Malignant mesothelioma of the tunica vaginalis testis is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. Gross examination of testicular mesotheliomas typically reveals tumor nodules studding the thickened tunica vaginalis and, in some cases, infiltrating the testicular parenchyma, leading to diagnostic challenges. Microscopically, the tumor is characterized by epithelioid cells arising from the tunica vaginalis with papillary, tubulopapillary, or solid architectural patterns. The papillae are usually lined by a single layer of cells with relatively bland cytologic features. An epithelial cell phenotype admixed with a sarcomatoid pattern has also been described in a few cases. Immunohistochemically, the tumor is usually positive for calretinin, Wilms tumor-1, epithelial membrane antigen, D2-40, thrombomodulin, cytokeratin 7, and cytokeratin 5/6. Electron microscopic studies reveal epithelial cells joined by tight junctions, forming lumina, and displaying long microvilli with length to width ratios often greater than 10. The most important differential diagnostic considerations include florid mesothelial hyperplasia, adenomatoid tumor, carcinoma of the rete testis, and serous papillary tumors. In addition, the various types of testicular germ cell tumors should be considered, including seminomas, embryonal carcinomas, and intratubular germ cell tumors, particularly in tumors with testicular parenchymal involvement. Pleomorphic sarcomas should also be considered, particularly when dealing with the biphasic variant. The prognosis for this entity is grave, with a median survival of 23 months. Aggressive therapy with radical orchiectomy remains the mainstay of treatment.
Mesothelioma of the tunica vaginalis testis arises from the serosal membrane of the tunica vaginalis and has a mesenchymal origin. Most mesotheliomas arise from the pleura representing 68% to 85% of all malignant mesothelioma cases, whereas 9.1% to 24.1% of malignant mesotheliomas arise from the peritoneum.1 Mesothelioma of the tunica vaginalis testis is a distinctly rare tumor, representing only 0.3% to 5% of all mesotheliomas.1 The first case was described by Barbera and Rubino2 in 1957 and since then, approximately 100 cases have been reported.1 Exposure to asbestos, trauma, herniorrhaphy, and long-standing hydrocele have all been implicated as predisposing factors.3 The casual relation between asbestos exposure and mesothelioma was first described in 1960 by Wagner et al,4 detailing 47 cases of diffuse mesotheliomas observed within 5 years in people from South Africa exposed to asbestos. Later, Plas et al5 reviewed 74 cases of mesothelioma of the tunica vaginalis testis and found that 34.2% had a history of asbestos exposure.7–8 The latency period from the initial asbestos exposure to the clinical diagnosis is variable but is usually long, sometimes as long as 40 years.9
Mesothelioma of the tunica vaginalis occurs in middle-aged to elderly men (mean, 53.5 years); however, there is one case in the literature10 that describes this entity occurring in the pediatric population. Patients usually present with insidious, painless enlargement of the scrotum, and ultrasonography usually reveals hydrocele (56.3%); however, some patients present with a paratesticular solid mass (32.8%).1 Thickening of the tunica vaginalis on ultrasonography and gross examination is an important sign of this disease.1,3 Most cases are unilateral on presentation, and thus far, only 4 cases of bilateral mesothelioma of the tunica vaginalis have been reported, to our knowledge.1
Gross examination often reveals a firm, yellow or white tumor with a solid or cystic-cut surface. The tunica vaginalis is usually thickened, with tumor coating it, or it is studded with nodules of varying size. The tumor arises from the tunica vaginalis, and it may invade the testicular parenchyma and destroy adjacent structures, such as the epididymis and spermatic cord (Figure 1). In some cases, overwhelming inflammation may mask the classic gross finding of a mass with thickened tunica vaginalis, making diagnosis challenging. In such cases, microscopic findings as well as immunohistochemical stains play an invaluable role in diagnosis.
Microscopically, most of the tumors are epithelial with papillary, tubulopapillary, or solid patterns (Figure 2, a through c). The neoplastic cells are classically cuboidal with scant to moderate amounts of eosinophilic cytoplasm and bland cytologic features in the well-differentiated tumors; however, they may appear highly malignant in poorly differentiated tumors. Typically, the papillae have thick, hyalinized fibrovascular cores. In a few cases, the tumors are biphasic with epithelial and sarcomatoid patterns admixed (not shown). In such tumors, the sarcomatoid component typically has well-oriented spindle cells with significant cytologic atypia. In a review of the literature, there was one reported case5 with a purely sarcomatoid pattern in a mesothelioma of the tunica vaginalis testis; however, such tumors have been more often described in pleural and peritoneal malignant mesotheliomas.
The immunohistochemical profile of mesotheliomas that arise from the tunica vaginalis testis is similar to those that arise from the pleura and is typically positive for calretinin, Wilms tumor antibody (WT1), D2-40 (Figure 3, a through c), epithelial membrane antigen (EMA), thrombomodulin, and CK7, variably positive for CK5/6, and negative for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20).3,11–13
Electron Microscopy Features
Ultrastructural examination reveals epithelial cells joined by intercellular junctions, including desmosomes and junctional complexes, with lumen formation. Numerous cytoplasmic filaments are observed, including tonofibrils; cytoplasmic glycogen is also present. Long, slender, and at times torturous microvilli are typically seen on the surface of the tumor cells as well as in intracellular and intercellular lumina (Figure 4). The length to diameter ratio of the microvilli is typically greater than 10.14
Pathogenesis and Cytogenetics
Exposure to asbestos, particularly occupational exposure, long-standing hydrocele, trauma, herniorrhaphy, and potassium bromate in drinking water in animal models have all been implicated in the pathogenesis of this disease.1 There is a relatively stronger correlation between asbestos exposure and this disease entity than with the other predisposing factors. In one study,7 asbestos exposure was found in 34.2% of mesotheliomas of the tunica vaginalis testis from the 74 cases that were reviewed.15 The molecular basis of malignant mesothelioma in general is poorly characterized. In one study,9 losses of chromosomal regions in 1p, 8p, 14q, and 22q and gains in 5p, 6p, 8q, 15q, 17q, and 20 were reported. In a separate study, chromosomal abnormalities, such as losses of 1p, 3p, 6q, 9q, and monosomy 22, were shown,5,7 implying that mesotheliomas harbor multiple cytogenetic abnormalities with no specific diagnostic characteristics. It is not now possible to define the most important genetic alterations involved in the tumorigenesis of mesotheliomas, and future studies will be needed to delineate it at the molecular level.
The major differential diagnosis includes mesothelial hyperplasia, either the reactive or the inflammatory type. The clinical presentations of florid mesothelial hyperplasia are usually distinct from mesothelioma of the tunica vaginalis testis. For example, mesothelial hyperplasia is commonly associated with a hernia sac, whereas hydrocele sac involvement is associated with malignant mesothelioma of the tunica vaginalis testis. Furthermore, mesothelial hyperplasias are generally limited to the serosal surfaces, whereas invasion into the underlying stroma and dense cellularity of the stroma are useful indicators of malignant mesothelioma. In addition, cytologic atypia is commonly seen in poorly differentiated malignant mesotheliomas, whereas only minimal atypia is seen in mesothelial hyperplasia.14
Another differential diagnosis to consider is adenomatoid tumor, which is also of mesothelial origin. It usually presents as a unilateral mass that is relatively smaller. Histologically, it has a cystic appearance with round to oval or slitlike tubules and cords. The tubules or cords are lined by flat to columnar cells with moderate amounts of eosinophilic or vacuolated cytoplasm. In contrast, malignant mesotheliomas are usually larger and have a diffuse and infiltrative growth pattern. In addition, the cytologic atypia seen in malignant mesothelioma greatly exceeds that seen in adenomatoid tumor.12,14
Rete testis adenocarcinoma is also an important differential diagnosis, particularly when the tumors are infiltrative into the adjacent testicular hilus and lack the classic presentation of thickened tunica vaginalis, which is commonly seen in mesothelioma of the tunica vaginalis testis. Both tumors can have papillary and tubular patterns microscopically; however, rete testis carcinoma is predominantly located within the rete testis, particularly within the hilus, and the tumor is continuous with the rete testis epithelium. In addition, the tubules in rete testis carcinoma usually have a slitlike pattern in contrast to malignant mesothelioma, which rarely displays this pattern. Immunohistochemically, malignant mesotheliomas of the tunica vaginalis testis are usually negative for immunohistochemical markers Ber-EP4, CEA, Leu-M1, and tumor-associated glycoprotein (TAG-72), all of which are typically positive in adenocarcinoma, including rete testis adenocarcinomas, epididymal carcinoma, and metastatic adenocarcinoma. In addition, electron microscopy can be used as a final resort to differentiate between these 2 entities if other methods fail. The ultrastructural characteristics of adenocarcinoma are distinct from mesothelioma because there are fewer microvilli in adenocarcinoma, and they are usually short and blunt.14
In some cases, serous papillary tumors of the testis and epididymis, particularly those that are borderline tumors of the tunica vaginalis or serous carcinoma of the testis, may be confused with malignant mesothelioma of the tunica vaginalis testis. In making the distinction, the papillae in well-differentiated mesotheliomas of the tunica vaginalis testis are usually not as broad and do not exhibit the same degree of cellular budding and stratification that are typically seen in serous tumors. In addition, the papillae in well-differentiated mesotheliomas of the tunica vaginalis testis are typically lined by more uniform cuboidal cells with eosinophilic cytoplasm and bland cytologic features when compared with serous carcinoma, but this is not true when mesothelioma of the tunica vaginalis testis is poorly differentiated. Similar to rete testis carcinomas, serous papillary tumors of the testis are frequently positive for the adenocarcinoma markers mentioned above, setting them apart from mesothelioma of the tunica vaginalis testis.14 Cancer antigen 125 (CA-125) expression is reported in most intratesticular Müllerian papillary serous tumor as is the case in female genital papillary serous tumor.16,17 However, other studies concluded that even though CA-125 is a sensitive marker for serous tumors, it has no or little utility in differentiating between malignant mesothelioma and serous carcinoma.18,19
The differential diagnosis for the biphasic variant of mesothelioma of the tunica vaginalis testis is limited given the biphasic nature of this tumor. However, one must consider pleomorphic sarcomas, including pleomorphic rhabdomyosarcoma and malignant fibrous histiocytoma, when dealing with such cases. Both of these tumors are negative for the immunohistochemical markers mentioned above that are positive in malignant mesotheliomas.14
Occasionally, germ cell tumors of the testis such as seminomas, embryonal carcinomas, and intratubular germ cell tumors may be considered in the differential diagnosis when the tumor is infiltrating into the testicular parenchyma. In such cases, immunohistochemical stains are very useful. The germ cell tumors are typically positive for placental alkaline phosphatase (PLAP), octamer-binding transcription factor 4 (OCT4), and CD30 (positive in embryonal carcinoma), whereas malignant mesotheliomas of the tunica vaginalis testis are negative for these markers.14
TREATMENT AND PROGNOSIS
The management of mesothelioma of the tunica vaginalis testis is radical orchiectomy. Additionally, chemotherapeutic regiments are used for metastatic disease, although their efficacy has been marginal.5 The prognosis in testicular mesothelioma is generally grave, with median survival of 23 months and a range of 2 to 64 months.8,15 The extent of disease process at presentation is an important prognostic factor.5
Diagnosis of mesothelioma of the tunica vaginalis testis can be challenging given its rarity and at times obscure gross presentation. Often a fatal malignancy, it should be considered in the differential diagnosis of testicular masses, especially if the patient has been exposed to asbestos. The differential diagnosis of testicular mass is broad and should include both benign and malignant tumors that can arise in the testis. Immunohistochemical studies are important in differentiating many of these tumors from malignant mesothelioma of the tunica vaginalis testis. In addition, electron microscopy studies can be used to confirm the diagnosis because malignant mesotheliomas have specific ultrastructural characteristics that are distinct from other tumors.
We extend special thanks to John Papadimitriou, MD, PhD, for his editorial assistance and tireless support in improving this review. In addition, we thank Jonathon Heath, MD; Max Fischer, MD, MPH; and Joel Pinczewski, MD, PhD, for their technical support and critical review of this article.
From the Department of Pathology, University of Maryland Medical Center, Baltimore.
The authors have no relevant financial interest in the products or companies described in this article.