Abstract

INTRODUCTION

Testicular cancer represents between 1% and 1.5% of male neoplasms and 5% of urological tumours. The vast majority of tumours are diagnosed in the third and fourth decade of life. The histological type varies, although there is a clear predominance (90-95%) of germ cell tumours ¹. The incidence of germinal cell tumors (GCTs) declines markedly towards the age of 50, and tumours in patients above the age of 60 are extremely rare, while the incidence of spermatocytic seminoma (a distinct GCT with a generally benign behavior), primary lymphoma, stromal tumors, usually of the Leydig cell type, and rarely metastasis progressively increases. In addition, although most masses encountered within the scrotal sac are within the testis, a subset (2-3%) of these tumors is extratesticular and arises from paratesticular tissue that includes the spermatic cord, testicular tunics, epididymis, and vestigial remnants ² , ³. Although uncommon, these tumors have been recorded as the main urogenital site of sarcomas in the elderly, whereas primary sarcoma of the testis is a rare entity in which a diagnosis is made only after the exclusion of the more common paratesticular neoplasm ⁴ , ⁵ , ⁶.

TESTICULAR GERM CELL TUMORS

Testis germ cell tumors (TGCTs) can be subdivided into three different biological and clinical entities: (a) prepubertal teratoma-yolk sac tumors; (b) seminoma and nonseminoma; and (c) spermatocytic seminoma. The first group includes tumors that develop in prepubertal age but seminoma and nonseminoma may develop also after puberty. On the contrary spermatocytic seminoma is encountered mainly in elderly men ⁷ , ⁸ , ⁹. The developement of this histological kind of tumors starts during fetal period, through changes occurring in primordial germ cells either during migration to the embryonic genital ridges or later when cells localize in the gonads. Post-pubertal TGCTs, instead, derives from initially cellular changes defined not invasive intratubular germ cell neoplasia (ITGCNU) that following successive amendments evolve into seminoma or nonseminoma or both subtypes, around or after puberty ¹⁰ , ¹¹. In the past, in elderly were reported only sporadic cases of seminoma and non-seminoma. Seminomas and nonseminomas are also extremely rare in patients younger than 60 years of age. In a recent work of Berney and colleagues, were analyzed a large number of TGCTs in elderly patients (mean age 67 years) and 82% (41 cases) were seminomas, 12% (6 cases) were nonseminomas like yolk sac, teratoma, embryonal carcinoma, and choriocarcinoma and 6% (3 cases) mixed seminoma/nonseminoma. Tumor size was markedly larger than that in younger men and TGCTs present at a higher stage than in younger men probably because they may present to clinicians at a later stage or may be diagnostic on delay because of the lack of clinical examination of the testis. In addition, there is also a difference in the cure of the neoplasm; in fact, the tendency to present at a higher stage and less tolerance to chemotherapy in older patients make the tumors in this group less curable ¹² , ¹³. Seminomas are composed of cells similar to ITGCNU, showing a homogenous appearance, and organized in one or more nodules with a lymphocytic infiltrate in the supportive stroma. Nonseminoma could be both pure and mixed with other nonseminoma elements (embryonal cell carcinoma, yolk sac tumor, choriocarcinoma, teratoma) ¹⁴. The management of these tumors remains the same also in elderly and the first curative approach is surgery with orchiectomy. These neoplasms are chemiosensitive (cisplatinum based therapy). The seminoma has a marked radiosensitivity too. Nonseminoma TGCT are less sensitive to radiation and when metastatic, often requiring both chemotherapy and surgery ¹⁵.

TESTICULAR CELL TUMORS

Spermatocytic seminoma is a rare germ cell tumor that typically occurs in the elderly, with distinctive clinical and pathological characteristics. The incidence increases with age and the peak is in the sixth decade, representing the 1.3-2.3% of all patients with seminomas. Generally, spermatocytic seminoma is presented with painless and unilateral swelling, not associated with history of cryptorchidism and without increasing markers ¹⁶ , ¹⁷. This tumors tend not to metastasize. Usually, the tumor is well circumscribed and encapsulated, rarely extending into the paratesticular soft tissue. Microscopically, the tumor consists of a diffuse proliferation of polymorphic cells of different sizes: small, 6-8 mm, eosinophilic cytoplasm lymphocyte-like; large, 80-100 mm, sometimes multinucleated; and intermediate, 15-20 mm, which are predominant in the tumor and with a round nucleus and granular chromatin ¹⁸. Spermatocytic seminomas cells generally show an immunohistochemical expression of c-Kit in around 40% of the spermatocytic seminomas. Cytogenetic anomalies aid the differentiation of spermatocytic seminomas from conventional seminomas and other GCTs: the gain of chromosome 9 appears to be a consistent finding in all spermatocytic seminomas ¹⁹. Classic seminomas, in contrast, show a consistent structural chromosomal abnormality of isochromosome 12p ²⁰. The neoplastic transformation of progenitor cells in spermatocytic seminoma and their relationship with other GCT remain controversial ²¹ , ²² , ²³. The best hypothesis considers the spermatocytic seminoma as derived from progenitor cells capable of maturation at least up to the stage of spermatogonia-pachytene spermatocyte. In fact, spermatocytic seminoma expressing proteins related to this range of aging in normal GC, as synaptonemal complex protein 1 (SCP1), xeroderma Type pigmentosa A (XPA), and synovial sarcoma on X chromosome (SSX). SCP1 and XPA are expressed normally in primary and pachytene spermatocyte stage, which SSX is normally observed in spermatogonia and primary spermatocytes, as well as in germ cells from the 17th week of intrauterine development. The absence of these protein in conventional seminoma supports the embryonic germ cells as the cell of origin ²⁴. Lim et al ²⁵ have identified two subsets of spermatocytic seminoma features based on OCT2 or SSX2-4 immunoexpression and conclude that the expression pattern of three markers reflects the origin of spermatocytic seminoma from spermatogonia and demonstrate that the tumor is a heterogeneous group. Finally, the expression profile of 156 miRNAs showed that spermatocytic seminoma cluster occurs with more differentiated tissues as normal testis and teratomas, in contrast microRNAs in seminomas and dysgerminomas, which also cluster with embryonal carcinomas ²⁶. In consideration of their favorable behavior is being cured by only orchidectomy. A worst prognosis can occur when appears a sarcomatous dedifferentiation that gives a metastasizing potential ²⁷.

STROMAL TESTICULAR NEOPLASM

Leydig cell tumors (LCTs) are rare tumors representing 1-3% of all testicular malignancies and they have two peaks of incidence: between 5 and 10 years and in men aged 30 to 82 years. Its malignant variant that represent only 10% of cases, occured more frequently in the elderly. The frequent site of metastatization is to the retroperitoneal lymph nodes (70%), liver (45%), lung (40%), and bone (25%), usually within 2 years of the diagnosis ²⁸. Frequently, the tumor cells produce testosterone, but it can be characterized by an increase in estrogen, either because of the direct production of estradiol or because of peripheral aromatization of the testosterone ²⁹. Thus, androgen-secreting tumors in adults and in elderly patients are asymptomatic, whereas in estrogen-secreting tumors, patients generally present with endocrinological disorders such as gynecomastia, impotence, infertility, and loss of libido ³⁰. Clinically, patients commonly show painless testicular enlargement or a palpable mass. This kind of tumor can be pure or mixed with germ cell tumors or other sex-cord stromal tumors ³¹. Histologically, we can observe four types of cells: (a) large polygonal cells with abundant granular eosinophilic cytoplasm, oval nuclei, and indistinct cell borders; (b) cells similar to type 1, but with distinct cell borders and smaller nuclei; (c) small cells with grooved nuclei; and (d) spindle cells. The cytoplasm less frequently may be clear for the presence of abundant lipid and lipofuscin ³². The degree of malignancy is defined by more tumor size (> 5 cm), infiltrative margins, foci of necrosis, absent signs of hormonal activity cancer (gynecomastia), vascular and lymphatic invasion, nuclear atypia, mitotic count greater than 3/10HPF, increased MIB-1 and DNA aneuploidy ³³. The positive immunohistochemical markers for LCT are inibin, vimentin, Melan-A, and calretinin ³⁴. The benign variant can be cured by surgery, such as orchiectomy or nodule enucleation. In adult and elderly patients, in whom malignant LCTscan be observed more frequently, the best treatment is radical orchiectomy and retroperitoneal lymphadenectomy. Malignant LCT does not respond favorably to chemotherapy and irradiation and the prognosis is poor (median, 2 years) ³⁵.

PRIMARY LYMPHOMAS

Primary testicular lymphoma (PTL) is an uncommon disease that comprises only 1-9% of testicular neoplasm ³⁶. However, it is the most common malignancy in men older than 50 years of age and 85% of cases are diagnosed in men beyond the sixth decade. According to the current literature, PTL should be considered when no other tumor masses are observed on the rest of the body or when such tumors are smaller in volume than the testicular tumor mass ³⁷. In HIV-positive patients, the incidence of PTL is increased and it is found at an earlier age, where it is associated with a poor prognosis ³⁸. In adult testis, primary diffuse large B cell lymphoma (DLBCL) is the most observed lymphoma (80-90%). The most common clinical presentation of TL is with unilateral painless scrotal swelling. In 25-41% of patients the disease presentation is with fever, night sweats, and weight loss but are more frequent in the advanced stage ³⁹ , ⁴⁰ , ⁴¹. The involvement of retroperitoneal lymph nodes often leads to pain and ascites ⁴². In 43% of patients is found hydrocele without evidence of a testicular mass. On clinical examination, TL appears as a firm mass. Bilateral testicular involvement synchronous at diagnosis or, more frequently, asynchronous has been documented in up to 35% of patients ⁴³ , ⁴⁴. Local lymphoma diffusion through the epididymus, spermatic cord, is quite frequent, whereas dissemination to several extranodal sites including the controlateral testis, central nervous system (6-16%), skin (0-35%), Waldeyer’s ring (5%), lung, pleura, and soft tissue is less frequent. The diagnosis of TL is better made on orchiectomy samples rather than on fine needle biopsy. In addition, orchiectomy provides good local tumor control and facilitates the removal of a sanctuary site, as the blood-testis barrier makes testis tumors a chemotherapy sanctuary ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸. Most TLs are B-cell lymphomas. DLBCL represents 80-90% of all cases. Burkitt’s and Burkitt’s-like lymphomas are found in only 10-20% of cases, mainly in HIV+ patients. B-cell lymphoma, unclassifiable, with characteristics intermediate between DLBCL and Burkitt lymphoma, has also been reported. Follicular or T cells lymphomas have rarely been described ⁴⁹ , ⁵⁰. Most common expressed markers are CD19, CD20, CD79a and CD22 (B cell marker), while CD10 MUM1 are found in 30-65% of cases and the nuclear BCL6 expression has been reported in 60-90% cases ⁵¹ , ⁵². DBCLs can be distinguished into two subclasses based on the expression of CD10, BCL6, and MUM1: germinal Center B-cell-like and a center nongerminal B-cell-like, the germinal center B-cell lymphomas as is the most frequent at this site ⁵³ , ⁵⁴. The diagnostic definition of these diseases is of primary importance infact an error in differential diagnosis, may cause fatal consequences in view of the completely different treatment ⁵⁵. Unfortunately, in view of the high disease aggressivity, the prognosis is very poor and often patients with stage I/II show early recurrence ⁵⁶. Overall survival at 5 and 10 years for stage I patients PTL was 58 and 29%, and for stage II patients PTL, was 46 and 29%, respectively ⁵⁷. Stage IV patients show a higher rate of recurrence of 90% and a 5-year survival of 20-25%. It have been proposed several prognostic factors such as age, performance status, symptoms, tumor burden greater than 9 centimeters, the spermatic cord involvement, lactate dehydrogenase serum levels, histologic grade, vascular invasion, degree of sclerosis and stage of the disease ⁵⁸ , ⁵⁹ , ⁶⁰. In IELSG series of 373 patients PTL, the parameters associated with a long overall survival were low/low-intermediate risk, according to the international prognostic index, absence of B symptoms, anthracycline-based chemotherapy, and prophylactic scrotal radiotherapy ⁶¹.

PARATESTICULAR SARCOMA

Paratesticular sarcoma is an uncommon disease. It is so difficult to provide series of sufficient cases to document the natural history of these tumors and the treatment results ⁶². According to the Memorial Sloan- Kettering Cancer Center large case series, 2.1% of soft tissue sarcomas arise in the genitourinary tract, and almost 44% are paratesticular ⁶³ , ⁶⁴. Usually, a paratesticular tumor appears as a scrotal mass occasionally associated with a hydrocele. Seventy percent of all cases are benign and 30% are malignant. The most frequent benign tumors are lipomas, adenomatoid tumors, and leiomyomas ⁶⁵. Among the paratesticular sarcomas, liposarcoma is the most frequent, followed by leiomyosarcoma, both found mainly in the elderly ⁶⁶.

PARATESTICULAR LIPOSARCOMA

Liposarcoma is the most common type of soft tissue sarcoma, accounting for 30% of all mesenchymal tumors, whose peak occurs in the sixth to seventh decade ⁶⁷. Paratesticular liposarcoma is low-grade malignancy ⁶⁸. It appears as a painless, fluctuant, slow-growing mass, with a maximum diameter of 5-10 cm ⁶⁹. Rapid growth, large size, and pain are indicative of more aggressive histotypes. Histologically, they are classified into five categories, as the WHO Committee for the Classification of Soft Tissue Tumors proposed in 2002: well differentiated, dedifferentiated, myxoid, pleomorphic, and mixed ⁷⁰ , ⁷¹. The most frequent histotype in paratesticular site is the well-differentiated variant, characterized by diffuse mature lipomatous differentiation associated with the presence of lipoblasts in fibrous septa. It is a low-grade tumor with no metastatic potential, but with high rate of local recurrence ⁷². De-differentiation can occur ab-initio or in case of relapse with potential hematogenous and lymphatic spreading ⁷³ , ⁷⁴, ⁷⁵.

The prognosis for well-differentiated liposarcoma remains good, with overall 5- and 10-year survivals of 75 and 55%, respectively. The high relapse rate and metastasis observed in high-grade

liposarcoma worsen the prognosis significantly ⁷⁶. Initial treatment consists of orchiectomy with high ligation of the spermatic cord at the inguinal canal. Surgery can be combined with radiation therapy. Spermatic cord liposarcoma is the most radiosensitive of all sarcomas. This therapy has been particularly indicated in the relapse of intermediate-grade or high-grade lesions. The role of retroperitoneal lymph node dissection is uncertain and is recommended in case of intermediate/high-grade disease with evidence of lymphnode involvement by a computed tomographic scan ⁷⁷. The role of adjuvant chemotherapy remains uncertain, in case of high-grade liposarcoma can be represented by the use of combined chemotherapy (vincristine, cyclophosphamide, ifosphamide and anthracyclines) ⁷⁸.

PARATESTICULAR LEIOMYOSARCOMA

Leiomyosarcoma is the most commonly reported histologic type of paratesticular sarcoma ⁷⁹. The reported average age for paratesticular leiomyosarcoma was 60 years and most cases were in the 40-70 age group ⁸⁰. Rarely, pure intratesticular leiomyosarcomas are reported as single case reports, with an average age of 50 years ⁸¹. Definitive diagnosis requires a histologic examination of a resected specimen to observe morphological and immunohistochemical smooth muscle differentiation, neoplastic cells immunostain for smooth muscle actin, muscle-specific actin, and desmin; moreover, h-caldesmon may be used to confirm smooth muscle differentiation and myogenin to exclude spindle cell rhabdomyosarcoma ⁸². The preferred site of involvement is the spermatic cord, rarely epididymis ⁸³ , ⁸⁴.It appears as a generally painful mass or swelling, oftennear the spermatic cord, occasionally accompanied by asmall hydrocele. Histologically, leiomyosarcoma is characterized by typical features of spindle cell neoplasm with a fascicular architecture, foci of cytologic atypia, and mitoses, the presence of a large amount of necrosis is generally observed in high-grade tumors ⁸⁵ , ⁸⁶. The clinical and biological behavior of paratesticular leiomyosarcoma is generally unpredictable. The main prognostic factors of leiomyosarcomaa are the site, size, grade of primitive tumors and nodal or distant metastasis ⁸⁷. The best treatment remains controversial but radical inguinal orchiectomy is the primary treatment including high ligation of the spermatic cord. Local recurrence is common for high grade tumor and for positive margins, difficult to obtain in the paratesticular region ⁸⁸. Adjuvant locoregional radiation after surgery may be recommended to reduce the rate of local recurrence. The role of chemotherapy is unknown.

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