Section 4 -

Tumor-like and Benign Mimics of Testis and Paratesticular Structures Ferran Algaba Pathology section. Fundacio Puigvert Barcelona, Spain Department of Morphological Sciences, School of Medicine Universitat Autónoma de Barcelona (UAB) Spain

There are many lesions that can imitate a neoformation and its incidence among the masses within the scrotal sac would vary according to the series between 6% and 30% [1, 2] since a tumor-like or benign mimic being confused with true neoplasia depends on many circumstances. These pseudo-neoplastic lesions can be divided into those that form masses that macroscopically imitate neoplasia, but that the microscopic study easily shows that they are not truly neoformations (tumor-like lesions) (Table 1) and those that microscopically imitate a neoplasia, whether or not they form a macroscopic mass (benign mimics) (Table 2). This latter group is the one that causes more problems to the pathologist. From this it is understood that this type of lesions is formed by a group of very diverse processes, and of different etiopathogenies. In order to avoid an exposure with disordered appearance the lesions are grouped according to their principal pathogenesis, with it being impossible to avoid the existence of a miscellaneous group. Tumor-like Testicular and Paratesticular Structures Given that this group of lesions refers to those that macroscopically imitate a neoplasia, and that in turn the anatomical relationship between testicle and paratesticular structures is very narrow, they are not going to be differentiated, since both compartments are sometimes affected. Vascular lesions The majority of the vascular disorders of the masculine gonad are not confused with a tumor because in addition to being characterised by being acute phenomena they usually affect the entire structure; however, upon occasion the vascular lesion is segmentary and can manage to imitate a neoplasia, and they have been described in this way: INTRATESTICULAR HEMORRHAGE, simulating a tumor through sonography, which can be spontaneous [3] as well as being in the context of a anticoagulating treatment [4]. SEGMENTAL TESTICULAR INFARCTION, which clinically can be expressed by a slight local pain without the patient relating it to any acute episode [5]. In some cases, the study of the testicle has shown isolated or systemic vasculitis [6, 7] both in the form of polyarteritis nodosa [8] and of giant cell vasculitis [9] or Wegener granulomatosis [10], having been reported in the literature, up to the year 2000, 83 cases of systemic vasculitis with testicular tumor-like lesion [10]. In other occasions there is a hemopathy (sickle cell disease) [11] and other times only moderate unspecified fibrosis of the surrounding vessels is observed. ORGANIZED TESTICULAR HEMATOCELE and other vaginal hemorrhages are rarely confused with a neoplasia [12], although in cases of long evolution, the thickening with Cholesterol granuloma of the tunica vaginalis can make one suspect a neoplasia [13]. Inflammatory lesions Similar to what was stated for vascular tumor-like lesions, the inflammatory lesions that imitate a neoplasia usually have very special shapes or have an atypical clinical expression. NON-SPECIFIC INFECTIOUS INFLAMMATORY LESIONS with a tumor-like aspect are usually chronic processes that in a sub-clinical manner evolve towards a phenomenon of progressive fibrosis that can be confused clinically [14] and with sonography [15] with a neoformation. Occasionally a testicular and epididymal abscess and chronic xantogranulomatous inflammations in testis [16] or spermatic cord [17] can look like a neoplasia. Very occasionally testicular neoplasia can clinically imitate an acute inflammatory process [18]. SPECIFIC INFECTIOUS INFLAMMATORY LESIONS. The entities of this group that with greatest frequency have been confused with neoplasias are granulomatous diseases and were described in Tuberculosis [19], Brucellosis [20], Syphillis [21] Fungal infections [22] and Parasites [23]. All these lesions are not usually problematic for the pathologist. NON INFECTIOUS INFLAMMATORY LESIONS. This group of tumor-like lesions include different entities among which can be highlighted: (a) Idiopathic granulomatous orchitis, probably of autoimmune etiology, is characterised by tubular granulomas (tubular orchitis) or interstitial granulomas (interstitial orchitis), the presence of intratubular giant cells differentiate this entity from the infectious granulomatous orchitis [24]. (b) Malakoplakia. This lesion is characterised by an inflammatory reaction with eosinophilic macrophages with Michaelis-Gutman bodies, without or very occasional giant cells, the epididymal-testicular involvement is not frequent (only 12% of the genital malakoplakia) [25, 26], it has been correlated with the idiopathic granulomatous orchitis [25] and it is exceptional that it only affects the epididymis [27]. (c) Sarcoidosis. Much rarer than the lesions described above is the testicular location in a systemic sarcoidosis [28], very exceptional is the primary form and in these cases the epididymis is that which is affected more with the testicle being involved by contiguity [29]. MECHONIUM PERIORCHITIS . This is an infrequent situation that can be presented in the first months of life and the majority of times there is a clinical history of some obstetric problem that has caused the passing of mechonium towards the testicular surrounding structures [30]. The macroscopic appearance is a mixoid material with calcified pearls resulting from the calcification of the remains of squamous cells or lanugo hairs [31]. The suspicion of a neoplasia, although in this period of life it is very infrequent, it is a consequence of the scrotal mass and the sonographically detectable calcifications [32]. SPERM GRANULOMA . As its name indicates, this granulomatous lesion with few giant cells is the consequence of the post-vasectomy (40%) or other causes of extravasation of spermatozoa. When it produces a tumor-like lesion, it usually does it in the deferent duct or the epididymis [33], they are usually firm nodes of 0.7 to 4 cm with occasional cysts. Cysts A large part of the cysts with a tumor-like appearance are of the paratesticular structures, but the testicle can occasionally have some cystic lesions that can be confused with a neoplasia. TESTICULAR CYSTS occur in approximately 8%-10% of patients, including those of the tunica albuginea or the parenchyma [34]. The Tunica albuginea cysts do not usually cause any diagnostic problem, unless if they are complex cysts [35], while the Parenchyma testicular cysts can be more difficult to distinguish from a neoplasia and if there is the slightest suspicion of an intracystic content one must suspect a malignant neoplasia [36]. The Epidermoid cyst, which must only be constituted by squamous epithelium represents a special situation that must be fully studied in order to discard any element of teratoma (especially among the adults), or of intratubular germ cell neoplasia since sonographically it is impossible to distinguish both lesions [37, 38], represents 1% of the tumor masses and its origin is unknown. Finally, another cystic variant of interest the Tubular ectasia of the rete testis secundary to obstruction and generally located in the mediastinum testicular area [39], is usually bilaterial and very rarely manages to constitute a Cystic displasia of the rete testis as a congenital lesion within complete testicular parenchyma substitution [40]. EPIDIDYMAL CYSTS AND SPERMATOCELES are relatively frequent and the majority are in relation to the inflammatory processes. The differential diagnosis with other entities are related to its size and similar to the other cystic formations an authentic neoplasia must be suspected in case of observing any content in its interior [41]. SPERMATIC CORD CYSTS. The majority of these cysts do not cause any diagnostic doubts, only the occasional Epidermoid cysts described [42] can simulate a neoplasia. Ectopic tissues ADRENAL CORTICAL RESTS are relatively frequent both in tunica albuginea and in rete testis, epididymis and spermatic cord, with an incidence that oscillates between 3.8% to 15% [43] but it is present in 5-mm nodes that are not palpable, only in case of congenital adrenal hyperplasia or Cushing syndrome these remains can be prominent and appear as a tumor-like lesion [44]. SPLENIC-GONADAL FUSION, as its name indicates, is the fusion of spleen and gonad, is somewhat more frequent in ailments and as can be expected it appears on the left side. In cases of complex malformations, there is an actual cord that joins the normal spleen with the testicle, but in cases without other malformations the splenic node is presented like a tumor-like lesion in the head of the epididymis or upper pole of the testis [45, 46]. Testicular appendages There are five testicular appendages but for surgical pathology only three can be interesting (Appendix testis or hydatid of Morgagni, Appendix epididymis, Paradidymis or organ of Giraldes). These structures are not usually origin of a tumor-like lesion, only in the case of large-sized cysts can be presented as a paratesticular mass [47]. Miscellaneous other lesions FIBROUS PSEUDOTUMORS. This name refers to a fibrosis phenomenon with paucicellular hyalinized collagen in a nodular (single or multiple) or diffuse way of the testicular tunics [48, 49]. Sometimes a node can be free (scrotal moues) [41]. This broad spectrum has received very diverse names [41]. Although radiologically it is not difficult to recognize, upon occasion an intraoperative frozen section becomes necessary. AMYLOIDOSIS The testicular infiltration is usually bilateral in a patient with a prior history of amyloidosis [50], more rarely it is a primary form that by being a cryptorquidic patient simulates a testicular tumor [51]. POLYORCHIDISM or supernumerary testes is a rare condition, easy to recognize, but upon occasion the sonography can be different as the normal testis in this situation can looks like a tumor [52]. Benign Mimics of Testicular and Paratesticular Structures As was said at the beginning, those lesions or cellular changes that macroscopically imitate a neoplasia are included under this name, whether or not they make a macroscopical mass. Given that these changes are usually closely related to the structure of each of the organs, its exposure shall be done according to them. Testicular INFLAMMATORY-REACTIVE LESIONS Although in this group those already described xantogranulomatous orchitis, idiopathic granulomatous orchitis and malakoplakia could be considered, their microscopic confusion with a neoplasia (seminoma for example) is not currently a usual event, which is why it is preferred to include them in the tumor-like lesions. Another different situation is that called lymphocitic orchitis or testicular pseudolymphoma [53, 54] characterized by a lymphocytic and plasmocelular polyclonal reaction that can be confused with a pymphoma, but the immunohistochemical study will show us its polyclonality. Among these idiopathic lesions we can include the Rosai-Dorfman disease, the histological examination of the testicular mass revealed an inflammatory lesion comprising lymphocytes, plasma cells and sheets of pale staining histiocytes, some containing lymphocytes within their ample cytoplasm, suggestive of emperipolesis. S100 immunohistochemistry stained the histiocytes, while ultrastructural examination confirmed emperipolesis [55]. SERTOLI CELL HYPERPLASIA In a series of situations nodular accumulations of Sertoli cells can be found, especially in cryptoquidic testicles, catalogued as Pick's adenomas [56], because of their appearance these should be distinguished from the actual Sertoli cell tumors, and sometimes there are areas that recall Call-Exner bodies, although a deferential diagnosis with a yolk-sac tumor is not usually posed. INTERSTITIAL CELL HYPERPLASIA In testicles with marked tubular atrophy, such as in the Klinefelter syndrome, it is possible to see Leydig cell nodules that must be distinguished from the Leydig cell tumors. Nodules appearing to be Leydig cells are found in the patients with adrenogenital syndrome are usually bilateral and of a large size [57, 58]. HYPERPLASIA OF THE RETE TESTIS The normal rete testis epithelium is flat, but in some hyper estrogenic situation (treatment or hepatic dysfunction) a columnar aspect can acquire and rarely a micropapillary growth of bland cells can be observed, for these reasons almost always the diagnosis of hyperplasia of the rete testis is subjective and only very infrequently a macroscopic expression is present with adenomatous aspect [59, 60]. In some cases there are intracytoplasmic hyaline eosinophilic globules that looks-like a yolk sac tumor, but the no AFP or PLAP expression distinguishes both lesions [61]. Pseudohyperplasia of the rete testis and epithelial reaction in case of germ cell invasion must be differentiated from real hyperplasia of the rete testis [60]. Epididymis Very rarely there are benign mimics in the epididymis and when be observed a cystic occupied lesion a neoplasm most be considered, but some cases of adenomatoid hyperplasia of the rete testis can involve the epididymis and occasionally it may be macroscopic [47]. Tunica albuginea and vaginalis Mesothelial lesions involving the paratesticular region include mesothelial cysts, reactive mesothelial hyperplasia, adenomatoid tumors, benign cystic mesothelioma, well-differentiated papillary mesothelioma, and malignant mesothelioma [62]. The MESOTHELIAL HYPERPLASIA is the most important benign mimic of the testicular tunicas. It is present in the reactive situations as hydrocele or hernia but it is possible to find (microscopically] in older men [63]. The microscopic aspect is epithelial, and rarely spindle cell proliferation can be present. In the differential diagnosis with mesothelioma the bland nucleus, no true invasion and associated inflammatory elements, can be useful [64, 65]. There is published a recent case with "atypical" mesothelial hyperplasia in a site and "well differentiated" mesothelioma in the contalateral [66], This case is an example of the subjective interpretation of some proliferativo lesion of the mesothelio because in some mesothelioma lacks the cellular atipia, in these cases an extensive confluence or prominent infiltration favors the malignant diagnosis. Unfortunately the immunohistochemical reaction of benign and malignant mesothelium is similar [67] and only subtle differences with the intermediate filaments are referred [64]. Spermatic cord The vas deferens and the soft tissues of spermatic cord can have benign mimics. VASITIS NODOSA Is a ductular proliferation, generally after vasectomy [68], with a microglandular aspect with mild nuclear atipia and perineural growth [69] that may be mistaken for malignancy. In some cases a tumor-like aspect can be observed [70]. The frequent hyperplasia of nerve fibers in the adventitia can explain the painful symptoms in some patients [68]. The coincidence with microscopic sperm granulomas and inflammatory reaction can help in the correct diagnosis. An analogous epididymal lesion also occur [71]. We have a similar observation in seminal vesicle. PROLIFERATIVE FUNICULITIS . The inflammation of the spermatic cord usually as the result of the extension of a vasitis, but the soft tissues of the spermatic cord are also the most common site in the male genital tract of the Inflammatory pseudotumor present in many other places [72, 73, 74]. The lesion is ill defined, mixoid and white-grey color with a moderate cellular proliferation with a loose collagen fibers and irregular inflammatory cells infiltration. In some cases a prominent spindle cell proliferation mimics a sarcoma (pseudosarcomatous myofobroblastic proliferation) but no atypical mitosis, low mitotic index, the capillary pattern and the presence of inflammatory cells is against the sarcoma diagnosis. unfortunately the immunohistochemistry is partly helpful. Miscellaneous other lesions EMBRYONIC REMNANTS . The presence of seminiferous tubules within the tunica albuginea [75], Leydig cells in rete testis, albuginea, spermatic cord, or within sclerotic tubules. Prostate gland in the epididymis [76] and special circumstances with muscular hypertrophy [77] can mimics a neoplasia. But in spite of all these tumor-like and benign mimics we most remember that the patient with one o these lesions can have a concomitant or ulterior true neoplasm. Table 1: Tumor-like Lesions of Testis and Paratesticular Structures VASCULAR LESIONS Intratesticular hemorrhage Segmental testicular infarction Organizad testicular hematocele Cholesterol granuloma of the tunica vaginalis INFLAMMATORY LESIONS Non-specific infectious inflammatory lesions Specific infectious inflammatory lesions Non-infectious inflammatory lesions Idiopathic inflammatory lesions Idiopathic granulomatous orchitis Testicular malakoplakia Testicular sarcoidosis Meconium periorchitis Sperm granuloma CYSTS Testicular cysts Albuginea cysts Parenchymal cysts (Epidermoid cysts) Rete-testis cysts- Cystic displasia of the rete testis Epididymal cysts and Spermatoceles Spermatic cord cysts. ECTOPIC TISSUES Adrenal cortical rests Spleno-gonadal fusion TESTICULAR APPENDAGES MISCELLANEOUS OTHER LESIONS Fibrous pseudotumors; (Fibromatous periorchitis-Nodular periorchitis) Amyloidosis Polyorchididm Sclerosing lipogranuloma Table 2: Benign Mimics of Testis and Paratesticular Structures TESTICULAR Inflammatory-reactive lesions Lymphocitic orchitis (Testicular pseudolymphoma) Rosai-Dorfman disease Sertoli cell hyperplasia Pick adenoma Hamartomatous proliferation testicular feminization syndrome Interstitial cell hyperplasia Leydig cell hyperplasia Testicular "tumor" of the adrenogenital syndrome Hyperplasia of the rete testis EPIDIDYMIS Adenomatoid hyperplasia TUNICAS ALBUGINEA-VAGINALIS Mesotelial hyperplasia SPERMATIC CORD Vasitis nodosa Inflammatory pseudotumor (Funiculitis proliferans) MISCELLANEOUS OTHER LESIONS References Collins DH, Pugh RC.: Classification and frequency of testicular tumors. Br. J. Urol. 1964; 36 (Suppl): 1-11. 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