Printer Friendly

Difficult differential diagnoses in testicular pathology.

The incidence of testicular tumors has been increasing in recent decades, with 8480 new cases predicted in 2010 in the United States. (1,2) It is estimated that the lifetime risk for testicular cancer for males born in the United States from 2005 to 2007 is 1 in 271. (3) Testicular cancers are the most common solid malignancy and the second leading cause of cancer death in young men. (2,3) However, many general pathologists may have limited experience with testicular tumors because they account for only approximately 1% of human malignancies. Pathologists must be aware of important diagnostic pitfalls in testicular neoplasia that could affect patient management.

Testicular tumors can be broadly classified into germ cell tumors, sex cord-stromal tumors, mixed germ cell/sex cord-stromal tumors, and miscellaneous tumors. They are treated differently. Testicular germ cell tumors (TGCT) account for more than 95% of all testicular malignancies and are highly curable with currently available treatment, especially if the disease is in the early stages. Seminomas are sensitive to both radiation and chemotherapy, whereas nonseminomatous TGCT respond to chemotherapy only. In contrast, malignant sex cord-stromal tumors are resistant to both of these modalities and are generally treated with orchiectomy and retroperitoneal lymphadenectomy. The most common and most significant challenges in testicular pathology are differential diagnoses between seminoma and nonseminomatous TGCT, as well as between TGCTs and testicular tumors of non-germ cell type, particularly the sex cord-stromal tumors. Two recent reviews summarized important diagnostic pitfalls and workup recommendations in testicular pathology in 2008 and 2010, respectively. (4,5) In this article, we will revisit some of these problems, as well as discuss some new ones, and incorporate additional information, including the application of recent immunomarkers, to these problematic differential diagnoses.

"ATYPICAL" SEMINOMA VERSUS EMBRYONAL CARCINOMA

Seminoma and embryonal carcinoma are closely related entities. Seminoma cells morphologically and immunophenotypically resemble embryonic germ cells (primordial gonocytes/gonocytes), whereas embryonal carcinoma cells resembles pluripotent stem cells from the inner cell mass of the blastocyst. (6,7) Not unexpectedly, both seminoma and embryonal carcinoma express markers of "sternness," including OCT3/4 (POU5F1) and NANOG. (8-12) In the current histogenetic model of TGCTs, embryonal carcinoma may arise from seminoma through transformation. (6,7,13,14) Despite these close relationships, however, they are treated differently. Seminomas are sensitive to both radiation and cisplatin-based chemotherapy and are thus treated with radiation in early stage tumors and chemotherapy in more advanced disease. Embryonal carcinomas are sensitive to chemotherapy but resistant to radiation. The accurate distinction of these 2 tumors is, therefore, of great importance. An additional consideration regarding the correct recognition of these 2 entities is that the percentage of embryonal carcinoma in a mixed TGCT is considered a prognostic indicator and an important consideration in deciding whether patients who have clinical stage I disease are good candidates for surveillance management protocols. (15-17)

One can usually separate these 2 entities based on differences in tumor architecture and cytologic features. Seminomas are typically composed of uniform, round to polygonal cells with pale to clear cytoplasm and distinct cell membranes arranged in solid sheets that are divided by lymphocyte-bearing fibrovascular septa and have admixed granulomata. (18) Embryonal carcinomas usually consist of anaplastic tumor cells with larger, crowded, irregular nuclei; more-dense, amphophilic cytoplasm; and less-distinct cell membranes. The cells are more cohesive than they are in seminoma and may be arranged in trabecular, glandular, papillary, and solid patterns. In our experience, 2 variants of seminoma may closely mimic embryonal carcinoma on routine stains. One is seminoma having increased nuclear atypia, darker cytoplasm, and increased cell crowding (Figure 1, A). (18) These features may be diffusely present in some "atypical" seminomas (18) or occur focally within separate nodules of a single tumor. Similar findings are often identified in areas surrounding small, punctate foci of tumor necrosis in typical seminomas, (4,18) and in that circumstance, these findings are likely reflective of ischemia-induced changes. Helpful light microscopic clues that an "atypical seminoma" is still a seminoma include its retention of the typical tumor architecture and lymphocytic reaction and the absence of any distinct epithelial differentiation. Although pathologists must be aware that occasional seminomas may display unusual or atypical features, we do not recommend that any term other than seminoma be used in a diagnostic report for such cases; otherwise, clinical confusion will result.

The other mimicker is the tubular variant of seminoma, in which the tumor architecture resembles gland-forming embryonal carcinoma yet retains the cytologic features of seminoma (Figure 1, B). (19-21) The tubular structures in these seminomas are formed by pseudoglandular arrangements in solid sheets of tumor cells, with no real glandular lumens, similar to embryonal carcinoma (Figure 1, C).

When the light microscopic findings in a seminoma leave the pathologist with a sense of unease regarding the possibility of embryonal carcinoma, a panel of immunostains that are available in many laboratories can be performed, including AE1/AE3 cytokeratin, CD30, CD117, and podoplanin (D2-40). (22-25) The AE1/AE3 and CD30 stains are diffusely positive in embryonal carcinoma and are negative (or focally positive) in seminoma, whereas CD117 and podoplanin (D2-40) are diffusely positive in seminoma and negative (or focally positive) in embryonal carcinoma. More-recent markers that also have utility in this differential diagnosis, but that may not be as readily available, are the transcription factors SOX2 and SOX17. SOX2 is expressed in the nuclei of embryonal carcinoma but is not expressed in those of seminoma, (26-29) whereas SOX17 shows nuclear reactivity in seminoma but not in embryonal carcinoma. (27,29)

SEMINOMA VERSUS YOLK SAC TUMORS

It is similarly important to distinguish seminoma from yolk sac tumors because yolk sac tumors, like embryonal carcinoma, are radioresistant. Seminoma may resemble a yolk sac tumor by forming tubular and microcystic growth patterns. (21,30) As mentioned above, the tubular structures in seminoma are pseudoglands formed by discohesion of tumor cells in a nested arrangement. In contrast, a yolk sac tumor grows in separated or merged true glands with well-defined lumens and sharp, luminal borders. Microcystic structures in seminoma are typically formed by edema, frequently with detached tumor cells floating in the edema fluid, although, on occasion, they may appear empty (Figure 1, D). The spaces usually have irregular luminal outlines and, most importantly, are lined by the typical polygonal tumor cells characteristic of seminoma. In comparison, microcystic structures in a yolk sac tumor are formed by either myxoid stroma or empty vacuoles, and the tumor cells bordering microcystic spaces are characteristically flattened (Figure 1, E), in contrast to the polygonal lining cells of microcystic seminoma.

Conversely, a yolk sac tumor may mimic seminoma by growing in solid sheets of cells, with clear cytoplasm and distinct cell membranes similar to seminoma. (31) However, yolk sac tumor cells are more pleomorphic than seminoma cells, and the solid variant of yolk sac tumor is almost always associated with other, more-distinctive patterns if a sizable specimen is available for examination, (32) although this is not always the case, especially when dealing with metastatic lesions. Of additional help, solid-pattern yolk sac tumor frequently contains intracytoplasmic hyaline globules and extracellular basement membrane deposits (Figure 1, F), (32) features that are rarely found in seminomas. (33) Seminoma is associated with fibrous septa containing lymphocytes and sometimes granulomas, whereas lymphocytic infiltrates occur in only 17% of solid yolk sac tumors, (32) and granulomas are rare.

In challenging cases, a concise panel of immunomarkers including OCT3/4, AE1/AE3, and glypican-3 can separate these 2 entities. (8,22,32,34-36) The first marker labels seminoma but not solid yolk sac tumor, and the latter 2 are positive in solid yolk sac tumors but negative (glypican-3) or mostly negative (AE1/AE3) in seminomas. We have found a-fetoprotein (AFP) much less sensitive than glypican-3 in solid yolk sac tumors, with both markers being 100% specific in the differential diagnosis versus seminoma. (32) Even given the improved sensitivity of glypican-3 over AFP for solid yolk sac tumor, the intensity of staining in solid patterns of yolk sac tumor is less than it is in the other yolk sac tumor patterns. We have not found CD117 helpful in this differential diagnosis because it stained 59% of solid yolk sactumorsaswellasseminomas. (32)

SEMINOMA VERSUS CLEAR CELL SEX CORD-STROMAL TUMOR

Sex cord-stromal tumors, mainly Sertoli cell tumor and Leydig cell tumor, can show solid growth patterns with diffuse clear cell change that resemble seminoma. (37) Benign sex cord-stromal tumors are cured by orchiectomy. Malignant sex cord-stromal tumors do not respond to radiation or chemotherapy, unlike seminomas; they are often treated with retroperitoneal lymphadenectomy. (38) Clear cell sex cord-stromal tumors lack the thin fibrous septa and granulomatous reaction that are commonly seen in seminoma, although they may show a prominent lymphocytic reaction that complicates the differential diagnosis. (37) The clear cytoplasm of sex cord-stromal tumors is caused by lipid accumulation that may impart a microvesicular to macrovesicular pattern at high magnification. This is especially apt to be the case in Leydig cell tumors with clear cell change but may also be identified in occasional Sertoli cell tumors (Figure 2, A). In contrast, clear cytoplasm in seminoma is due to abundant glycogen, which gives the cytoplasm a "water-clear" appearance (Figure 2, B). Nonetheless, some clear cell sex cord-stromal tumors also have "water-clear" cytoplasm and a solid, nested to diffuse arrangement strongly reminiscent of seminoma (Figure 2, C). Probably the most helpful distinguishing feature is the differing nuclear appearance. Compared with seminoma cells, sex cord-stromal tumor cells usually do not have polygonal nuclei, prominent nucleoli, and frequent mitotic figures. Instead, their nuclei are usually smaller, are round to oval to irregular, and vary more than do those of seminomas, sometimes having intranuclear cytoplasmic inclusions (Figure 2, D). Of additional help, sex cord-stromal tumors have no association with intratubular germ cell neoplasia, unclassified type (IGCNU), whereas IGCNU is identified in the tubules adjacent to seminomas in 90% of cases. (39) Immunophenotypically, sex cord-stromal tumors are often positive for inhibin, Melan-A, and calretinin and are uniformly negative for fetal germ cell and other markers that stain seminoma, including OCT3/4, SALL4, PLAP, CD117, and D2-40. (8,9,24,40-42) Note that inhibin consistently stains Leydig cell tumors but is positive in only 30% to 80% of Sertoli cell tumors; therefore, a negative inhibin stain does not exclude a Sertoli cell tumor. (40,41)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

TERATOMA VERSUS DERMOID CYST AND EPIDERMOID CYST

Epidermoid cysts are relatively uncommon, and dermoid cysts are rare. Both need to be distinguished from the usual teratoma of the adult testis because they are uniformly benign, whereas the usual postpubertal teratoma may have associated metastases of either teratomatous or nonteratomatous germ cell tumors. (43,44) We feel that dermoid cysts likely develop from benign germ cells with retained embryonic properties, probably similar to pre-pubertal testicular teratomas and ovarian teratomas. Epidermoid cysts either have a similar histogenesis or may possibly arise from displaced metaplastic mesothelial cells. Usual testicular teratoma of the postpubertal type, in contrast, develops from malignant germ cells (IGCNU), usually indirectly, by differentiation from other types of invasive germ cell tumors. It, therefore, represents a differentiated, malignant neoplasm that forms through a process of "maturation" from more primitive types of germ cell tumors.

Grossly, dermoid cysts and epidermoid cysts are unilocular cystic masses filled with keratinous material that may have a laminated appearance (Figure 3, A). Dermoid cyst may have a mural protuberance in the wall and contain hair. In comparison, teratoma often presents as a multilocular solid-cystic complex mass, and we have never grossly identified hair in a usual teratoma of the adult testis. Microscopically, a dermoid cyst is lined by squamous epithelium and skin adnexal structures (Figure 3, B). Prominent lipogranulomas may be seen in the testis, presumably as a reaction to sebaceous material leaked from the cyst contents (Figure 3, C). In addition to the cutaneous-type components, dermoids may have components of other tissues, including glandular elements, adipose tissue, cartilage (Figure 3, B), and bone, further mimicking postpubertal teratoma. (45) An epidermoid cyst is a simple cyst lined by squamous epithelium, with no adnexal structures or other tissue types (Figure 3, D). (46,47) In contrast, a teratoma often contains multiple cysts, lined by glandular or squamous epithelium, neuroectodermal tissue, noncystic glands, and mesenchymal tissues, such as adipose tissue and cartilage (Figure 3, E). A critical feature of both dermoid and epidermoid cysts, which distinguishes them from the usual teratoma, is the absence of IGCNU in the adjacent testis (Figures 3, C and D), whereas IGCNU occurs with a usual teratoma in 90% of the cases (Figure 3, F). (48) Extreme care is needed when diagnosing dermoid cyst or epidermoid cyst in postpubertal testes. The presence of IGCNU (or other germ cell tumor elements) excludes a dermoid cyst and an epidermoid cyst and indicates that the lesion is a usual teratoma. Additional helpful features that aid in the distinction of the dermoid cyst from the usual teratoma include the presence in a usual teratoma of cytologic atypia of its elements and associated testicular atrophy with impaired spermatogenesis. Dermoid cysts lack cytologic atypia, and in most cases, the adjacent testis has a normal appearance with active spermatogenesis (Figure 3, C), although there may be compressive atrophy in the parenchyma immediately adjacent to the cyst. Isochromosome 12p by cytogenetic studies can be confirmatory in difficult cases. It is present in most postpubertal teratomas, but not epidermoid cysts. (49) Based on light microscopic observations of dermoid cysts, we anticipate that they would also lack i(12p) or other forms of 12p amplification, but that has not, to our knowledge, been studied yet. As a general marker for TGCT, SALL4 is frequently expressed in teratoma, (41) but its expression in dermoid and epidermoid cysts is, to our knowledge, unknown.

[FIGURE 3 OMITTED]

REGRESSED TGCT VERSUS NONSPECIFIC SCAR

Testicular germ cell tumors are one of the most common human neoplasms to undergo spontaneous regression, which can occur in all types, although regressed seminoma is the most frequent. (50) Many "pure" teratomas are, in fact, mixed germ cell tumors with the nonteratomatous component spontaneously regressed. In many cases, patients present with distant metastases of germ cell tumor and are subsequently found to have evidence of a regressed germ cell tumor in the testis. For patients who present with a scarred nodule in the testis in the absence of metastases, one must distinguish a completely regressed TGCT, which has metastatic potential, from nonspecific scars that result from injuries or vascular lesions. On gross examination, completely regressed or "burnt-out" TGCT often presents as a discrete nodule (Figure 4, A) or a stellate scar in the testicular parenchyma. Microscopically, the background testicular tissue often shows dysgenetic features, including impaired spermatogenesis, tubular atrophy, and microliths. IGCNU and Leydig cell hyperplasia are frequently present. Within the burnt-out fibrotic nodule, it is common to see clusters of hemosiderin within macrophages (Figure 4, A), hyalinized "ghost" tubules, many small vessels, and lymphoplasmacytic infiltrates (Figure 4, B). (50) Calcifications within the scarred focus are less common, but if they are large and coarse and have an intratubular configuration (Figure 4, B), they are pathognomonic of a regressed germ cell tumor. They represent dystrophic calcification that developed in the necrotic debris that commonly occurs in the comedocarcinomalike pattern of intratubular embryonal carcinoma. The other finding that we consider diagnostic of a regressed germ cell tumor is the presence of IGCNU associated with a scar. Unfortunately, these 2 diagnostic findings (coarse intratubular calcifications and IGCNU) occur in only somewhat more than one-half of the cases; therefore, the constellation of other findings must often be relied on to support or detract from the possibility of a regressed germ cell tumor.

[FIGURE 4 OMITTED]

NONNEOPLASTIC ATYPICAL GERM CELLS VERSUS IGCNU

Coexisting IGCNU is a key feature in distinguishing TGCT from many mimickers. IGCNU is present in the seminiferous tubules adjacent to approximately 90% of TGCTs. (39) If IGCNU is present in testicular biopsies (usually received for fertility evaluation), orchiectomy or radiation treatment is indicated. Men with IGCNU have a 50% chance of developing a TGCT in 5 years, (51) and the current viewpoint is that eventually all patients will develop a germ cell tumor if the follow-up interval is sufficiently long. IGCNU can usually be diagnosed based on the histologic features alone. IGCNU cells resemble seminoma cells morphologically. They are located at the basilar aspects of seminiferous tubules lacking spermatogenesis, often in a patchy distribution. These cells usually stand out at low magnification because they have a clear cytoplasm, and their nuclei are approximately 1.5 times larger than the nuclei of the background spermatogonia. At high magnification, IGCNU cells have enlarged, hyperchromatic, polygonal nuclei with clumped chromatin and frequently "squared-off," flat edges; thickened nuclear membranes; 1 or 2 prominent nucleoli; and distinct cell membranes (Figure 3, F).

[FIGURE 5 OMITTED]

Atypical germ cells, some of which may simulate IGCNU, can be seen in the testes of patients with cryptorchidism, hypofertility or infertility, sex development disorders, and, sometimes, in the background testis of pediatric TGCTs. They are germ cells with delayed maturation (in the pediatric cases), abnormal germ cells reflective of testicular maldevelopment, mature spermatogonia with reactive changes to an adjacent mass lesion, or atypical germ cells of unknown significance. Their features may include enlarged nuclei (Figures 5, A though C), multinucleation (Figures 5, B and D), nucleolar prominence (Figure 5, C), or nuclear hyperchromasia in the absence of nucleolar prominence (Figures 5, A, B, and D). Many lack large nucleoli and coarsely clumped chromatin, and some lack clear cytoplasm (Figure 5, A). They may or may not be present in tubules with impaired spermatogenesis, whereas IGCNU usually occurs in tubules lacking spermatogenesis. Some atypical germ cells, although not neoplastic precursors themselves, may develop secondarily to factors that are also important in the pathogenesis of germ cell tumors. (52,53) This is supported by the frequent finding of hypertrophic and multinucleated spermatogonia in the parenchyma adjacent to germ cell tumors, (52) usually in conjunction with other "dysgenetic" changes. Atypical germ cells may, therefore, imply that the patient is at some hypothetical increased risk for the subsequent development of a germ cell tumor, but the magnitude of such risk is not known, but certainly is much less than that of IGCNU, emphasizing the importance of this distinction.

[FIGURE 6 OMITTED]

Germ cells with delayed maturation have been described in the gonads of patients with undervirilization syndromes (usually complete or partial androgen insensitivity syndrome or 17[beta]-hydroxysteroid dehydrogenase deficiency). (54) They may closely resemble IGCNU cells, but, in contrast to true IGCNU, they lack basilar location and segmental distribution. (54) In our experience, analogous cells may be encountered in pediatric cases outside the context of a disorder of sex development, with nonbasilar localization (Figure 5, C). In one study, which examined biopsies from prepubertal cryptorchid testes taken at the time of orchiopexy, cells that were "morphologically identical" to IGCNU, including positive staining for placental alkaline phosphatase, were identified in 22 of 440 patients (5%). (55) These cells, however, were not located at the base of the tubules but were distributed randomly. None of the 15 patients with follow-up (median duration, 21 years) had any subsequent evidence of testicular cancer. In our opinion, these cases likely reflect germ cell maturation delay, given their different behavior compared with IGCNU. It is entirely possible that, on occasion, germ cells with maturation delay can progress to an invasive tumor, which is the likely scenario in one case report. (53,56) Again, however, the magnitude of risk for progression appears to be greatly reduced from that of IGCNU.

Fetal gonocyte markers, including OCT3/4, NANOG, placental alkaline phosphatase (PLAP), podoplanin (D2-40), and stem cell factor (SCF), stain IGCNU but not normal, hypertrophic, multinucleated, or reactively enlarged spermatogonia. However, most of these markers may be positive in germ cells with maturation delay, indicating the need for caution before interpreting a positive immunostain for such a marker as evidence for IGCNU. It has been claimed that SCF can potentially be used to distinguish IGCNU from nonneoplastic germ cells with delayed maturation, (57) although that observation still needs more study to be fully validated. As matters now stand, a pathologist should require a seminoma-like morphology, basilar localization, and nondiffuse distribution (the latter primarily in pediatric cases) before concluding that a given atypical germ cell proliferation represents IGCNU. Positive staining for the usual markers of IGCNU is supportive, but not sufficient, for the diagnosis in the absence of the other morphologic features.

[FIGURE 7 OMITTED]

REAL VERSUS PSEUDOVASCULAR INVASION IN GERM CELL TUMORS

Lymphovascular invasion is one of the adverse prognostic factors for TGCTs. The presence of lymphovascular invasion in an organ-confined TGCT changes the tumor stage from pT1 to pT2. (58) Additionally, lymphovascular invasion is considered a relative contraindication for surveillance management in patients with clinical stage I nonseminomatous germ cell tumors because of an increased risk of clinically occult metastases or relapse on surveillance protocols. (59,60) There are several mimickers of lymphovascular invasion, including artifactual tumor cell carryover, intratubular tumor and seminoma and embryonal carcinoma with retraction artifact. In sections of spermatic cord, histiocytic aggregates in blood vessels can sometimes lead to a false diagnosis of tumor thrombi (Figure 6, A). The best locations to identify lymphovascular invasion are at the periphery of the tumor and in the tunica albuginea adjacent to the tumor. Features of intravascular tumor cell aggregates that support the diagnosis of a real tumor thrombus include a smooth outline, attachment to the endothelium, and admixture with fibrin (Figure 6, B). In contrast, pseudovascular invasion typically consists of discohesive collections of tumor cells "floating" in vascular lumens (Figure 6, C). This is a result of knife implantation of tumor cells into tissue spaces and is often seen in conjunction with "buttered-on" tumor implants on tissue surfaces (Figure 6, D). A positive stain for vascular markers, including CD31, CD34, and D2-40, can help establish lymphovascular invasion as opposed to intratubular tumor if there is ambiguity at the light microscopic level. Cases of intravascular TGCT versus histiocytes can be stained with germ cell tumor markers and CD68, although, in most cases, that is not necessary. Even with our best efforts, some cases have indeterminate findings for lymphovascular invasion. In that circumstance, we note the ambiguous findings in our report but stage those cases as pT1 because the presence of vascular invasion was not established.

SERTOLI CELL NODULE VERSUS SERTOLI CELL TUMOR

Sertoli cell nodules, sometimes termed Pick adenomas, are nonneoplastic, probably self-regressing lesions that are usually incidental findings in either cryptorchid or normally descended testes. (61-64) Although they usually present as incidental microscopic findings, Sertoli cell nodules may form macroscopic testicular masses up to 1 cm or greater, which present clinically as either palpable masses or ultrasonographic lesions in the testis of a patient being investigated for nonspecific testicular symptoms, such as pain. (63) Macroscopic Sertoli cell nodule is a source of potential confusion with Sertoli cell tumor, (63) and that distinction is important because Sertoli cell tumors have malignant potential. Sertoli cell nodules are typically small (<1 cm), even those that are macroscopic, and are composed of small, bland, immature (fetal-type) Sertoli cells forming tubules, cords, and cribriform nests (Figure 7, A). The immature Sertoli cells are frequently admixed with scattered spermatogonia (Figure 7, B), and in patients also having germ cell tumors, there may be intermingled IGCNU (Figure 7, C). The Sertoli cells are usually associated with prominent basement membrane material that forms hyaline globules and interconnecting hyaline trabeculae (Figure 7, A and B). In some cases, calcifications develop in the hyaline matrix (Figure 7, C). In contrast, Sertoli cell tumors are usually larger (>1 cm), composed of cells that are larger than fetal-type Sertoli cells, often with increased pleomorphism, mostly lack associated spermatogonia, and typically do not have prominent basement membrane deposits (Figure 7, D). Conspicuous mitotic figures may occur in some Sertoli cell tumors, and approximately 10% exhibit malignant behavior. (65,66) An additional consideration for the Sertoli cell nodules that have been colonized by IGCNU is gonado blastoma, especially when there is matrix calcification. Clinical information is very helpful in this situation because gonadoblastomas occur in patients with disorders of sex development (intersex syndromes), and the patients exhibit features of those conditions. Additionally, gonadoblastoma is usually a larger lesion than Sertoli cell nodule. Of key importance is the absence of dysgenetic features in the testis of patients with Sertoli cell nodules, unlike those with gonadoblastoma. Furthermore, the IGCNU cells in Sertoli nodules are often patchily distributed, whereas they are more diffuse in gonadoblastomas. Although both lesions progress to invasive germ cell tumors, their distinction remains important because of the much higher likelihood of bilateral involvement in patients with gonadoblastoma.

CONCLUSIONS

In this article, we summarized our experience with clinically important diagnostic pitfalls in testicular pathology. The Table provides important morphologic features and key ancillary tools that can be used to solve these diagnostic dilemmas. In most cases, an accurate diagnosis can be achieved based on careful examination of the morphology of the lesion and its surrounding tissue; for particularly problematic cases, a selective panel of immunostains provides diagnostic assurance.

References

(1.) American Cancer Society. Cancer facts & figures 2010. http://www.cancer. org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010. Accessed September 9, 2011.

(2.) Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004; 54(1):8-29.

(3.) National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) program. http://seer.cancer.goV/statfacts/html/testis.html#incidence-mortality. Accessed September 20, 2011.

(4.) Ulbright TM. The most common, clinically significant misdiagnoses in testicular tumor pathology, and how to avoid them. Adv Anat Pathol. 2008; 15(1): 18-27.

(5.) Young RH. The problematic testicular tumor. Int J Surg Pathol. 2010; 18(3)(suppl):149S-155S.

(6.) Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nature Rev Cancer. 2005; 5(3):210-222.

(7.) Gilbert D, Rapley E, Shipley J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nature Rev Cancer. 2011; 11(4):278-288.

(8.) Looijenga LH, Stoop H, de Leeuw HP, et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003; 63(9):2244-2250.

(9.) Jones TD, Ulbright TM, Eble JN, Cheng L. OCT4 staining in testicular tumors: a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol. 2004; 28(7):935-940.

(10.) Hoei-Hansen CE, Almstrup K, Nielsen JE, et al. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology. 2005; 47(1):48-56.

(11.) Hart AH, Hartley L, Parker K, et al. The pluripotency homeobox gene NANOG is expressed in human germ cell tumors. Cancer. 2005; 104(10):2092 2098.

(12.) Cheng L, Sung MT, Cossu-Rocca P, et al. OCT4: biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol. 2007; 211(1): 1-9.

(13.) Oosterhuis JW, Castedo SM, de Jong B, et al. Ploidy of primary germ cell tumors of the testis: pathogenetic and clinical relevance. Lab Invest. 1989; 60(1): 14-21.

(14.) Srigley JR, Mackay B, Toth P, Ayala A. The ultrastructure and histogenesis of male germ neoplasia with emphasis on seminoma with early carcinomatous features. Ultrastruct Pathol. 1988; 12(1):67-86.

(15.) Wishnow KI, Johnson DE, Swanson DA, et al. Identifying patients with low-risk clinical stage I nonseminomatous testicular tumors who should be treated by surveillance. Urology. 1989; 34(6):339-343.

(16.) Moul JW, McCarthy Wf, Fernandez EB, Sesterhenn IA. Percentage of embryonal carcinoma and of vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer. Cancer Res. 1994; 54(2):362364.

(17.) de Riese WT, de Riese C, Ulbright TM, et al. Flow-cytometric and quantitative histologic parameters as prognostic indicators for occult retroperitoneal disease in clinical-stage-I non-seminomatous testicular germ-cell tumors. Int J Cancer. 1994; 57(5):628-633.

(18.) Tickoo SK, Hutchinson B, Bacik J, et al. Testicular seminoma: a clinicopathologic and immunohistochemical study of 105 cases with special reference to seminomas with atypical features. Int J Surg Pathol. 2002; 10(1):23 32.

(19.) Young RH, Finlayson N, Scully RE. Tubular seminoma: report of a case. Arch Pathol Lab Med. 1989; 113(4):414-416.

(20.) Zavala-Pompa A, Ro JY, El-Naggar AK, et al. Tubular seminoma: an immunohistochemical and DNA flow-cytometric study of four cases. Am J Clin Pathol. 1994; 102(4):397-401.

(21.) Ulbright TM, Young RH. Seminoma with tubular, microcystic, and related patterns: a study of 28 cases of unusual morphologic variants that often cause confusion with yolk sac tumor. Am J Surg Pathol. 2005; 29(4):500-505.

(22.) Niehans GA, Manivel JC, Copland GT, Scheithauer BW, Wick MR. Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer. 1988; 62(6):1113-1123.

(23.) Ferreiro JA. Ber-H2 expression in testicular germ cell tumors. Hum Pathol. 1994; 25(5):522-524.

(24.) Izquierdo MA, Van der Valk P, Van Ark-Otte J, et al. Differential expression of the c-kit proto-oncogene in germ cell tumours. J Pathol. 1995; 177(3):253-258.

(25.) Idrees M, Saxena R, Cheng L, Ulbright TM, Badve S. Podoplanin, a novel marker for seminoma: a comparison study evaluating immunohistochemical expression of podoplanin and OCT3/4. Ann Diagn Pathol. 2010; 14(5):331-336.

(26.) Santagata S, Ligon KL, Hornick JL. Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ celltumors. Am J Surg Pathol. 2007; 31(6):836-845.

(27.) de JJ, Stoop H, Gillis AJ, et al. Differentialexpression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. J Pathol. 2008; 215(1):21-30.

(28.) Gopalan A, Dhall D, Olgac S, et al. Testicular mixed germ cell tumors: a morphological and immunohistochemical study using stem cell markers, OCT3/ 4, SOX2 and GDF3, with emphasis on morphologically difficult-to-classify areas. Mod Pathol. 2009; 22(8):1066-1074.

(29.) Nonaka D. Differential expression of SOX2 and SOX17 in testicular germ cell tumors. Am J Clin Pathol. 2009; 131(5):731-736.

(30.) Henley JD, Young RH, Wade CL, Ulbright TM. Seminomas with exclusive intertubular growth: a report of 12 clinically and grossly inconspicuous tumors. Am J Surg Pathol. 2004; 28(9):1163-1168.

(31.) Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005; 18(suppl 2):S61-S79.

(32.) Kao C-S, Idrees MT, Young RH, Ulbright TM. Solid pattern of testicular yolk sac tumor: a morphologic and immunohistochemical study of 52 cases. Mod Pathol. 2011; 24(suppl 1):202A.

(33.) Ulbright TM, Roth LM, Brodhecker CA. Yolk sac differentiation in germ cell tumors: a morphologic study of 50 cases with emphasis on hepatic, enteric and parietal yolk sac features. Am J Surg Pathol. 1986; 10(3):151-164.

(34.) Eglen DE, Ulbright TM. The differential diagnosis of yolk sac tumor and seminoma: usefulness of cytokeratin, alpha-fetoprotein, and alpha-1-antitrypsin immunoperoxidase reactions. Am J Clin Pathol. 1987; 88(3):328-332.

(35.) Zynger DL, Dimov ND, Luan C, Teh BT, Yang XJ. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006; 30(12):1570-1575.

(36.) Ota S, Hishinuma M, Yamauchi N, et al. Oncofetal protein glypican-3 in testicular germ-cell tumor. Virchows Archiv. 2006; 449(3):308-314.

(37.) Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumors of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol. 2002; 26(5):541-550.

(38.) Mosharafa AA, Foster RS, Bihrle R, et al. Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors? Cancer. 2003; 98(4):753-757.

(39.) Jacobsen GK, Henriksen OB, von der Maase H. Carcinoma in situ of testicular tissue adjacent to malignant germ-cell tumors: a study of 105 cases. Cancer. 1981; 47(11):2660-2662.

(40.) Kommoss F, Oliva E, Bittinger F, et al. Inhibin-alpha CD99, HEA125, PLAP, and chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome. Hum Pathol. 2000; 31(9):1055-1061.

(41.) Comperat E, Tissier F, Boye K, de Pinieux G, Vieillefond A. Non-Leydig sex-cord tumors of the testis. The place of immunohistochemistry in diagnosis and prognosis: a study of twenty cases. Virchows Arch. 2004; 444(6):567-571.

(42.) Cao D, Li J, Guo CC, Allan RW, Humphrey PA. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009; 33(7): 1065-1077.

(43.) Leibovitch I, Foster RS, Ulbright TM, Donohue JP. Adult primary pure teratoma of the testis: the Indiana experience. Cancer. 1995; 75(9):2244-2250.

(44.) Simmonds PD, Lee AH, Theaker JM, Tung K, Smart CJ, Mead GM. Primary pure teratoma of the testis. J Urol. 1996; 155(3):939-942.

(45.) Ulbright TM, Srigley JR. Dermoid cyst of the testis: a study of five postpubertal cases, including a pilomatrixoma-like variant, with evidence supporting its separate classification from mature testicular teratoma. Am J Surg Pathol. 2001; 25(6):788-793.

(46.) Price EB, Jr. Epidermoid cysts of the testis: a clinical and pathologic analysis of 69 cases from the testicular tumor registry. J Urol. 1969; 102(6):708 713.

(47.) Dieckmann KP, Loy V. Epidermoid cyst of the testis: a review of clinical and histogenetic considerations. Br J Urol. 1994; 73(4):436-441.

(48.) Manivel JC, Reinberg Y, Niehans GA, Fraley EE. Intratubular germ cell neoplasia in testicular teratomas and epidermoid cysts: correlation with prognosis and possible biologic significance. Cancer. 1989; 64(3):715-720.

(49.) Cheng L, Zhang S, MacLennan GT, et al. Interphase fluorescence in situ hybridization analysis of chromosome 12p abnormalities is useful for distinguishing epidermoid cysts of the testis from pure mature teratoma. Clin Cancer Res. 2006; 12(19):5668-5672.

(50.) Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases. Am J Surg Pathol. 2006; 30(7):858-865.

(51.) Skakkebaek NE, Berthelsen JG, Visfeldt J. Clinical aspects of testicular carcinoma-in-situ. Int J Androl. 1981; 4(suppl):153-162.

(52.) Nistal M, Gonzalez-Peramato P, Regadera J, Serrano A, Tarin V, De Miguel MP. Primary testicular lesions are associated with testicular germ cell tumors of adult men. Am J Surg Pathol. 2006; 30(10):1260-1268.

(53.) Skakkebaek NE, Holm M, Hoei-Hansen C, Jorgensen N, Rajpert-De Meyts E. Association between testicular dysgenesis syndrome (TDS) and testicular neoplasia: evidence from 20 adult patients with signs of maldevelopment of the testis. APMIS. 2003; 111(1):1-9.

(54.) Cools M, van Aerde K, Kersemaekers AM, et al. Morphological and immunohistochemical differences between gonadal maturation delay and early germ cell neoplasia in patients with undervirilization syndromes. J Clin Endocrinol Metab. 2005; 90(9):5295-5303.

(55.) Engeler DS, Hoslipo, John H, et al. Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome. Urology. 2000; 56:144 148.

(56.) Muller J, Skakkebaek NE, Nielsen OH, Graem N. Cryptorchidism and testis cancer: atypical infantile germ cells followed by carcinoma in situ and invasive carcinoma in adulthood. Cancer. 1984; 54(4):629-634.

(57.) Stoop H, Honecker F, van de Geijn GJ, et al. Stem cell factor as a novel diagnostic marker for early malignant germ cells. J Pathol. 2008; 216(1):43-54.

(58.) American Joint Committee on Cancer. Testis. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti AI, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:469-478.

(59.) Divrik RT, Akdoan B, Ozen H, Zorlu F. Outcomes of surveillance protocol of clinical stage I nonseminomatous germ cell tumors-is shift to risk adapted policy justified? J Urol. 2006; 176(4, pt 1):1424-1429.

(60.) Ondrus D, Ondrusova M, Hornak M, Matoska J. Nonseminomatous germ cell testicular tumors clinical stage I: differentiated therapeutic approach in comparison with therapeutic approach using surveillance strategy only. Neoplasma. 2007; 54(5):437-442.

(61.) Govender D, Sing Y, Chetty R. Sertoli cell nodules in the undescended testis: a histochemical, immunohistochemical, and ultrastructural study of hyaline deposits. J Clin Pathol. 2004; 57(8):802-806.

(62.) Halley JB. The growth of Sertoli celltumors: a possible index of differential gonadotrophin activity in the male. J Urol. 1963; 90(2):220-229.

(63.) Vallangeon BD, Eble JN, Ulbright TM. Macroscopic Sertoli cell nodule: a study of 6 cases that presented as testicular masses. Am J Surg Pathol. 2010; 34(12):1874-1880.

(64.) Nistal M, Paniagua R, Abaurrea MA, Santamaria L. Hyperplasia and the immature appearance of Sertoli cells in primary testicular disorders. Hum Pathol. 1982; 13(1):3-12.

(65.) Nielsen K, Jacobsen GK. Malignant Sertoli cell tumour of the testis: an immunohistochemical study and a review of the literature. APMIS. 1988; 96(8):755-760.

(66.) Young RH, Koelliker DD, Scully RE. Sertoli cell tumors of the testis, not otherwise specified: a clinicopathologic analysis of 60 cases. Am J Surg Pathol. 1998; 22(6):709-721.

Huihui Ye, MD; Thomas M. Ulbright, MD

Accepted for publication November 16, 2011.

From the Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Dr Ye); and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis (Dr Ulbright).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Thomas M. Ulbright, MD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Room 4014, 350 W 11th St, Indianapolis, IN 46202 (e-mail: tulbrigh@iupui. edu).
Features of Potential Value in Specific Differential Diagnoses

Testicular Architecture or Gross
Pathology Features Cytology

"Atypical" Solid or Round to polygonal
 seminoma pseudoglandular cells with some
 pleomorphism,
 variably dense
 cytoplasm
Embryonal Solid, glandular, Anaplastic cells,
 carcinoma papillary nuclear overlapping

Seminoma Solid, Monotonous, round
 pseudoglandular, to polygonal cells
 or microcystic
Yolk sac tumor Other associated More pleomorphic,
 patterns flat cell lining, if
 microcystic

Seminoma Solid Empty cytoplasm,
 larger nuclei,
 frequent mitoses

Clear cell sex Solid Vesicular cytoplasm,
 cord-stromal smaller nuclei,
 tumor fewer mitoses

Postpubertal Multilocular Variable cytologic
 teratoma and solid atypia

Dermoid and Unilocular 6 solid No cytologic atypia
 epidermoid (in dermoid cyst);
 cysts "organoid"
 arrangements
 (dermoid)

Atypical germ Randomly located [+ or -] Multinucleation,
 cells in the tubules [+ or -] clear cytoplasm,
 lack large nucleoli
 and coarse
 chromatin
IGCNU Basilar location, Clear cytoplasm,
 segmental large nucleoli,
 distribution coarse chromatin

Sertoli cell Small (often Small, immature
 nodule <1 cm) (fetal-type) Sertoli
 cells

Sertoli cell Larger (usually Larger cells, more
 tumor >1 cm) pleomorphic,
 increased mitoses

Testicular
Pathology Associated Features

"Atypical" Fibrous septa,
 seminoma lymphocytes,
 granulomata

Embryonal Variable
 carcinoma

Seminoma Fibrous septa,
 lymphocytes,
 granulomata
Yolk sac tumor Hyaline globules,
 basement
 membrane deposits

Seminoma Fibrous septa,
 lymphocytes,
 granulomata;
 IGCNU
Clear cell sex Variable lymphocytes,
 cord-stromal no IGCNU
 tumor

Postpubertal IGCNU
 teratoma

Dermoid and No IGCNU,
 epidermoid lipogranulomas (in
 cysts dermoid cyst), intact
 spermatogenesis

Atypical germ [+ or -] Impaired
 cells spermatogenesis

IGCNU Impaired
 spermatogenesis

Sertoli cell Often basement
 nodule membrane
 deposits, admixed
 spermatogonia
Sertoli cell Infrequent, admixed
 tumor spermatogonia

 New
Testicular Usual Immunomarkers
Pathology Immunophenotype Additional Tools

"Atypical" AE1/[AE3.sup.-]; [SOX22.sup.-];
 seminoma [CD30.sup.-]; [SOX17.sup.+]
 [CD117.sup.+];
 [D2-40.sup.+]

Embryonal AE1/[AE3.sup.+]; [SOX2.sup.+];
 carcinoma [CD30.sup.+]; [SOX17.sup.-]
 [CD117.sup.-];
 [D2-40.sup.-]

Seminoma AE1/[AE3.sup.-];
 [glypican-3.sup.-];
 [OCT3/4.sup.+]
Yolk sac tumor AE1/[AE3.sup.+];
 [glypican-3.sup.+];
 [OCT3/4.sup.-]

Seminoma [OCT3/4.sup.+], [SALL4.sup.+]
 [PLAP.sup.+],
 [CD117.sup.+],
 [D2-40.sup.+]
Clear cell sex [OCT3/4.sup.-], [SALL4.sup.-]
 cord-stromal [PLAP.sup.-],
 tumor inhibin variable,
 calretinin variable

Postpubertal Variable depending on [SALL4.sup.+];
 teratoma tissues isochromosome
 arm [12p.sup.+]
Dermoid and Variable, depending on SALL4(?);
 epidermoid tissues (dermoid cyst) isochromosome
 cysts arm [12p.sup.-] in
 epidermoid cyst

Atypical germ OCT3/4, PLAP, CD117, [SCF.sup.-] in delayed
 cells D2-40: neg. in maturation
 atypical
 spermatogonia, pos.
 in delayed maturation
IGCNU [OCT3/4.sup.+], [SCF.sup.+]
 [PLAP.sup.+],
 [CD117.sup.+], and
 [D2-40.sup.+]

Sertoli cell Intensely inhibin pos.
 nodule

Sertoli cell Variable inhibin
 tumor reactivity

Abbreviations: IGCNU, intratubular germ cell neoplasia, unclassified
type; neg., negative; pos., positive; SCF, stem cell factor.
COPYRIGHT 2012 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Ye, Huihui; Ulbright, Thomas M.
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2012
Words:6615
Previous Article:Role of immunohistochemistry in diagnosing renal neoplasms: when is it really useful?
Next Article:Renal cell carcinoma with clear cell and papillary features.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters