When serous fluid accumulates between the visceral and parietal layers of the tunica albuginea, a hydrocele develops. These cystic lesions are associated with a history of trauma and obstruction. Hydroceles are lined by mesothelium, though they may become denuded over time (Figures 5.7 and 5.8). In chronic hydrocele, the lining may become thickened and fibrotic with chronic inflammation and mesothelial hyperplasia (Figure 5.9). There is a low, but measurable risk of development of malignant mesothelioma in long-standing hydroceles, and any thickened or papillary areas of a hydrocele should be sampled extensively.

Spermatoceles occur when efferent ductules of the head of epididymis become dilated, often due to obstruction. These lesions can reach large sizes and are more commonly identified on the right side. Histologically, they comprise a dilated cystic lesion with a fibromuscular wall lined by cuboidal to pseudostratified epithelium, which may demonstrate cilia (Figures 5.13,5.14,5.15). The key diagnostic feature of spermatoceles is the identification of sperm within the cyst lumen; however, the sperm are commonly absent in opened specimens (Figure 5.16).

Dilation of the venous pampiniform plexus and internal testicular veins due to incompetent valves, or obstruction from tumor, leads to the formation of a varicocele. Physical examination of the mass reveals a tortuous tangle of vessels, the “bag of worms.” The mass may enlarge with the Valsalva maneuver. Unlike spermatoceles, varicoceles are more commonly identified on the left side that has more valves, due to the drainage of the right internal spermatic vein directly into the inferior vena cava. These vascular lesions are located above the testis and may be large enough to extend through the inguinal ring. The vessels in a varicocele show numerous thickened veins with hypertrophic smooth muscle (Figure 5.21). These lesions are not frequently submitted for pathologic evaluation in our experience, as they are routinely treated by vessel ligation.

Numerous benign cystic lesions occur in the paratesticular region, all of which are benign. Some “cysts” are actually dilations of normal structures, like a cystic change of the rete testis. Determining the precise origin of a cyst or cystic process is dependent largely on the presence and type of epithelial lining of the cyst wall.

Cystic changes in the rete testis have various etiologies (Figure 5.22). Cystic dysplasia of the rete testis occurs in children and is associated with renal malformations. There are multiple cysts lined by rete testis epithelium, which may be flattened. Acquired cystic transformation of the rete testis is a similar lesion, associated with renal dialysis. The cysts are lined by rete testis epithelium that is columnar to pseudostratified, and the luminal spaces contain proteinaceous fluid, spermatozoa, and calcium oxalate crystals.

Other cysts of the paratesticular region include tunica albuginea cysts, isolated rete cysts, cystic Walthard nests, epididymal cysts, multilocular cysts of paradidymal origin, and mesothelial cysts. As with rete testis cystic lesions, these entities are all defined by their anatomic location and lining cells.

Vasitis nodosa is a reactive proliferation of ductular cells arising from the damaged vas deferens, usually following vasectomy procedure. The condition may also arise after damage leading to obstruction or transection from a hernia repair or trauma. Small reactive ducts proliferate, and the epithelial lining may demonstrate mild reactive atypia with nucleoli (Figures 5.23 and 5.24). The reactive ducts can extend far beyond the intact vas lumen with surrounding smooth muscle proliferation resulting in a mass mimicking adenocarcinoma.
The infiltrative growth pattern is suggestive of a malignant process; however, the cytologic features are very bland and similar to the vas epithelium (Figure 5.25). The proliferative ducts often contain sperm, demonstrating a continuity with the intact vas (Figures 5.26 and 5.27). Compounding this pitfall is that the ducts may intimately involve nerves and vessels.² Usually the diagnosis is straightforward due to the location and clinical scenario (post vasectomy); however, when the differential diagnosis includes urothelial or prostatic carcinoma, immunohistochemistry may be helpful. The proliferative glands diffusely express PAX8 and patchy GATA3, but are negative for PSA and NKX3.1.³

Adenomatoid tumor is a benign mesothelial neoplasm involving the paratesticular region that can mimic adenocarcinoma. These tumors are common, usually identified in men in the fourth to sixth decade of life. They should be truly paratesticular in location, although rarely an adenomatoid tumor can involve the testicular parenchyma. The tumors are usually small and well circumscribed, with a firm, white to gray cut surface. The classic architectural pattern of these tumors demonstrates gland-like structures with flattened mesothelial lining (Figure 5.28). The identification of thread-like strands that bridge across the lumen is a helpful feature.⁴ Because of the numerous patterns (see Pearls and Pitfalls below) and the possibility of testicular involvement, the differential diagnosis of adenomatoid tumor is broad. Depending on the pattern, consideration of germ cell tumors (yolk sac tumor in particular), sex cord-stromal tumors, adenocarcinoma, and mesothelioma may be entertained (Figure 5.29). In these instances, the classic immunoprofile of adenomatoid tumors is helpful with the expression of D2-40, calretinin, and WT-1 (Figures 5.30 and 5.31). However, this pattern does not serve to exclude malignant mesothelioma, but mesotheliomas would be expected to be larger and have more cytologic atypia with possible necrosis present.

Adenomatous hyperplasia is a rare benign process in the rete testis, comprising tubular and papillary epithelium proliferating into rete lumen (Figures 5.32,5.33,5.34).The lining shows bland low cuboidal cells without significant atypia. A clue to the diagnosis is the identification of hyaline globules, resembling those found in yolk sac tumors (Figure 5.35).⁸ A confounding issue is that rete hyperplasia may also occur as a reaction to germ cell tumor invasion (Figure 5.36).⁹

This is an exceedingly rare adenocarcinoma located in the testicular hilum and derived from the rete epithelium. The location of the tumor and identification of intrarete growth can help support this diagnosis, although specific criteria have been proposed for this entity (see FAQ). Because of its rarity, it is important to exclude other more common entities before diagnosing a primary rete testis adenocarcinoma. Architecturally, rete testis adenocarcinoma classically shows infiltrative glandular growth with slit-like spaces, which may merge into more solid or spindle-shaped areas (Figures 5.37 and 5.38). Other architectural patterns have been reported, including papillary, tubulopapillary, cribriform, and nested. Necrosis is a helpful feature to distinguish from benign rete testis hyperplasia (Figure 5.39).

There is no specific immunohistochemical profile for these tumors; however, one study found positivity of AE1/AE3 cytokeratin, CK7, epithelial membrane antigen (EMA), and vimentin in the majority of cases. A subset of these cases shows nuclear positivity for
WT-1 and PAX-8.¹⁰ These tumors have poor outcomes, with a high frequency of retroperitoneal lymph node metastasis. The main differential diagnosis in these tumors is secondary involvement by another metastatic adenocarcinoma, serous tumors, and malignant mesothelioma.

Another exceedingly rare tumor, primary epididymal adenocarcinoma is the malignant counterpart of papillary cystadenoma. Centered in the epididymis, these tumors show frank invasive growth. The patterns of growth described in these tumors include tubular, tubulocystic, or tubulopapillary. Cytologically, the malignant cells show abundant clear cytoplasm containing glycogen.¹² Similar to adenocarcinoma of the rete testis, it is critical to exclude other primary sites of adenocarcinoma before making this diagnosis.

The tunica vaginalis may give rise to malignant mesothelioma centered in the paratesticular region. However, paratesticular mesotheliomas make up only 1% of all mesotheliomas, which are far more common in the pleura and peritoneum.¹³ The tunica vaginalis is in continuity with the abdominal peritoneal lining, and in many ways, this lesion is similar to primary peritoneal mesothelioma, including a poor prognosis. These tumors show a lower association with asbestos exposure when compared to pleural mesothelioma.¹⁴ Chronic hydroceles are linked with mesothelioma, and any hydrocele specimen with thickened or roughened areas should be sampled carefully (Figures 5.40 and 5.41).

Similar to malignant mesothelioma in other anatomic locations, in paratesticular mesothelioma, the mesothelial lining is grossly thickened and studded with tumor nodules. On sectioning, the malignant mesothelial cells infiltrate deeply into fat and other structures with a truly invasive pattern of growth. One should be aware that mesothelial hyperplasia may involve superficial clusters of mesothelial cells below the surface, a reactive pattern.

Architectural patterns in epithelioid mesotheliomas (which are most common) include papillary, tubulopapillary, tubular, and solid.¹⁵ Biphasic or sarcomatoid mesothelioma is discussed later in the section on spindle cell pattern. Psammoma bodies may be present (Figure 5.45). The less common biphasic malignant mesotheliomas show both epithelial and sarcomatous components. The malignant epithelioid cells are plump with abundant, dense eosinophilic cytoplasm with pleomorphic nuclei and large nucleoli. Mesothelial markers (calretinin, D2-40, WT-1) are positive and may be used to distinguish these tumors from invasive adenocarcinomas.

Papillary cystadenoma arises from the epididymis as a papillary and cystic neoplasm lined by bland cells with ample clear cytoplasm. These benign tumors are associated with von Hippel Lindau syndrome.¹⁶,¹⁷ An underlying genetic syndrome is more likely when tumors are present bilaterally. Histologically, it is nearly identical to clear cell papillary renal cell carcinoma. The architectural pattern shows blunt papillary cores and numerous cystic spaces, with intervening fibrous stroma (Figures 5.46,5.47,5.48). Cytologically, the cells demonstrate cleared out cytoplasm and nuclei may align themselves at the luminal aspect of the cell leading to subnuclear vacuoles (Figures 5.49 and 5.50). Benign cytology is essential for this diagnosis—no increased atypia, mitotic figures, or necrosis is permitted. The immunoprofile is also identical to that of clear cell papillary renal cell carcinoma, with positive expression of PAX8, carbonic anhydrase IX in a cup-shaped pattern, and CK7 and lack of expression of CD10, RCC marker, and α-methylacyl-CoA racemase.¹⁸

The main differential diagnosis for these lesions includes metastatic conventional clear cell renal cell carcinoma, which should exhibit some atypia, a more nested growth pattern, and should lack true papillary fronds. The immunoprofile should also differ, with the expression of CD10 and RCC in a metastatic clear cell renal cell carcinoma. A second differential diagnosis includes tumors of Mullerian origin—serous borderline tumor and papillary serous carcinoma. Both of these lesions exhibit more architectural complexity and cytologic atypia than expected in papillary cystadenoma.

Well-differentiated papillary mesotheliomas are associated with hydroceles and often occur in younger men when compared to malignant mesotheliomas. These tumors are noninvasive, exophytic proliferations of mesothelial cells that stud the peritoneal/tunical surface. The papillary fronds are simple, without complex branching architecture and lined by a single layer of bland cuboidal mesothelial cells (Figures 5.51 and 5.52).¹⁹ Mitotic figures should be minimal to absent, and no necrosis or invasive growth is permitted. Classic well-differentiated papillary mesotheliomas are considered benign entities and can be treated with hydrocelectomy.

Occasionally, there is more cytologic atypia or complex architecture identified in these lesions that appear to exist on a morphologic spectrum with malignant mesothelioma. The term “well-differentiated papillary mesothelioma with borderline malignant potential” has been applied to lesions with any of the following features identified in focal areas: atypia or stratification of lining mesothelial cells, increased mitotic figures, tubular or cribriform pattern, or fused papillary fronds (Figures 5.53 and 5.54).²⁰ If these features are extensive, then a close search for an invasive component is warranted to rule out the possibility of a frankly malignant mesothelioma.

Ovarian-type epithelial tumors are named after their ovarian counterparts and include serous cystadenomas, serous tumors of borderline malignant potential, serous carcinomas, and both benign and malignant mucinous cystic tumors.¹³ These tumors are hypothesized to arise from the tunica vaginalis with Mullerian metaplasia or other Mullerian remnants within the paratesticular region.²¹,²² Although extremely rare, serous tumors are slightly more common than mucinous tumors. They are morphologically identical to the ovarian tumors of the same name.

Serous tumors of borderline malignant potential are usually cystic lesions lined by stratified tubal-type epithelial cells with minimal cytologic atypia, negligible mitotic activity, and architectural complexity in the form of branching, complex papillary fronds (Figures 5.55,5.56,5.57). Consistent with their Mullerian origin, these tumors strongly express PAX-8 (Figure 5.58). In a series of seven cases of serous borderline tumor of the paratestis, there were no recurrences or metastases reported after radical orchiectomy.²³ In contrast, serous carcinomas show invasive growth of tumor cells with high-grade nuclear atypia, frequent mitotic figures, and necrosis and are often associated with psammoma bodies.

Similar to the ovary, mucinous tumors of the paratestis occur on a spectrum of benign (mucinous cystadenoma) to malignant (mucinous carcinoma). In the middle are mucinous borderline tumors, which show atypical mucinous epithelium without invasive growth, whereas mucinous carcinoma shows invasion. Tumors can show either intestinal-type or endocervical-like epithelium. With mucinous tumors of this area considered so rare, it is critical to exclude metastasis from other sites before making the diagnosis of a primary mucinous neoplasm of the paratestis.²⁴

Other less common ovarian-type malignancies include Brenner tumor of testis, endometrioid adenocarcinoma, and clear cell adenocarcinoma.

The most common paratesticular mesenchymal tumor is lipoma. Despite their benign nature, these are controversial lesions in the genitourinary and surgical literature. Many authors consider these fatty accumulations about the cord to represent retroperitoneal fat that has tracked down the cord, rather than a true neoplasm. For those that consider it a discrete entity, “cord lipomas” are discrete, encapsulated masses attached to the spermatic
cord rather than an indistinct aggregate of adipose tissue present in the inguinal canal. Regardless, these lesions comprise mature adipose tissue without atypia, similar to lipomas occurring in the other regions (Figures 5.59,5.60,5.61). Large true lipomatous neoplasms of the spermatic cord (>10 cm) are “deep” lipomatous tumors and should be evaluated for the possibility of atypical lipomatous tumor/well-differentiated liposarcoma, such as with fluorescence in situ hybridization (FISH) for MDM2 amplification.²⁵

Liposarcomas are malignant adipocytic tumors primarily occurring in older individuals. Similar to lipomas in this area, they may arise as true paratesticular/spermatic cord lesions or extension from a retroperitoneal liposarcoma. In the latter case, radiographic imaging would be necessary to determine the tumor extent. Well-differentiated liposarcomas are readily identifiable as lipomatous neoplasms, with an abundance of adipocytes and morphologic overlap with lipoma; however, there is nuclear atypia. Atypical features include enlarged, hyperchromatic nuclei, frequently present within fibrous septa (Figures 5.62 and 5.63). Dedifferentiation in a liposarcoma may confound the diagnosis, especially in small biopsy specimens. Amplification of MDM2, best assessed by FISH studies, is useful in the distinction of lipoma from liposarcoma.

Fibrous pseudotumors of the paratestis are uncommon mass-forming lesions that occur within the scrotum and are often associated with hydroceles or a history of trauma. The masses may be plaque-like or nodular and are frequently multifocal, leading to an alternate terminology “nodular periorchitis.”¹³ Histologically, the masses comprise dense fibrous tissue with hyalinization and some degree of inflammation, usually lymphoplasmacytic (Figures 5.68 and 5.69). The differential diagnosis of this entity includes inflammatory myofibroblastic tumor and fibromatosis. By immunohistochemistry, fibrous pseudotumors lack ALK and β-catenin expression, which distinguishes them from inflammatory myofibroblastic tumors and fibromatosis.²⁶ These lesions behave indolently and are cured with conservative excision.

A rare bland smooth muscle proliferation encircling ducts of the epididymis is one of the typical patterns of smooth muscle hyperplasia of the testicular adnexa (SMH-TA), which is a benign process of unknown etiology. These lesions are not true neoplasms, rather they are made up of a benign excess of the patient’s usual smooth muscle component of the paratestis or spermatic cord. In one series, the mean age of patients with SMH-TA was 51 years, and the majority presented with testicular pain or mass.²⁷ The smooth muscle proliferates within the interstitium, between vessels, or interdigitates with or “cuffs” the efferent ducts of the epididymis. Histologically, SMH-TA demonstrates fascicular growth of smooth muscle that lacks the interlacing pattern of leiomyoma.²⁸

Leiomyosarcomas rarely arise in the paratesticular area, presenting as a scrotal mass. They may arise from the tunica vaginalis, spermatic cord, scrotal subcutaneous soft tissue, dartos muscle, or epididymis.²⁹ Like leiomyosarcomas elsewhere, these tumors comprise a fascicular arrangement of malignant spindle cells with cigar-shaped nuclei (Figure 5.71). Frank malignant features such as nuclear pleomorphism, increased mitotic rate, and necrosis are present, which distinguishes these tumors from their benign leiomyoma counterpart. In poorly differentiated leiomyosarcomas, other sarcomas may enter the differential diagnosis including dedifferentiated liposarcoma and spindle cell rhabdomyosarcoma. In this instance, immunohistochemistry and FISH can help confirm the diagnosis with leiomyosarcoma expressing the usually smooth muscle markers desmin, muscle-specific actin, and smooth muscle actin. The lack of MDM2 amplification makes a liposarcoma less likely, and rhabdomyosarcoma is discussed more below.

Malignant mesotheliomas often show a biphasic growth pattern with a combination of epithelial component (often papillary) and sarcomatoid component. Biphasic mesotheliomas occur about one-third as frequently as epithelial mesotheliomas in this anatomic location. No pure sarcomatoid mesotheliomas have been described in the paratestis region.¹³ These tumors frequently exhibit local recurrence and lymph node metastasis, with overall poor prognosis. Histologically, the epithelial component may show any of the patterns described above in the papillary pattern section. The sarcomatoid component shows a spectrum of fascicles of low-grade-appearing spindle cells to high-grade pleomorphic nuclei (Figures 5.72,5.73,5.74,5.75).