Abstract

The novelties in WHO 5^th edition classification of genitourinary tumours are: a) nomenclature changes, including the replacement of the term “primitive neuroectodermal tumour” with “embryonic-type neuroectodermal tumour” and of “carcinoid” with “neuroendocrine tumour”. Also, seminoma is now placed in a “germinoma” family of tumours, while sertoliform cystoadenoma was moved from adnexal tumours to Sertoli cell tumours; b) new entities, specifically signet ring stromal tumour, myoid gonadal stromal tumour and welldifferentiated papillary mesothelial tumour.

Introduction

Testicular neoplasms are rare tumours, accounting for less than 6 cases for 100,000 males for year in Italy ¹. Some rare histotypes will not be encountered even once a decade! The 5^th edition of the World Health Organization (WHO) ² was published in June 2022. This new blue book was built upon the work of the 4^th edition ³, especially concerning germ cell tumours (GCTs). Indeed, GCTs are still subdivided into germ cell neoplasia in situ (GCNIS)-derived and GCNIS-unrelated groups, as introduced in the 4^th edition.

GCNIS-derived germ cell tumours

Among GCNIS-derived GCTs, the most common type is testicular seminoma, that have been reported in a “germinoma” family of tumours in the new classification. The reason is the unification of terminology (i.e.: dysgerminoma, seminoma and germinoma) used for neoplasms with similar morphology, immunochemistry and molecular features throughout the body ⁴. Seminoma with syncytiotrophoblastic cells is recognised as the only subtype of seminoma and it gives the possibility of an accurate follow-up by measuring serum beta-human chorionic gonadotrophin. Among non-seminomatous GCTs, the latest blue book introduced some important and substantial changes for teratoma with somatic transformation (TST). In the WHO 4^th ed. ³, the diagnosis of TST was established with a pure population of atypical mesenchymal or epithelial cells occupying at least one low-power field (i.e. a x4 objective, 5 mm in diameter). As there is a need of standardisation of microscopical low power fields and a growing shift towards digital pathology, in the 5^th ed. ² only the size cutoff (≥ 5 mm) is present among essential diagnostic criteria. Another change is related to teratomas featuring areas of small round blue cells with neural differentiation (Fig. 1), often referred to as ‘transformed teratoma’ among urologists. These were previously defined as “primitive neuroectodermal tumours” (PNETs), one of the most common forms of TST ^5,6. Nevertheless, PNET has now been replaced with “embryonic-type neuroectodermal tumour” (ENET) both in testicular and ovarian tumours ⁷. This change has been introduced to avoid the confusion with a true Ewing sarcoma which has been rarely identified in the testis ⁸. The absence of the Ewing sarcoma translocation of EWS1:FLI1 and the similarity with their CNS counterparts were already highlighted in the previous WHO 4^th edition, but in the 5^th edition the terminology has finally been modified.

GCNIS-unrelated germ cell tumours

Spermatocytic tumour (ST) maintains the same nomenclature considering its indolent nature in the great majority of cases. However, there are few reports of metastatic ST in the literature with associated GCNIS-related tumours that are worthy of further investigations ^9,10. An important change has been made in the classification of neuroendocrine tumours, as the term “carcinoid” has been discarded throughout the current WHO classifications. The new denomination “testicular neuroendocrine tumour, prepubertal-type” (prepubertal NET) underlines the GCNIS-unrelated origin of a neoplasm that arises in the setting of a prepubertal teratoma in about 25% of cases. The assessment of testis NET prognosis is difficult, but mitotic index and Ki-67 may be of importance. GCNIS-derived NET is instead reported in rare cases to arise in post-pubertal type teratoma ¹¹.

Sex cord stromal tumours of the testis

Sex-cord stromal tumours (SCSTs) represent about 5% of all testicular tumours. They are usually purely composed of sex cord elements, but they can also combine variably with cells of the testicular gonadal stroma. Leydig cell tumours (LCTs) are the most common subtype (75% of cases), followed by Sertoli cell tumours (SCTs). A large percentage of the latter molecularly shows a mutation in the CTNNB1 gene, leading to nuclear staining of β-catenin in neoplastic cells. This feature can also be used diagnostically ^12,13.

In the 5^th ed. of the WHO classification, two new entities were added. Firstly, the signet ring stromal tumour ^14-16 (Fig. 2 A-B), although there is a debate about whether it belongs to the morphological spectrum of SCTs as they both show an identical marker profile, including the aforementioned positive nuclear staining reaction of b-catenin. Secondly, the myoid gonadal stromal tumour which is listed as a separate entity because it differs from other sex cord tumours both morphologically and immunohistochemically (Fig. 2 C-D) ¹⁷.

The sertoliform cystadenoma is located in the rete testis and it was previously classified among the testicular adnexal tumours. It is now listed with the SCTs due to strong histological and immunohistochemical overlaps ¹⁸.

The intratubular large cell hyalinising SCT was allocated to “genetic tumour syndromes” in the new WHO classification because it is only described in patients with Peutz-Jeghers syndrome ¹⁹. In contrast, the large cell calcifying SCT continues to be included both among sporadic tumours and genetic tumour syndromes, as it can also occur as part of the Carney complex (Fig. 3) ²⁰.

Mixed and undifferentiated SCSTs are now divided into two separate categories. Mixed SCSTs consist of a variable combination of germ line tumour elements and stromal elements. SCST NOS is instead reserved for SCSTs made up of undifferentiated/immature sex cord stromal cells which cannot be subtyped precisely.

SCSTs are usually indolent tumours with a good prognosis. Nevertheless, metastases can occur, even in morphologically typical tumours. These cases show a progressive course, due to the poor response to chemotherapy. Since only metastases represent a clear (but late) criterion for malignancy ²¹, it is important to collect histopathological parameters to predict malignant biological behaviour. These include size (> 5 cm), presence of necrosis, infiltrative growth, lymphatic or blood vessel invasion, moderate to severe nuclear atypia and an increased mitotic rate (> 5 mitoses/2 mm²) ²². The Leydig cell tumour Scaled Score (LeSS) was introduced for LCTs, but it still needs to be further established ²³. At the same time, it remains unclear how patients with SCSTs should be treated because so far only studies with small cohorts have addressed this topic. Orchiectomy is sufficient for tumours without risk factors ^24,26. If only one risk factor is present, an orchiectomy and regular check-ups should be performed ²⁷. An additional retroperitoneal lymph node dissection is favoured in patients with 2 or more risk factors or UICC stage IIa ²⁸.

Tumours of the testicular adnexa

The rare adnexal tumours of the testis are described in a separate, systematically structured chapter. The category includes tumours of the rete testis, the epididymis, the spermatic cord, the testicular appendices and the mesothelium of the tunica vaginalis ²⁸. Adenomatoid tumour is the most common entity and it habitually shows indolent behaviour. Only about 23% of adnexal tumours are malignant, including malignant mesothelioma and some types of carcinoma ^27,28. Well-differentiated papillary mesothelial tumour is an entity that has been introduced in the latest WHO blue book. It features bland papillary neoplasms without evidence of invasive foci or with minimal stromal invasion ²⁹, retained BAP1 expression and no CDKN2a deletion. So far, there is evidence that it carries a favourable prognosis.

Conclusions

For testicular tumours, only minor changes introduced in the 2022 WHO 5^th edition of genitourinary tumours are worthy of mention. Nomenclature changes and the introduction of new entities (i.e. Signet ring stromal tumour, myoid gonadal stromal tumour, and Well-differentiated papillary mesothelial tumour) are the true novelties and pathologists must be aware of them for a correct reporting.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

FUNDING

None.

ETHICAL CONSIDERATION

The authors declare no ethical conflicts.

AUTHORS’ CONTRIBUTIONS

MC conceptualization, writing, review; FB writing, review; GMP review.

Figures and tables

Figure 1.Embryonic neuroectodermal tumour in teratoma with somatic transformation. A typical appearance (HE).

Figure 2.(A) Signet ring cell stromal tumour (HE). (B) Signet ring cell stromal tumour (β-catenin stain). (C) Myoid stromal tumour (HE) (D) Myoid stromal tumour (S100 stain).

Figure 3.(A) Large cell calcifying Sertoli cell tumour (HE). (B) Large cell calcifying Sertoli cell tumour (Inhibin stain).

References

1. Gurney JK, Florio AA, Znaor A. International Trends in the Incidence of Testicular Cancer: Lessons from 35 Years and 41 Countries. Eur Urol. 2019; 76:615-623. DOI | PubMed
2. World Health Organisation (WHO). WHO Classification of tumours of the Urinary System and Male Genital Tumours. IARC: Lyon (France); 2022.
3. World Health Organisation (WHO). WHO Classification of tumours of the Urinary System and Male genital organs. IARC: Lyon (France); 2016.
4. Berney DM, Stoneham S, Arora R. Ovarian germ cell tumour classification: views from the testis. Histopathology. 2020; 76:25-36. DOI | PubMed
5. Colecchia M, Necchi A, Paolini B. Teratoma with somatic-type malignant components in germ cell tumours of the testis: a clinicopathologic analysis of 40 cases with outcome correlation. Int J Surg Pathol. 2011; 19:321-327. DOI | PubMed
6. Mikuz G, Colecchia M. Teratoma with somatic-type malignant components of the testis. A review and an update. Virchows Arch. 2012; 461:27-32. DOI | PubMed
7. Flood TA, Ulbright TM, Hirsch MS. “Embryonic-type Neuroectodermal Tumour” Should Replace “Primitive Neuroectodermal Tumour” of the Testis and Gynecologic Tract: A Rationale for New Nomenclature. Am J Surg Pathol. 2021; 45:1299-1302. DOI | PubMed
8. Heikaus S, Schaefer KL, Eucker J. Primary peripheral primitive neuroectodermal tumour/Ewing’s tumour of the testis in a 46-year-old man-differential diagnosis and review of the literature. Hum Pathol. 2009; 40:893-897. DOI | PubMed
9. Mikuz G, Böhm GW, Behrend M. Therapy-resistant metastasizing anaplastic spermatocytic seminoma: a cytogenetic hybrid: a case report. Anal Quant Cytopathol Histpathol. 2014; 36:177-182. PubMed
10. Wagner T, Grantham M, Berney D. Metastatic spermatocytic tumour with hybrid genetics: breaking the rules in germ cell tumours. Pathology. 2018; 50:562-565. DOI | PubMed
11. Merino J, Zuluaga A, Gutierrez-Tejero F. Pure testicular carcinoid associated with intratubular germ cell neoplasia. J Clin Pathol. 2005; 58:1331-1333. DOI | PubMed |
12. Bremmer F, Behnes CL, Schildhaus HU. The role of beta-catenin mutation and sox9 expression in sex cord-stromal tumours of the testis. Virchows Arch. 2017; 470:421-428.
13. Perrone F, Bertolotti A, Montemurro G. Frequent mutation and nuclear localization of beta-catenin in sertoli cell tumours of the testis. Am J Surg Pathol. 2014; 38:66-71. DOI
14. Michal M, Hes O, Kazakov DV. Primary signet-ring stromal tumour of the testis. Virchows Arch. 2005; 447:107-110. DOI
15. Fichtner A, Fisseler-Eckhoff A, Kramer W. Primary signet-ring stromal tumour of the testis: Case report with literature review. APMIS. 2019; 127:45-49. DOI
16. Kuo CY, Wen MC, Wang J. Signet-ring stromal tumour of the testis: A case report and literature review. Hum Pathol. 2009; 40:584-587. DOI
17. Renne SL, Valeri M, Tosoni A. Myoid gonadal tumour. Case series, systematic review, and Bayesian analysis. Virchows Arch. 2021; 478:727-734. DOI | PubMed
18. Paluru S, Ulbright TM, Amin M. The morphologic spectrum of sertoliform cystadenoma of the rete testis: a series of 15 cases. Am J Surg Pathol. 2018; 42:141-149.
19. Ulbright TM, Amin MB, Young RH. Intratubular large cell hyalinizing sertoli cell neoplasia of the testis: a report of 8 cases of a distinctive lesion of the Peutz-Jeghers syndrome. Am J Surg Pathol. 2007; 31:827-835. DOI | PubMed
20. Anderson WJ, Gordetsky JB, Idrees MT. Large cell calcifying Sertoli cell tumour: a contemporary multi-institutional case series highlighting the diagnostic utility of PRKAR1A immunohistochemistry. Histopathology. 2022; 80:677-685. DOI | PubMed
21. Young RH, Koelliker DD, Scully RE. Sertoli cell tumours of the testis, not otherwise specified: A clinicopathologic analysis of 60 cases. Am J Surg Pathol. 1998; 22:709-721. DOI
22. Kim I, Young RH, Scully RE. Leydig cell tumours of the testis. A clinicopathological analysis of 40 cases and review of the literature. Am J Surg Pathol. 1985; 9:177-192. DOI
23. Colecchia M, Bertolotti A, Paolini B. The leydig cell tumour scaled score (less): a method to distinguish benign from malignant cases, with additional correlation with mdm2 and cdk4 amplification. Histopathology. 2021; 78:290-299. DOI
24. Calaway AC, Tachibana I, Masterson TA. Oncologic outcomes following surgical management of clinical stage ii sex cord stromal tumours. Urology. 2019; 127:74-79. DOI
25. Nicolai N, Necchi A, Raggi D. Clinical outcome in testicular sex cord stromal tumors: testis sparing vs. radical orchiectomy and management of advanced disease. Urology. 2015; 85:402-406. DOI | PubMed
26. Shamash J, Ansell W, Alifrangis C. The impact of a supranetwork multidisciplinary team (SMDT) on decision-making in testicular cancers: a 10-year overview of the anglian germ cell cancer collaborative group (AGCCCG). Br J Cancer. 2021; 124:368-374. DOI
27. Al-Obaidy KI, Alruwaii FI, Ulbright TM. Appendageal tumours and tumour-like lesions of the testis and paratestis: A 32-year experience at a single institution. Hum Pathol. 2020; 103:25-33. DOI
28. Amin MB. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumours, mesothelial lesions and secondary tumours. Mod Pathol. 2005; 18:S131-145. DOI
29. Churg A, Galateau-Salle F. Well differentiated papillary mesothelial tumour: a new name and new problems. Mod Pathol. 2022; 35:1327-1333. DOI | PubMed