Epididymitis/Orchitis

Non-Granulomatous Inflammation
Epididymitis, orchitis and more typically epididymo-orchitis are common conditions usually recognized at the clinical level. [4, 5] Some cases, especially longstanding examples, may give rise to a mass and simulate a neoplasm. [6, 7] Bacterial epididymitis is often secondary to Neisseria gonorrhoeae or it may be caused by gram negative organisms, specially in prepubertal boys and older patients. Chlamydia trachomatis is also a relatively common cause of epididymitis, especially in the young adult males. Viral infections more typically involve the testis and while mumps is perhaps the most well known etiology, other viruses including coxsackie and influenza viruses may be associated with orchitis. [8]

In most instances, these inflammatory conditions are clinically diagnosed and resolve with treatment but in some cases, persistent inflammation, abscess and fibrosis leads to an enlarged firm epididymis and/or testis leading to surgical exploration. At the microscopic level, the inflammatory nature of the process is readily evident. In rare instances, mumps orchitis or other viral illnesses may result in testicular enlargement and be macroscopically confused with seminoma or lymphoma. Microscopically, a heterogeneous lymphoid infiltration is present and the tubular architecture is generally non-effaced.

Granulomatous Inflammation
Granulomatous inflammation may also involve the testis, epididymis or both. Infectious and non-infectious forms exist. The most common type of granulomatous epididymitis is that caused by tuberculosis. [9, 10, 11] When there is extensive involvement, secondary hydrocele and fibrosis with adhesions may be seen. This may result in a mass lesion simulating neoplasm. [11] Other organisms such as brucellosis and rare fungal diseases such as blastomycosis and histoplasmosis may at times involve the testis. [12, 13, 14] Additionally, conditions such as syphilis, leprosy and toxoplasmosis may affect the testis and end up being surgically removed.

Sarcoidosis [15, 16, 17, 18, 19] may uncommonly involve the epididymis, mostly in black patients. The epididymal involvement may be unilateral or bilateral and may be either diffuse or nodular. When lesions are larger, they may have a tumorous appearance. Sarcoidosis may also involve spermatic cord and simulate a neoplasm at that particular site. [19] Histologic examination shows typical non-caseating epithelioid granulomas as seen in other more common sites.

Idiopathic granulomatous orchitis [1, 20] is a rare condition which in one series accounted for 0.2% of testicular masses. This lesion generally occurs in the fifth or sixth decades and is commonly associated with a prior history of gram negative urinary tract infection. A history of trauma is sometimes noted. While some cases have an antecedent history of flu-like illness, other present as a mass in the testis simulating testicular neoplasm such as seminoma and lymphoma. The testicular enlargement may be associated with some tenderness.

The tunica albuginea is typically thickened and the testicular parenchyma is replaced by lobulated gray, tan or white tissue. The whole surface area may be involved or a more discrete nodule may be identified. The epididymis and spermatic cord are involved in about one-half of cases. The epididymis on rare occasions may be the dominant or exclusive site of involvement. [21] Occasionally, the epididymal disease can have a xanthogranulomatous appearance. Interestingly, Nistal et al have described a granulomatous epididymal lesion of possible ischemic origin. [22]

Microscopically, there is a tubulo-centric process characterized by swollen seminiferous tubules filled with epithelioid histiocytes usually admixed with lymphocytes and plasma cells. Langerhans-type giant cells may also be seen. Interstitial chronic inflammation including lymphocytes, plasma cells and eosinophils is present in most cases. The process typically has a nodular (follicular) pattern of growth. The inflammation may extend into epididymal tubules. Important differential diagnoses include other infective causes of granulomatous orchitis, malignant lymphoma and seminoma with a granulomatous stromal reaction.

Malakoplakia may affect the testis alone or the testis and epididymis in about one-third of cases. [23, 24, 25] Interestingly, the right testis is affected more commonly than the left. Isolated epididymal involvement is uncommon. The testis is usually enlarged clinically and on gross inspection, the testicular parenchyma is lobulated, yellow, tan or brown in coloration. The consistency is usually soft and small abscesses may be seen. At the microscopic level, tubules and interstitium are replaced by von Hansemann histiocytes and scattered Michaelis-Gutmann bodies are identified. In some cases, the histiocytes may have a more spindled configuration creating some confusion with spindle cell neoplasms. Admixed acute and chronic inflammation, fibrosis and abscess formation may be seen. Malakoplakia may be confused with Leydig cell tumor but the latter does not involve tubules and does not show the typical von Hansemann histiocytes. In problematic cases, immunohistochemical markers such as inhibin A and a histiocytic marker (CD68) may be used.

Periorchitis
There are two major forms of periorchitis, meconium periorchitis and nodular (fibromatous) periorchitis.

Meconium periorchitis is an uncommon condition generally associated with the clinical presentation of a scrotal mass during the first few months of life. [26, 27]

Macroscopically, the tunica vaginalis shows yellow/green, granular/nodular tissue. Microscopically, there is typically myxoid tissue with spindle cells, macrophages and foci of calcification. Squames and rare lanugo hairs may be seen. Some accompanying mesothelial hyperplasia may be seen. Confusion with a neoplasm is unlikely at the microscopic level since neonatal tumors are rare with the majority being juvenile granulosa cell tumors.

Nodular (fibromatous) periorchitis also referred to as "fibrous pseudotumor" is an uncommon condition associated with one or more fibromatous masses involving the testicular tunics. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37] The process is usually nodular but occasionally may be a plaque-like lesion coating the testis. Nodular periorchitis may occur at any age and usually present as a mass sometimes associated with hydrocele. There may be a history of infection or trauma. A rare case has been associated with idiopathic retroperitoneal fibrosis.

Solitary or multiple, grey or white nodules and uncommonly diffuse fibrous plaques are present. They may be discrete, confluent and in some examples completely coat the testis. Massive examples may be seen. Rare instances of bilaterality are noted.

At the histologic level, one typically sees dense hyalinized collagen, sometimes associated with focal calcification. Sometimes patchy granulation tissue or chronic inflammation is seen. Differential diagnosis includes inflammatory myofibroblastic tumor and fibromatosis of the paratesticular soft tissue. In some cases, nodular periorchitis may represent a late phase of inflammatory myofibroblastic tumor involving tunics (see later section).

Sperm Granuloma
Sperm granulomas [38, 39, 40, 41, 42, 43] result when there is a granulomatous response to extravasated sperm usually resulting in a nodule. In many cases, this finding is microscopic, however, in some instances, clinical and macroscopic nodules may be produced. While most sperm granulomas are under 1 cm, they have been described up to 4 cm in diameter. Sperm granulomas are usually related to prior vasectomy but other etiologies including prior surgery other than vasectomy, trauma, infection and urinary tract obstruction may be present. Vasitis nodosum is a common accompaniment of sperm granulomas in cases associated with vasectomy (see later section).

At the microscopic level, the appearance of sperm granulomas varies depending on the stage of the process. Early on, neutrophils may be seen but typically epithelioid histiocytes and occasional giant cells may be present. Intact sperm or sperm heads are identified within histiocytes. Eventually, calcification and fibrosis are seen. Sperm granulomas are generally not confused with other types of granulomatous orchitis or epididymitis.

Sclerosing Lipogranuloma
Sclerosing lipogranulomas have been described in the testis, epididymis and spermatic cord. [44, 45, 46, 47] They result from the injection of lipids, generally to enhance the size of the genitalia. While in most instances, a history of exogenous lipid injection is noted, an occasional case has been associated with trauma and rare ones are labeled idiopathic.

Microscopically, empty vacuoles demarcated by fibrous tissue are typically seen. The spaces lack an epithelial lining. Lipid is easily identified using the fat stains. Scattered lymphocytes, plasma cells and eosinophils may be seen. Sometimes the differential diagnosis with adenomatoid tumor is evoked, however, the latter tend to have irregular small tubules lined by attenuated cuboidal cells. Sclerosing lipogranuloma may be associated with scattered atypical cells with hyperchromatic nuclei dispersed in a fibrous background.

There are other rare examples of granulomatous disease simulating tumors including ones caused by foreign material (glove powder) and contrast media as well as cholesterol granulomas involving the tunica vaginalis. [48, 49, 50, 51]

Leydig Cell Hyperplasia
Leydig cell hyperplasia is often caused by elevated levels of luteinizing hormone or chorionic gonadotrophin. The former may be seen in central sexual precocity and androgen insensitivity syndrome and the latter in association with a variety of tumors, especially the germ cell neoplasms. [52, 53, 54]

Gonadotrophin-independent sexual precocity may also be associated with Leydig cell hyperplasia. [55] In other conditions such as Klinefelter syndrome and testicular atrophy associated with aging, ischemic and radiation, Leydig cells may be prominent and sometimes nodular.

Leydig cell hyperplasia may occur as multiple nodules or as a diffuse intertubular process. Occasionally, Leydig cells are even present within seminiferous tubules. Extratesticular collections of Leydig cells may also be identified within tunica albuginea, epididymis or spermatic cord. [56, 57] Perineural involvement may also be seen. In hyperplastic conditions, the Leydig cells have essentially normal cytologic features. Distinction from Leydig cell neoplasms rests in the multiplicity of nodules, the lack of effacement of the tubular architecture and the bland cytoarchitectural appearance.

Sertoli Cell Nodules
Sertoli cell nodules may be identified within a variety of non-neoplastic conditions. [1, 58] In some situations, these represent a hamartomatous change while in others, they are truly hyperplastic.

The Sertoli cell (Pick's) adenoma consists of a nodule of immature Sertoli cells usually in the setting of cryptorchidism. While usually microscopic, occasional nodules may be palpable or grossly visualized. Rounded hyaline bodies encircled by immature Sertoli cells is noted. Occasionally, spermatogonia are present within these immature tubules. Their small size and characteristic morphology allows distinction from the Sertoli cell neoplasms.

In the testicular feminization (androgen insensitivity) syndrome, [59, 60, 61, 62, 63] the gonads (testes) are frequently undescended and may be found in the abdomen (pelvic brim), groin or in other sites such as the labia majora.

These patients have a male genotype but a female habitus and external genitalia with well formed breasts and a short blind vaginal pouch. Commonly, the gonads contain nodular collections of immature Sertoli tubules which may on occasion simulate Sertoli cell neoplasia. In some instances, true sex cord-stromal neoplasms and germ cell tumors may occur in this setting.

The typical gonads of testicular feminization are smaller than normal adult testes and surrounded by thick tunica albuginea. Multiple tan nodules may be seen on the cut surface. Tightly packed immature seminiferous tubules are identified and there is commonly Leydig cell hyperplasia as well.

Testicular Tumor of the Adrenogenital Syndrome (TTAGS)
Patients with the adrenogenital syndrome may develop masses of steroid-type cells in the testis and paratesticular region. [64, 65, 66, 67, 68, 69, 70, 71] While most occur in the testis proper and appear to originate from the hilar region, others are present within tunica albuginea, epididymis or spermatic cord. The steroid cell masses may manifest in childhood or adulthood, usually in the setting of untreated or inadequately treated adrenogenital syndrome, most commonly the salt-losing form associated with 21-hydroxylase deficiency. These tumor-like masses may enlarge after administration of ACTH and decrease in size when the ACTH is suppressed by corticosteroids. Surgical excision is generally not required, however, there is a reported case of a malignant Leydig cell tumor arising in the setting of the adrenogenital syndrome. [2]

These nodules grossly appear to originate from the hilar region and may reach sizes up to 10 cm in diameter. They typically have a lobulated dark brown appearance with fibrous septae. Microscopically, the large pink steroid cells resemble Leydig cells and may grow diffusely or in large nodules separated by hyalinized connective tissue. The cells have abundant eosinophilic cytoplasm and rather bland round to oval nuclei. On occasion, the nuclei may show atypical changes. The cytoplasm contains lipochrome pigment but lacks the typical crystals of Reinke.

The clinical history of an adrenal syndrome, bilaterality and multifocality serve to separate this tumor from the usual Leydig cell neoplasm. The latter typically has a yellow tan coloration and the masses associated with TTAGS are usually brown. The cells tend to be larger with more abundant cytoplasm and crystals of Reinke are not found.

Testicular and paratesticular steroid cell nodules may be found in other unusual situations such as Nelson's syndrome [72, 73, 74] (rapid growth of ACTH-secreting pituitary adenoma after bilateral adrenalectomy for Cushing syndrome) and in some examples of Carney's syndrome. [75]

Hyperplasia of Rete Testis
In atrophic testes, the rete testis may be relatively prominent resulting in an appearance which simulates true hyperplasia. The latter condition is a more expansile nodular or diffuse proliferation, often with a tubulopapillary (adenomatous) morphology. [76, 77, 78] In one series, 3 of 9 patients had a grossly visible solid or cystic mass in the testicular hilum. [76] Hyperplasia of the rete testis may be associated with a variety of conditions including testicular atrophy and may be seen in patients with carcinoma of the prostate gland or breast. The pathogenesis is poorly understood but may relate in part to estrogen excess. In one reported case, a patient received DES and androgen blockade for prostate cancer nineteen months before a diagnosis of adenomatous hyperplasia of the rete testis. [76] Rarely, rete hyperplasia may be associatead with hyaline globules causing diagnostic confusion with yolk sac tumor. [79] Other rare lesions of rete testis which may result in nodule formation include so-called nodular proliferation of calcifying connective tissue, rete hamartoma and a variety of unusual cystic conditions including cystic dysplasia and cystic transformation of rete testis. [78, 80, 81]

Hyperplasia of the rete testis has on occasion been associated with epididymal cribriform change (so-called "hyperplasia"). [1, 2] The latter is characterized by a prominent cribriform pattern of epididymal tubules with an absence of epithelial atypia. This process usually affects ductus epididymis but may involve efferent ductules as well.

Vasitis and Epididymitis Nodosa
Vasitis nodosa is typically identified at the time of vasovasostomy. [82] Grossly, it is associated with a firm nodule at the site of prior vas disruption, and is usually palpable in the scrotum superior to the testis. The lesions are typically small (1 cm or less) and may exude a milky fluid on their cut surface. An analogous condition occurs in the epididymis, so-called epididymitis nodosum. [83]

At the microscopic level, there is a proliferation of small gland-like structures with an irregular (pseudoinvasive) distribution within the muscular wall of vas deferens or epididymis. Involvement of connective tissue and nerves may cause confusion with invasive adenocarcinoma, usually secondary prostatic adenocarcinoma. [84, 85] The bland nature of the tubules, lack of appreciable nuclear atypia and mitotic activity as well as the occasional presence of sperm within lumens is helpful for differential diagnosis. Coexistent sperm granulomas are commonly seen.

Mesothelial Hyperplasia
Mesothelial hyperplasia may have a variety of forms. [86, 87] It is commonly secondary to an inflammatory or irritative process and may be seen in association with hernia sacs and hydroceles. Small tubules, nests and papillae are typically entrapped in a fibroinflammatory background. Occasionally, the hyperplasia may have a prominent papillary appearance and grow along the testicular tunics or involve a hydrocele sac. Such mesothelial cells may show some nuclear enlargement and nucleoli. However, they do not show complex architectural pattern, high grade atypia or tissue infiltration, the latter of which would point to a neoplastic mesothelial proliferation.

On occasion, more nodular collections of mesothelial cells embedded within connective tissue may invoke a differential diagnosis with metastatic adenocarcinoma. [88, 89] Rosai and Dehner have reported several cases of mesothelial hyperplasia associated with moderate degree of nuclear atypia and occasional mitosis. [88] In such cases, the differential diagnosis with other tumors such as metastatic carcinoma require the use of appropriate immunohistochemical studies.

Smooth Muscle Hyperplasia of Testicular Adnexa and Cord
Smooth muscle hyperplasia may result in a pseudoneoplastic intrascrotal mass. [90] Nodular collections of hyperplastic smooth muscle may involve the epididymis or spermatic cord. Additionally, such involvement of the tunica albuginea or vaginalis may also be seen. In one study, 16 patients presented with palpable lesions which ranged in size from 0.6 to 7 cm. The gross appearances were either as discrete nodules or more ill-defined fusiform masses. At the microscopic level, there is an increase in perivascular or interstitial smooth muscle with a nodular or diffuse organization. In some instances, the smooth muscle proliferation blends imperceptibly into the smooth muscle wall of the epididymis or vas deferens. No significant atypia or mitotic activity is noted.

Inflammatory Myofibroblastic (Pseudo) Tumor
Inflammatory myofibroblastic tumors (IMT) affect many sites within the genitourinary tract including urinary bladder, kidney and prostate. [91, 92] Intrascrotal examples of IMT usually involve the spermatic cord but rare examples have also been identified in the epididymis and rete testis. [93, 94, 95, 96, 97, 98, 99]

Most examples of IMT of the paratestis are grossly ill-defined, gray-white nodules which may be gelatinous or firm. Occasionally, hemorrhage and cystic change may be seen. They are generally less than 3 cm but may measure up to 7 cm across.

The microscopic appearance depends on the histologic age of the lesion. Early lesions consist of an irregular proliferation of delicate, stellate and spindle cells embedded in a myxomatous stroma. At times this appearance resembles a "tissue culture". In some cases, a more fascicular morphology is seen and in longstanding examples, areas of dense hyaline fibrosis are identified. Admixed inflammatory cells are common and vascularity may be prominently displayed. While mitoses are commonly present, atypical mitoses are unusual. Immuno- histochemistry shows spindle cells with a myofibroblastic phenotype. [96] Focal keratin positivity may also be identified. Anaplastic lymphoma kinase (ALK-1) staining is also present in a subset of IMT. [100]

The differential diagnosis includes mesenchymal malignancies such as rhabdomyosarcaoma, myxoid leiomyosarcoma, malignant fibrous histiocytoma and liposarcoma. In some cases of testicular torsion and infarction, one may see a rather exuberant proliferation of myofibroblastic and fibroblastic cells resulting in an appearance similar to inflammatory myofibroblastic tumor. [96] As mentioned earlier, there is some overlap between end stage IMT and nodular (fibromatous) periorchitis, and some of the latter may represent "burnt out" IMT involving tunics. While in many cases the IMT probably represents a reactive condition, there is evidence that a subset is clonal. [101, 102, 103] In some sites, a subset of IMT appears to behave in a neoplastic fashion and may give rise to recurrence. There are overlapping morphologies among IMT, inflammatory fibrosarcoma and myxofibrosarcoma. [91, 104]

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