—  SYMPOSIUM #34  —

Testicular Neoplasia
Moderators: Dr. Gregor Mikuz and Dr. Victor E. Reuter

Section 5 - Tumors of the Testicular Adnexa and Paratesticular Tissues

Victor E. Reuter
Memorial Sloan Kettering Cancer Center


The majority of testicular tumors are of germ cell origin, followed by gonadal-stromal neoplasms.
Nevertheless, other neoplasms do occur and, due to their rarity, often present diagnostic dilemmas.
It is beyond the scope of this presentation to discuss all intrascrotal lesions, but rather we will focus on
selected lesions that may present as intrascrotal masses and cause diagnostic challenges.


Lesions of the Rete Testis: Hyperplasia, Adenoma and Adenocarcinoma:
Hyperplasia of the rete testis is a common, usually incidental finding and may be associated with many conditions, including testicular atrophy and as a reaction to adjacent intragonadal neoplasms such as germ cell tumors. [1, 2, 3, 4] It has been associated with other conditions such as chronic hepatic insufficiency and renal dysplasia. Microscopically it is characterized by proliferation of the rete epithelium which forms exaggerated tubulopapillary channels which are interconnecting. The lining epithelium is composed of cuboidal to low columnar cells with banal nuclear cytology. The interanastomosing channels may become cystically dilated but usually merge with normal appearing rete testis. It is important to recognize hyperplasia of the rete when it is associated with germ cell tumors. For example, hyperplastic rete may be confused with a nonseminomatous component in cases of pure seminoma, leading to not only an inaccurate diagnosis but also to improper therapy. Clues to the correct diagnosis lie in the benign nuclear cytology of the hyperplastic rete epithelium and its close association to normal rete testis. Hyperplasia of the rete may also be seen in association to pagetoid spread of in situ germ cell neoplasia. Once again this phenomenon should not be confused with a nonseminomatous germ cell tumor. In other circumstances the hyperplasic rete testis epithelium associated with an invasive germ cell tumor may exhibit intracytoplasmic eosinophilic hyaline globules which likely represent absorbed proteinaceous material. In these cases one should not mistake this finding with yolk sac tumor.

Benign tumors of the rete testis have been described rarely and these have run the spectrum of adenoma, cystadenoma and cystadenofibroma, depending on their cellular components. [2] A distinctive variant has been called Sertoliform Cystadenoma. These circumscribed lesions have measured up to 3 cm in greatest diameter and contain benign appearing columnar tumor cells with basally located nuclei and prominent, regular nucleoli. If associated with a sclerotic stroma the tumor cells may be seen as cords or thin trabeculae. It should be blatantly apparent that this particular lesion may be very difficult to differentiate from a sertoli cell tumor, this observation being more acute since at least one case of sertoliform cystadenoma of the rete testis has been shown to be immunoreactive for inhibin. [3] The correct diagnosis can be made if transition with hyperplastic or normal rete epithelium is present.

Carcinoma of the rete testis is extremely rare with less than 40 bona fide cases described in the literature. [1, 5] In fact, many of the cases may well represent other tumors confused with carcinoma arising in the rete. Lesions that must be considered in the differential diagnosis include a). metastatic carcinoma, b). mesothelioma, and c). ovarian-type carcinoma. Before accepting a tumor as a primary carcinoma of the rete testis, the following conditions must be met.
  • Tumor centered in the hilum of the testis. This may be difficult to asses in masses of considerable size.

  • Transition from normal to neoplastic rete epithelium. Once again, this may be difficult to ascertain in large lesions that have destroyed the normal anatomy of the testicular hilum. One must also be cognizant of the fact that other tumors such as those of germ cell and mesothelial origin may involve the rete secondarily.

  • Absence of a primary elsewhere with similar histology.

  • Morphology incompatible with any other intratesticular, adnexal or scrotal primary.

  • Proper immunohistochemical panel excluding other primaries.
Rete testis carcinoma has been described in all ages but it is classically a tumor of adults with a peak incidence in the seventh decade of life. Most patients present with unilateral painful testicular swelling, with or without an associated hydrocele. Survival is poor with most patients dying within a year of diagnosis.

Grossly these tumors are usually solid but may be at least partially cystic. Microscopically they may exhibit variable patterns of growth, although a tubulopapillary architecture usually predominates. Other histologies include reteform (elongated and compressed tubules), sertoliform (tubular), solid, and biphasic with both epithelial and spindle cell areas. The tumor cells range from cuboidal-to-columnar with eosinophilic-to- basophilic cytoplasm and moderate to marked nuclear atypia.

As previously mentioned rete testis carcinomas are very rare and this diagnosis should be made only after other entities have been excluded. Malignant mesothelioma may have a very similar morphology although it is usually centered along the tunica and is immunoreactive for mesothelial-associated markers such as calretinin and WT-1 rather than those markers associated with adenocarcinoma such as CEA, CD-15 AND B72.3. Testicular Müllerian type tumors may also mimic adenocarcinoma of the rete testis morphologically, but they a more commonly cystic and associated with psammoma bodies. Immunoreactivity for WT-1 and CA-125 is characteristic. Another diagnosis that must be excluded is metastatic carcinoma. Metastases are more commonly bilateral but may occasionally be unilateral. It is usually a manifestation of advanced disease and seen in patients with an established diagnosis of metastatic carcinoma, most commonly from the prostate, lung or gastrointestinal tract.

Tumors of the epididymis are fleetingly rare and will not be discussed, with the exception of clear cell papillary cystadenoma. These lesions may occur sporadically but are usually associated with von Hippel-Lindau disease. [1, 6] Microscopically the lesions exhibit cystic spaces filled with papillary structures lined by cuboidal-to-columnar cells which contain clear cytoplasm, uniform nuclei with occasional inconspicuous nucleoli. Given these morphologic features, it is easy to see why the tumor may be confused with metastatic clear cell carcinoma, particularly of the kidney. A recent study demonstrated that the tumor cells of clear cell papillary cystadenoma are immunoreactive for CK7 but not RCC. Only one of five cases was immunoreactive for CD10. Clear cell renal cell carcinomas should not be immunoreactive for CK7 and CD10 should be positive in a distinct cytoplasmic membranous distribution. At the morphologic level one should remember that clear cell renal cell carcinomas, particularly low grade lesions, will rarely, if ever, have an associated papillary architecture.

Müllerian-Type Epithelial Tumors:
These rare tumors exhibit the full morphologic spectrum seen in their ovarian counterparts; for this reason most authors have used similar nomenclature to describe them. [1, 7, 8, 9, 10, 11, 12, 13] Serous and mucinous tumors are most common and the histology may range from a simple cystadenoma to borderline tumor to frank adenocarcinoma. Endometrioid, clear cell and Brenner tumors have also been described as single case reports. The histogenesis of these tumors is a matter of speculation with some authors suggesting Müllerian metaplasia of the tunica vaginalis and others originate from Müllerian rests in the paratesticular soft tissue. Some authors have raised the possibility of these tumors arising from the appendix testis. Interestingly, we have observed striking Müllerian-type metaplasia in this location in a significant number of orchiectomy specimens removed for various reasons. Some have even demonstrated a small amount of ovarian-type stroma undermining the Müllerian epithelium.

Müllerian-type serous tumors have been described in children and adults with a peak incidence in the sixth decade of life. They usually present with painful testicular swelling. While borderline lesions are commonly cystic, frankly malignant tumors may be predominantly solid. In the latter cases the tumors invariably are infiltrative and these tumors are capable of local recurrence and metastasis. The morphology of these tumors may exhibit the entire spectrum seen in the ovary. We have observed rare examples of borderline tumors with an associated ovarian-type stroma.

Müllerian-type mucinous tumors are rarer than their serous counterparts. They have a similar age distribution and, once again, exhibit the same morphologic spectrum seen in their ovarian counterparts. Some cases have been described as having an intratesticular rather than a paratesticular location. In these cases extreme care should be taken to rule out the possibility of teratoma primarily, but also metastatic carcinoma. Mucinous cystadenomas and borderline tumors are benign while carcinomas may recur and metastasize.

Lesions of Mesothelial origin; Hyperplasia, Adenomatoid tumor and Mesothelioma:
Mesothelial hyperplasia occurs as a result of chronic injury as seen in cases of chronic inflammation of adjacent tissues, hydrocele, hematocele, inguinal hernia and underlying tumors, whether benign or malignant. [1, 3, 14, 15] Microscopically one sees exophytic papillary projections in continuity with the mesothelial lining. Importantly, small tubular structures as well as nests and cords of cells may be present in the superficial submesothelial connective tissue, at times associated with submesothelial fibrosis. Extension into the underlying connective tissue is always superficial with a "horizontal" rather than "vertical" pattern of infiltration. The mesothelial cells will exhibit typical reactive features including binucleation, moderate increase in the nuclear to cytoplasmic ratio, mild hyperchromasia and pleomorphism and minimal mitotic activity. Features characteristic of mesothelioma such as extensive infiltration, solid growth and marked atypia are absent. It has been stated that reactive mesothelium is immunoreactive for Desmin whereas mesothelioma is not. In addition, reactive mesothelial cells are less likely to be immnoreactive for p53. Both will express Calretinin and WT-1. Nevertheless, close examination to the gross and microscopic features of the lesion are likely to lead to the correct diagnosis without the need of immunohistochemistry.

Adenomatoid tumors are a common benign tumor of mesothelial origin. [1, 15, 16, 17] Most are asymptomatic and associated with the head of the epididymis, although some may appear to arise within the testis. They may be large; up to 7 cm but are invariably well circumscribed and round-to-oval in shape. The neoplastic cells may be arranged in nests, tubules, cords and even solid sheets or lining small cystic cavities. The cells may be cuboidal, columnar or flattened. The cytoplasm is usually abundant and eosinophilic and may be vacuolated. The associated stroma may be sparse or abundant and can take on a rather fibrous, myoid and even hyalinized appearance. Rarely these tumors may become infarcted in which case they may be associated with severe pain. [18] Microscopically there may be a marked fibroblastic/myofibroblastic proliferation, mimicking a malignant mesenchymal tumor. In these cases the lesion appears to be infiltrative rather than circumscribed. Because of the diverse cytologic and architectural features which may be encountered in adenomatoid tumors, the differential diagnosis is quite extensive. Depending on the case, one may consider metastatic carcinoma (signet ring cells and tubules), liposarcoma (vacuolated cells), yolk sac tumor (vacuolated cells), mesothelioma (infarction with atypical reactive stroma), Sertoli cell tumor (tubules), and Leydig cell tumor (large eosinophilic cells). Taking note of the localization of the lesion, knowledge of the morphologic diversity which may be encountered and prudent use of immunohistochemistry is useful in establishing a correct diagnosis. As expected, these lesions are likely to be immunoreactive for calretinin and WT-1.

Malignant mesotheliomas arise from the tunica vaginalis and are most commonly seen in the sixth and seventh decades of life. [1, 15, 19, 20, 21, 22, 23] Rare examples have been described in young adults and children. Asbestos exposure has been documented in up to 40% of cases and remains the only established risk factor. A similar relationship with adenomatoid tumor has not been established. Patients usually present with unilateral painful testicular swelling and hydrocele. Gross examination reveals significant thickening of the tunica vaginalis which may also exhibit multiple nodules or masses along its surface. The tunica may be adherent to the underlying testicular tunica albuginea and the tumor mass may extend into the underlying testicular parenchyma. Microscopically the tumor cells have the same features seen in their pleural counterparts, although almost two thirds of cases are pure epithelial with the remaining exhibiting the classic biphasic histology. Rarely will one encounter a pure spindle cell mesothelioma at this site. The tumor cells may take on a complex tubulopapillary architecture superficially, while the invasive component may be composed of tubular structures or solid nest and cords. The tumor cells commonly will exhibit a high nuclear-to-cytoplasmic ratio with moderate-to-marked nuclear atypia and mitotic activity. Necrosis may be present as well as extensive stromal fibrosis. As previously mentioned tumor cells may infiltrate into the testicular hilum and testicular parenchyma, even with intratubular growth. In the former the tumor may mimic a rete testis primary, whereas in the latter the differential diagnosis will include metastatic carcinoma and a germ cell neoplasm such as yolk sac tumor.

Mesotheliomas of the tunica vaginalis have a poor prognosis with almost 50% of patients dying of disease within 2 years of diagnosis. If incompletely excised, they will recur and these inevitably will lead to disease progression and death. Recurrences may be as late as 10 years from diagnosis and for this reason long term clinical follow-up is mandatory.

The literature describes several mesothelial tumors that are solitary, cytologically banal and well circumscribed under the rubric of "well differentiated mesothelioma". [3, 24] Others with similar features but cystic have been called "benign cystic mesothelioma". [25] Great caution must be exercised in making these diagnoses since follow-up have shown the potential for recurrence and progression. While we make a note that mesothelial tumors with these features may be associated with indolent behavior, close clinical follow-up is still warranted. Personally I am very reluctant to make the diagnosis of "benign" mesothelioma.

Metastatic tumors:
As previously discussed, metastatic tumors to the testis, testicular adnexa and paratesticular tissues may mimic primary tumors arising at these sites. [1, 3, 26, 27] The incidence in resected specimens is low, only because metastases to the gonads usually present in a setting of advanced disease where orchiectomy is unwarranted. Nevertheless orchiectomy containing metastatic disease may be encountered in cases of occult primary, intractable pain or unusual clinical presentation such as unilateral disease.

Of the epithelial tumors, the most common to metastasize to the gonad include prostate, lung, gastrointestinal tract (including appendix, stomach and colon), and kidney, although tumors from virtually any site may be encountered. While not an epithelial tumor, it is important to be aware that metastases from malignant melanoma to the gonad (8%) are not rare.

Desmoplastic Small Round Cell Tumor:
Rare cases of this entity have been described in the scrotum in association with the paratesticular region. [1, 28, 29, 30] As in other sites, patients tend to be young and present with a scrotal mass which grossly is tan and firm. Microscopically one encounters the typical "small blue cells" with scant cytoplasm, arranged in tight tubules or solid nests and associated with a dense fibrotic stroma. A tumor-related microvascular proliferation is commonly encountered. Most cases have the typical immunohistochemical profile of cytokeratin, vimentin and desmin positivity with negative staining for S-100 protein, and CD-99. These are aggressive tumors which are likely to have positive regional lymph node or systemic involvement at diagnosis. Despite recent successes with aggressive systemic therapy, prognosis remains poor. [31] The differential diagnosis includes other tumors with "small blue cells" such as lymphoma, rhabdomyosarcoma, and primitive neuroectodermal tumor (PNET). In the rare cases with a tubular architecture, it is conceivable that other tumors such as mesothelioma or sertoli cell tumor may enter in the differential diagnosis.

References:
  1. Ulbright T, Amin M, Young RH. Miscellaneous primary tumors of the testis, adnexa, and spermatic cord; hematopoietic tumors; secondary tumors. In: Rosai J, ed. Atlas of Tumor Pathology. Vol 3rd Series Fascicle. Washington, DC: Armed Forces Institute of Pathology; 1997:235-290.

  2. Jones EC, Murray SK, Young RH. Cysts and epithelial proliferations of the testicular collecting system (including rete testis). Semin Diagn Pathol. Nov 2000;17(4):270-293.

  3. Amin MB. Selected other problematic testicular and paratesticular lesions: rete testis neoplasms and pseudotumors, mesothelial lesions and secondary tumors. Mod Pathol. Feb 2005;18 Suppl 2:S131-145.

  4. Nistal M, Castillo MC, Regadera J, Garcia-Cabezas MA. Adenomatous hyperplasia of the rete testis. A review and report of new cases. Histol Histopathol. Jul 2003;18(3):741-752.

  5. Nochomovitz LE, Orenstein JM. Adenocarcinoma of the rete testis: Consolidation and analysis of 31 reported cases with a review of the literature. J Urol Pathol. 1994;2:1-37.

  6. Aydin H, Young RH, Ronnett BM, Epstein JI. Clear Cell Papillary Cystadenoma of the Epididymis and Mesosalpinx: Immunohistochemical Differentiation From Metastatic Clear Cell Renal Cell Carcinoma. Am J Surg Pathol. Apr 2005;29(4):520-523.

  7. Young RH, Scully RE. Testicular and paratesticular tumors and tumor-like lesions of ovarian common epithelial and mullerian types. A report of four cases and review of the literature. Am J Clin Pathol. Aug 1986;86(2):146-152.

  8. Henley JD, Ferry J, Ulbright TM. Miscellaneous rare paratesticular tumors. Semin Diagn Pathol. Nov 2000;17(4):319-339.

  9. Jones MA, Young RH, Srigley JR, Scully RE. Paratesticular serous papillary carcinoma. A report of six cases. Am J Surg Pathol. Dec 1995;19(12):1359-1365.

  10. McClure RF, Keeney GL, Sebo TJ, Cheville JC. Serous borderline tumor of the paratestis: a report of seven cases. Am J Surg Pathol. Mar 2001;25(3):373-378.

  11. Ulbright TM, Young RH. Primary mucinous tumors of the testis and paratestis: a report of nine cases. Am J Surg Pathol. Sep 2003;27(9):1221-1228.

  12. Alasio TM, Borin J, Taylor K, Bar-Chama N, Unger PD. Intratesticular mucinous cystadenoma: immunohistochemical comparison with ovarian and colonic tissue. Arch Pathol Lab Med. Mar 2005;129(3):399-402.

  13. Tulunay O, Gogus C, Baltaci S, Bulut S. Clear cell adenocarcinoma of the tunica vaginalis of the testis with an adjacent uterus-like tissue. Pathol Int. 2004;54:641-647.

  14. Churg A, Colby TV, Cagle P, et al. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol. Sep 2000;24(9):1183-1200.

  15. Perez-Ordonez B, Srigley JR. Mesothelial lesions of the paratesticular region. Semin Diagn Pathol. Nov 2000;17(4):294-306.

  16. Tammela TL, Karttunen TJ, Makarainen HP, Hellstrom PA, Mattila SI, Kontturi MJ. Intrascrotal adenomatoid tumors. J Urol. Jul 1991;146(1):61-65.

  17. Delahunt B, Eble JN, King D, Bethwaite PB, Nacey JN, Thornton A. Immunohistochemical evidence for mesothelial origin of paratesticular adenomatoid tumour. Histopathology. Feb 2000;36(2):109-115.

  18. Skinnider BF, Young RH. Infarcted adenomatoid tumor: a report of five cases of a facet of a benign neoplasm that may cause diagnostic difficulty. Am J Surg Pathol. Jan 2004;28(1):77-83.

  19. Plas E, Riedl CR, Pfluger H. Malignant mesothelioma of the tunica vaginalis testis: review of the literature and assessment of prognostic parameters. Cancer. Dec 15 1998;83(12):2437-2446.

  20. Attanoos RL, Gibbs AR. Primary malignant gonadal mesotheliomas and asbestos. Histopathology. Aug 2000;37(2):150-159.

  21. Grove A, Jensen ML, Donna A. Mesotheliomas of the tunica vaginalis testis and hernial sacs. Virchows Arch A Pathol Anat Histopathol. 1989;415(3):283-292.

  22. Jaffe J, Roth JA, Carter H. Malignant papillary mesothelioma of tunica vaginalis testis. Urology. Jun 1978;11(6):647-650.

  23. Jones MA, Young RH, Scully RE. Malignant mesothelioma of the tunica vaginalis. A clinicopathologic analysis of 11 cases with review of the literature. Am J Surg Pathol. Jul 1995;19(7):815-825.

  24. Butnor KJ, Sporn TA, Hammar SP, Roggli VL. Well-differentiated papillary mesothelioma. Am J Surg Pathol. Oct 2001;25(10):1304-1309.

  25. Lane TM, Wilde M, Schofield J, Trotter GA. Benign cystic mesothelioma of the tunica vaginalis. BJU Int. Sep 1999;84(4):533-534.

  26. Patel SR, Richardson RL, Kvols L. Metastatic cancer to the testes: a report of 20 cases and review of the literature. J Urol. Oct 1989;142(4):1003-1005.

  27. Datta MW, Ulbright TM, Young RH. Renal cell carcinoma metastatic to the testis and its adnexa: a report of five cases including three that accounted for the initial clinical presentation. Int J Surg Pathol. Jan 2001;9(1):49-56.

  28. Cummings OW, Ulbright TM, Young RH, Del Tos AP, Fletcher CD, Hull MT. Desmoplastic small round cell tumors of the paratesticular region. A report of six cases. Am J Surg Pathol. Feb 1997;21(2):219-225.

  29. Gerald WL, Haber DA. The EWS-WT1 gene fusion in desmoplastic small round cell tumor. Semin Cancer Biol. Jun 2005;15(3):197-205.

  30. Ordonez NG. Desmoplastic small round cell tumor: I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol. Nov 1998;22(11):1303-1313.

  31. Lal DR, Su WT, Wolden SL, Loh KC, Modak S, La Quaglia MP. Results of multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surg. Jan 2005;40(1):251-255.