chromatin (HE, × 400). b Immunohistochemical nuclear positivity for SALL4 (SALL4, × 400). c Immunohistochemical membranous positivity for CD117 (CD117, × 400). d Negative immunohistochemical staining for OCT3/4 (OCT3/4, × 400)

The tumor demonstrated the typical immunohistochemical profile for spermatocytic tumors with diffuse positivity for SALL4, weak positivity for CD117 and Podoplanin (D2-40) as well as negative staining for OCT3/4 (Fig. 2b-d). GCNIS was detected neither in the adjacent, atrophic testicular parenchyma, nor in the biopsy of the contralateral right testis.

Right inguinoscrotal soft tissue

Histologically, the right inguinoscrotal tissue consisted of an inhomogeneous cellular proliferation of small to medium-sized cells, mostly showing a spindle cell morphology with focal epithelioid morphology. They showed little to medium cytoplasm and bland nuclei with infrequent nucleoli. The cells were surrounded by myxoid stroma with occasional small to medium-sized blood vessels, plasma cells and histiocytes dispersed in between. The overall appearance was relatively monotonous with moderate atypia (Fig. 3a-d). There were no mitoses and only very little necroses.

Fig. 3

Microscopic photographs of the right inguinoscrotal soft tissue tumor. a, b Alternating hypercellular and hypocellular areas embedded in a myxoid matrix with occasional prominent small to medium-sized blood vessels are shown (HE, × 50 and × 100). c, d High magnification reveals relatively monotonous, small to medium-sized epithelioid (c) and spindle (d) tumor cells with occasional nucleoli. (HE, × 400)

Immunohistochemically, the cells were focally positive for smooth muscle actin (SMA) and epithelial membrane antigen (EMA). The stains for SALL4, cytokeratins (AE1/AE3), Desmin, CD34, Mucin-4 (MUC4) and S100 protein yielded negative results. MDM2 showed nuclear negativity. The proliferation rate (ki-67) was approximately 10%.

Molecular findings

As the tumor in the left testis had the typical morphology and immunohistochemical profile, the diagnosis of a spermatocytic tumor was easily made. The spindle cell tumor in the right inguinoscrotal soft tissue however presented a greater diagnostic challenge.

Comparison of left spermatocytic tumor and right inguinoscrotal spindle cell tumor

Knowing that a small percentage of spermatocytic tumors show sarcomatous transformation [10], further comparative molecular genetic examinations were carried out on both tumors.

First, an Array Comparative Genomic Hybridization/Single Nucleotide Polymorphism Array (aCGH/SNP) was performed, showing various and divergent chromosomal losses and gains in both tumors. Second, Next-Generation Sequencing (NGS) (Oncomine Precision Assay (OPA) on Genexus™ Integrated Sequencer) was performed. The spermatocytic tumor showed a HRAS mutation p.G61R (90%) on Exon 3, whereas in the sarcoma a HRAS wildtype was detected. The results including the divergent immunohistochemical profiles are summarized in Table 1.

Table 1 Overview of the detected genetic alterations in the spermatocytic tumor and the spindle cell tumor using aCGH/SNP, NGS (Oncomine Precision Assay) and immunohistochemical profile

Further molecular testing of the right inguinoscrotal spindle cell tumor

Several differential diagnoses including a metastasis of the ST with sarcomatous transformation were considered. To narrow them down, further molecular genetic analyses were carried out. No gene fusions were detected in a customized Archer FusionPlex Sarcoma panel (Table 2). An additional Fluorescence in situ hybridization (FISH) showed no detection of an amplification in the MDM2 gene. Table 3 presents an overview of the differential diagnoses and the reasons for exclusion.

Table 2 The right inguinoscrotal soft tissue tumor was examined using a New-Generation Sequencing (NGS) procedure. The displayed panel consisting of 75 genes commonly associated with soft tissue tumors was used (Archer FusionPlex USZ Sarcoma Panel v2)

Table 3 Overview of some of the considered differential diagnoses for the right inguinoscrotal spindle cell tumor and the reasoning for exclusion

After the immunohistochemical and molecular genetic testing methods were unable to detect any specific line of differentiation or molecular alteration, the diagnosis of an undifferentiated sarcoma was established. The sarcoma was graded as grade 2 using the grading method of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) (Score 5 = 3/1/1).

Further therapeutic intervention and pathologic workup

After the left radical orchiectomy, biopsy of the right inguinoscrotal mass confirmed a concomitant undifferentiated sarcoma. On subsequent magnetic resonance imaging (MRI), the sarcomatous lesion measured 14.3 × 6.5 × 6.2 cm (Fig. 4a-b). An interdisciplinary tumor board for sarcomas recommended neoadjuvant radiotherapy followed by surgery, in alignment with current treatment guidelines for soft tissue sarcomas [11, 12]. Accordingly, the sarcoma was treated by neoadjuvant radiotherapy with 25 × 2 Gy = 50 Gy, followed by a radical resection including scrotectomy and preperitoneal mesh reinforcement.

Fig. 4

Magnetic resonance imaging (MRI) before radiotherapy. a Axial T2-weighted imaging revealed a homogeneously hyperintense, well-circumscribed lesion located in the inguinal canal at the level of the scrotum. The lesion measured 14.3 × 6.5 × 6.2 cm. b Sagittal contrast-enhanced T1-weighted imaging with fat saturation demonstrated diffuse, heterogeneous contrast enhancement of the lesion

The cut surface of the inguinoscrotal specimen showed an atrophic testis with a solid tumor in the adjacent soft tissue (Fig. 5). Histology showed a similar morphology to the tissue submitted before radiotherapy. Approximately 50% of the examined tumor tissue was vital, while the remaining 50% consisted of necrosis or fibrosis. The tumor also showed a slight decrease in cellularity compared to the biopsy taken before radiotherapy, compatible with post-radiotherapy regressive changes. There was no infiltration of the adjacent, atrophic testicle. No GCNIS or additional ST was found.

Fig. 5

Cut sections of the right inguinoscrotal specimen after radiotherapy. Adjacent to the atrophic right testis (white asterisks), a solid, homogeneously white tumor (black asterisks) is shown in the soft tissue, measuring 7.5 × 7.5 × 1.5 cm. The tumor was of soft to focally firm consistency. There is no adhesion between testis and soft tissue tumor

Follow-up

After surgery, no further therapy was administered. Follow-up testing for testicular cancer markers was not required. During the one-year follow-up period, no local recurrences, lymph node metastases, or distant metastases were observed. The patient experienced complications, including a preperitoneal seroma and chronic symphyseal infection with an osteocutaneous fistula which required ongoing treatment and multiple interventions, such as drainage, wound debridement, vacuum-assisted closure application and antibiotic therapy.

Final diagnosis

Spermatocytic tumor in the left testis, 5 cm. TNM Classification of Malignant Tumors, 8th edition (2016): pT1 L0 V0 Pn0 cN0 cM0.

Undifferentiated sarcoma of the right inguinoscrotal soft tissue, 7,5 cm. TNM Classification of Malignant Tumors, 8th edition (2016): ypT2 L0 V0 Pn0 R0, FNCLCC Grade 2, Score 5 (3/1/1).

Discussion

To our knowledge, we report the first case of a spermatocytic tumor (ST) and a coexisting, unrelated sarcoma of the contralateral inguinoscrotal soft tissue with divergent morphological, immunohistochemical and molecular genetic profiles.

ST are rare, accounting for approximately 0.61—1% of testicular germ cell tumors (GCT), and occur exclusively in the testes [13,14,15]. ST are reported typically, but not exclusively, in older men [6, 13, 16, 17] with the youngest documented patient being 19 years old [13, 17].

Due to the rarity of ST and the morphological similarities to seminoma, the diagnosis of ST can still be challenging, especially when encountered in an unusually young patient [6, 13]. In contrast to seminomas, ST show an increased but still overall low propensity for bilaterality and no association with cryptorchidism or germ cell neoplasia in situ (GCNIS) [13,14,15, 17]. ST are now recognized as a distinct entity since the World Health Organization (WHO) Classification of Tumors implemented a change of nomenclature from the previous term 'spermatocytic seminoma' to 'spermatocytic tumor' in 2016 [2].

In contrast to seminomas and other GCNIS-related GCT, ST are usually not associated with an isochromosome 12p (i(12p)) [18, 19]. Nevertheless, one recent study reported gains of 12p including i(12p) in few cases of ST with aggressive clinicopathologic features such as sarcomatous transformation [20]. Many ST are reported to have a characteristic amplification of the DMRT1 gene on chromosome 9 [5] and chromosomal gains and losses including +9, +20, −7, −13, −15 and −22 [20]. Furthermore, activating mutations in FGFR3 and HRAS genes have been reported in spermatogonia, which increase with paternal age and are thought to be facilitating tumor formation [5, 21,22,23]. More specifically, the HRAS p.Q61R mutation that was detected in the ST of our patient has been reported in other studies regarding ST [21, 22].

The clinical features and imaging findings of ST are not significantly different from those of classic seminomas. Laboratory results for serum lactate dehydrogenase (LDH), beta-human chorionic gonadotropin (bHCG) and alpha-1-fetoprotein (AFP) levels are usually not elevated [2, 9]. Ultrasound is useful for early detection of all testicular tumors and a preferred imaging modality for ST. Computed tomography (CT) provides more information about the involvement of surrounding structures and lymph node metastases.

In contrast to other GCT, most ST exhibit an indolent behavior characterized by slow growth and low potential for invasion and metastasis, resulting in a favorable prognosis [13, 15, 17]. The definite diagnosis can only be made by radical orchiectomy, which is also the curative therapy for non-metastatic ST. However, tumors that are larger than 4 cm in diameter, involve the epididymis or spermatic cord or have sarcomatous features may have an increased risk of malignant behavior and recurrence [9]. In such cases, long-term follow-up is required.

Sarcomatous transformation of ST is a rare event with less than 50 cases described in literature [8, 10, 13, 14, 16, 17, 20, 24,25,26,27,28,29,30,31,32,33,34]. In one review, sarcomatous transformation was reported to occur in approximately 6% of cases [10]. The sarcomatous component was usually reported to be an undifferentiated spindle cell sarcoma but rhabdomyomatous or chondromatous differentiation have also been described [6, 10, 13, 14, 20, 24, 25, 27,28,29, 31, 33, 35]. In some cases, the metastases were purely sarcomatous without any foci of ST present [14]. The clinical features of all ST, regardless of the presence of a sarcomatous component, are similar, but an initially slowly enlarging testicular mass followed by a sudden increase in volume seems to suggest a sarcomatous transformation [6, 25, 27, 29, 33]. The correct diagnosis of a ST with sarcomatous transformation is of utmost importance as they are associated with a significantly more aggressive clinical course due to their increased risk of metastasis and a high mortality rate [4, 14, 25, 29, 33].

Undifferentiated soft tissue sarcoma (USTS) is an umbrella term for a heterogeneous group of sarcomas characterized by the absence of a detectable line of differentiation or specific molecular alterations. USTS is a diagnosis of exclusion and can occur at any age and in any location. These tumors typically harbor complex genetic aberrations that are not useful for diagnostic purposes. The main role of molecular genetics is to exclude specific molecular alterations associated with certain tumor entities. USTS have the potential to metastasize and are usually treated with neoadjuvant radiotherapy followed by complete surgical resection [36]. Current ASTRO (American Society for Radiation Oncology) and ESMO (European Society for Medical Oncology) guidelines support neoadjuvant radiotherapy prior to surgery for retroperitoneal and trunk sarcomas, as it improves local control of soft tissue sarcomas, particularly in large and high-grade tumors where achieving negative surgical margins (R0 resection) is challenging.

In our case, several factors supported the decision to perform neoadjuvant radiotherapy prior to surgery. First, in large sarcomas (> 5 cm) as well as high-grade tumors, neoadjuvant radiotherapy leads to shrinkage of the tumor, facilitating complete resection with clear surgical margins, reducing the risk of positive microscopic margins (R1 resection), and thereby lowering the risk for local recurrence. Second, tumor shrinkage allows for a more conservative surgical approach, protecting inguinal structures such as femoral vessels, nerves, and lymphatics during resection. Therefore, the interdisciplinary tumor board for sarcomas appropriately recommended neoadjuvant radiotherapy prior to surgery, aligning with current treatment guidelines [11, 12, 37].

In our case, pathologic workup revealed a spermatocytic tumor in the left testis and a sarcoma in the right inguinoscrotal soft tissue. Several variables were taken into account to determine the relationship between the two tumors. Radiologically and clinically, there was no detectable contact between the two neoplasms. The theory that both tumors were two continuous parts of the same tumor was subsequently dismissed. The possibility of a second, contralateral ST with sarcomatous transformation and infiltration of the inguinoscrotal soft tissue was also dismissed when the contralateral testis showed no ST or possible regressive changes after radiotherapy. Instead, the question was raised whether the right inguinoscrotal sarcoma could represent a transformed metastasis of the left ST. It has been reported in literature that metastases of ST can have an exclusively sarcomatous morphology [19]. The comprehensive evaluation of our case revealed that the molecular profiles of both tumors were entirely distinct, uncovering a previously unreported combination of a spermatocytic tumor alongside a concomitant undifferentiated sarcoma.

Conclusion

Spermatocytic tumors are usually indolent and have a good prognosis in the non-metastatic stages. However, in the rare occurrence of a sarcomatous transformation prognosis worsens significantly. Our case is even rarer due to a coexisting sarcoma in the inguinoscrotal soft tissue. The spermatocytic tumor was confined to the testis without sarcomatous transformation and without contact to the contralateral inguinoscrotal mass. The immunohistochemical and molecular profiles underline the coexistence of two different entities, a spermatocytic tumor and an undifferentiated sarcoma. This rare constellation highlights the importance of a multidisciplinary approach for accurate diagnosis and optimal treatment-related decision-making.