ORIGINAL ARTICLE
Yolk Sac Tumor of the Testis in Infants and Children A Clinicopathologic Analysis of 33 Cases Kristine M. Cornejo, MD,*w Lindsay Frazier, MD, ScM,z Richard S. Lee, MD,y8 Harry P.W. Kozakewich, MD,wz and Robert H. Young, MD*w
Abstract: We report 33 pure yolk sac tumors of the testis from boys 5 to 71 months of age (mean 20.7 mo) diagnosed from 1918 to 2014. All except 1 underwent orchiectomy, with lymph node dissections (all negative) performed in 18; 21 also received chemotherapy and 12 radiotherapy. The tumors were 1.6 to 7.0 cm (mean 3.7 cm) and were nonencapsulated, with a gray to yellow, often mucoid, cut surface. The commonest pattern was reticularmicrocystic, but macrocystic, papillary, endodermal sinus (Schiller-Duval bodies), labyrinthine, myxomatous, glandular, and solid patterns were also observed. Follow-up was available for 32 patients (mean 100.5 mo; range, 3 to 456 mo). Twentyfour patients (including 4 who did not receive adjuvant therapy) were without evidence of disease, 8 had metastatic disease; 5 of the latter died of tumor and 1 of treatment complications. Two patients with metastasis were cured with radiation with or without chemotherapy. Two or more of the following were associated with a poor outcome in patients presenting with stage I cases: tumor size >4.5 cm (4/6 tumors [67%]), invasion of rete testis and/or epididymis (3/7 tumors [43%]), and necrosis (6/17 tumors [35%]). In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3/24 tumors (13%) (P = 0.0001). It is crucial that this tumor be distinguished from the juvenile granulosa cell tumor, which occurs at a slightly younger age and has distinctive features, although there may be some morphologic overlap. The survival of young boys with testicular yolk sac tumor is very good because of both effective chemotherapy and likely, the inherent characteristics of the tumor in this age group. Key Words: yolk sac tumor, endodermal sinus tumor, prepubertal, testis, germ cell tumor, prognosis, treatment (Am J Surg Pathol 2015;39:1121–1131)
From the *James Homer Wright Pathology Laboratories, Massachusetts General Hospital; Department of wPathology; yUrology, Harvard Medical School; zDepartment of Pediatric Oncology, Dana-Farber Cancer Institute; Department of 8Urology; and zPathology, Boston Children’s Hospital, Boston, MA. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Kristine M. Cornejo, MD, Department of Pathology, UMass Memorial Healthcare, One Innovation Drive, Biotech 3, Worcester, MA 01605 (e-mail: kristine.cornejo@umassmemorial. org). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Am J Surg Pathol
T
esticular tumors in the young (below 20 y of age) have a number of characteristics that differ from those seen in older patients,1 and account for 1% to 2% of neoplasms in the pediatric population.2–5 Benign lesions represent the majority, with most that are malignant being yolk sac tumor.4,6–13 The features of testicular yolk sac tumor, focusing on pediatric examples, were first elaborated in detail in 4 papers published from 1950 to 1962,14–17 shortly after the germ cell nature of this neoplasm was established by Dr Gunnar Teilum, a story recently reviewed in detail elsewhere.18,19 Subsequently, the majority of the focus on testicular yolk sac tumor from the pathology perspective has been with regard to its frequent presence in mixed germ cell tumors in older male individuals.20–22 There has been limited focus on pediatric testicular yolk sac tumors in the era of modern adjuvant therapy, which either did not exist or was not as developed as it is now, at the time of early reports. Those contributions were also undertaken before recent elaboration of some aspects of the histopathology of yolk sac tumors and the description of one important entity in its differential diagnosis, the juvenile granulosa cell tumor (JGCT).23–25 To investigate both its clinical and pathologic aspects, including differential diagnosis, we undertook a review of 33 cases and report our experience with pure yolk sac tumors in prepubertal boys.
MATERIALS AND METHODS Case Selection A search of the surgical pathology and consultation files of the Boston Children’s Hospital from 1918 to 2014 revealed 33 prepubertal pure yolk sac tumors of the testis with hematoxylin and eosin–stained slides available for review; the tumors were diagnosed from 1923 to 2012. Fifteen patients have been previously reported in prior studies from Boston Children’s Hospital.26,27 Ten cases were excluded from the study, as slides were not available for review. The number of slides per case ranged from 1 to 18 slides (mean 4.7). Immunohistochemical stains were reviewed if performed, or results were documented per the original pathology report. Clinical data including presentation, gross description and characteristics, and treatment were recorded. Follow-up was available in all but 1 case. The neoplasms were evaluated for gross aspects, histologic patterns, and
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cytologic features including mitotic count, lymphovascular invasion, and necrosis.
Statistical Analysis Tumors from the metastasizing and nonmetastasizing groups were compared using a Fisher exact test for the histologic features of size >4.5 cm, presence of necrosis, and invasion of the rete testes and/or epididymis. A 2-sided P value of 1980)
1
8
NA
6.0
Orch
NP
No
No
17
Yes
Yes
No
No
2 3 4 5
13 14 15 16
Left NA NA Right
4.0 4.0 4.0 7.0
Orch Orch Orch Orch
NP NP NP NP
Yes No Yes No
No No No No
26 6 42 37
Yes Yes Yes Yes
Yes No No Yes
No No No Yes
No No No No
6
17
NA
6.0
Orch
NP
No
Yes
27
Yes
Yes
No
No
7
20
Right
6.0
NP
NP
No
No
30
Yes
Yes
No
No
8
24
NA
5.0
Orch
NP
No
No
30
Yes
Yes
No
No
9 10 11 12
6 9 13 15
NA Right Right Left
2.5 2.5 3.0 4.0
Orch Orch Orch Orch
Bilat Right Right Left
Yes Yes Yes Yes
Yes Yes Yes Yes
20 21 27 45
Yes Yes No Yes
Yes No Yes Yes
No No No Yes
No No No No
13 14 15
18 18 22
Left Right Right
2.5 4.5 2.5
Orch Orch Orch
Left Right Bilat
Yes Yes Yes
Yes Yes Yes
53 33 31
Yes Yes Yes
Yes No Yes
No No Yes
No No Yes
16 17 18 19 20 21 22
22 23 25 46 71 19 41
NA Right Right Right Left NA Right
2.3 2.0 2.3 3.0 3.0 5.0 4.8
Orch Orch Orch Orch Orch Orch Orch
Bilat Right Bilat Bilat Left Yes Yes
Yes No Yes No Yes No No
Yes Yes Yes Yes Yes Yes Yes
30 47 31 14 42 43 17
No Yes No Yes Yes Yes Yes
Yes No No Yes Yes Yes Yes
No No Yes Yes No No Yes
No No No Yes No No Yes
23 24 25 26 27 28 29 30 31 32 33
42 54 5 6 6.5 7 10 13 16 21 27
Left NA Right Right Left Left Right Left Right Right Left
3.5 5.0 2.8 4.0 2.3 1.6 5.3 3.5 2.5 2.5 3.5
Orch Orch Orch Orch Orch Orch Orch Orch Orch Orch Orch
Yes Yes NP Right NP NP NP NP Right NP NP
No No No No No No No No No No No
Yes Yes Yes Yes No Yes No No No Yes Yes
63 27 15 33 32 13 30 50 48 27 37
Yes No No Yes No Yes No Yes No Yes Yes
Yes Yes No No No No Yes Yes No No No
Yes No No No No Yes NA No No No No
No No No No No No NA No No No No
Follow-up DOD at 3 mo, lung metastasis NED at 456 mo NED at 264 mo NED at 17 mo DOD at 12 mo, lung metastasis at 8 mo s/p rads+chemo DOD at 12 mo, metastasis to retroperitoneum at 11 mo s/p rads DOD at 11 mo, mets to retroperitoneum, liver, lymph nodes DOD at 18 mo, lung metastasis at 4 mo s/p rads+chemo NED at 192 mo NED at 252 mo NED at 72 mo NED at 180 mo, lung metastasis at 8 mo s/p rads+chemo NED at 132 mo NED at 192 mo NED at 168 mo, lung metastasis at 7 mo s/p rads NED at 144 mo NED at 192 mo NED at 144 mo NED at 72 mo NED at 240 mo NED at 72 mo DOOD at 8 mo, metastasis NED at 24 mo NED at 36 mo NED at 121 mo NED at 93 mo NED at 22 mo NED at 12 mo LTF NED at 24 mo NED at 16 mo NED at 12 mo NED at 4 mo
I, orchiectomy alone with minimal to no radiation or chemotherapy; II, combined modality of orchiectomy, RPLND, chemotherapy, and radiation; III, orchiectomy, RPLND and chemotherapy without radiation; IV, orchiectomy and chemotherapy only. Adj indicates adjuvant; chemo, chemotherapy; DOD, died of disease; DOOD, died of other disease; epidid, epididymal; inv, invasion; LTF, lost to follow-up; NA, not available; NED, no evidence of disease; NP, not performed; orch, orchiectomy; rads, radiation; rete, rete testis; s/p, status post; YST, yolk sac tumor.
count ranged from 6 to 63/10 high-power fields (HPF) (mean 31.6/10 HPF, 400). Adjacent testicular parenchyma was negative for intratubular germ cell neoplasia in all cases. Copyright
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Tumor invaded the tunica albuginea in 5 cases, the rete testis in 8, and epididymis in 3 cases. Tumor necrosis was observed in 20 (61%) cases, and lymphovascular invasion was seen in 25 (76%) cases. Immunostaining of 8
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FIGURE 3. Lobulated growth with solid pattern centrally and more typical patterns at the periphery.
FIGURE 1. Macroscopic image of a yolk sac tumor revealing a lobular tan to yellow neoplasm with a mucoid sectioned surface.
The following features correlated with an unfavorable outcome (ie, metastasis and/or death) in patients with pathologic stage (pStage) I disease at diagnosis: 4 of 6 tumors (67%) that were >4.5 cm in largest diameter (P = 0.007); 3 of 7 tumors (43%) in which rete testis and/or epididymal invasion occurred (P = 0.12); 6 of 17 tumors (35%) in which necrosis was identified (P = 0.02). Every tumor in the metastasizing group had 2 or more unfavorable features (6 of 6, 100%).
In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3 of 24 tumors (13%) (P = 0.0001), excluding the patient lost to follow-up. We compared the various treatment regimens with patient outcome. Of the 8 patients in group 1 who underwent orchiectomy alone, with minimal to no radiation or chemotherapy, 5 died of disease (63%). Of the 12 patients in group 2 who underwent orchiectomy with RPLND and chemoradiation, 2 died of disease (17%). Of the 4 patients who underwent orchiectomy with RPLND and chemotherapy alone in group 3, only 1 died, secondary to a complication of chemotherapy without disease. Lastly, of the 10 patients who underwent orchiectomy with or without RPLND and chemotherapy in group 4, all 9 patients with follow-up were alive without disease. Three of these patients underwent orchiectomy alone, 1 of whom had both lymphovascular invasion and necrosis, and a second with a tumor >4.5 cm and necrosis.
FIGURE 2. Lobular growth showing a typical microcystic pattern.
FIGURE 4. Classic reticular-microcystic appearance. A few solid aggregates are also seen.
neoplasms revealed cytoplasmic positivity for a-fetoprotein (AFP) in 6 (75%) tumors and cytokeratin in 4 (50%) tumors. All 8 tumors stained were negative for HCG (0%).
Prognostic Features and Outcome
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FIGURE 5. Several macrocysts are present in the background of reticular-microcystic morphology.
Yolk Sac Tumor of Testis in Infants and Children
DISCUSSION
FIGURE 7. Striking glandular pattern. Even at this low-power magnification, the cells are not as pleomorphic as typically seen in embryonal carcinoma. Also note the prominent myxoid stroma.
Malignant germ cell tumors of the testis are rare in children, and in contrast to postpubertal adolescents and adults in whom the majority are seminomas, embryonal carcinomas, and mixed germ cell tumors, yolk sac tumors and teratomas are the most common.1,10,29,30 The yolk sac tumor is by far the most frequently malignant, as prepubertal testicular teratomas rarely metastasize and have a good prognosis after orchiectomy alone.6–8,10–12,31 The yolk sac tumor is one of the most fascinating human neoplasms.19,32–36 The first recognizable case was a testicular example reported in 1910.37 Although Teilum likely saw examples of pure testicular yolk sac tumor, most of his early experience was based on yolk sac tumor as a component of mixed germ cell tumors of the adult testis.38 Although other early writers had recognized a distinctive aspect to the testicular yolk sac tumor as we know it today,39,40 Magner and colleagues first clearly delineated the tumor as a pure neoplasm occurring in young boys.14–16 The work of a British group in 196017
was a further significant, early contribution on the topic. As noted in the introduction, since the time the tumor was established as an entity, there has been relatively little focus overall on pediatric testicular yolk sac tumor, which accounts for the vast majority of pure examples, and its behavior in the contemporary clinical setting.41–46 Furthermore, early descriptions preceded detailed elaborations of morphologic variants of yolk sac tumor, such as hepatoid, glandular, and solid.47–49 Before discussing yolk sac tumor of the prepubertal testis, it is merited to briefly place its features in context with those of human yolk sac tumor overall. The yolk sac tumor occurs at diverse sites and has interesting features that differ from site to site. For example, in the ovary the tumors occur at significantly older age than in the testis, peaking at around 19 years of age, being uncommon in the age group when the pure testicular form is dominantly seen. In females, however, one does see a very similar
FIGURE 6. Admixture of reticular-microcystic and glandular patterns.
FIGURE 8. High-power view of a solid pattern. Note the lack of a lymphocytic infiltrate (in contrast to seminoma).
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TABLE 2. Pathologic Data of Testicular YST Cases (n = 33) Morphologic Feature Patterns Reticular/microcystic Glandular Solid Macrocystic Papillary Endodermal sinus (Schiller-Duval bodies) Myxomatous Labyrinthine Hyaline globules Mitotic count/10 HPF < 10 Z10-19 Z20 LVI Necrosis
FIGURE 9. Papillary pattern, largely endodermal sinus type with Schiller-Duval bodies. Note the presence of papillae with several blood vessels, best seen at the 3:00 to 5:00 position. Some papillae do not show vessels, likely because of the plane of section.
Cases (%) 31 28 21 19 13 7 7 5 24
(94) (85) (64) (58) (39) (21) (21) (15) (73)
1 5 27 25 20
(3) (15) (82) (76) (61)
LVI indicates lymphovascular invasion; YST, yolk sac tumor.
predilection to the early years of life in the case of the yolk sac tumor of the vagina,50 almost all of which occur in the first 2 years of life. Another site where yolk sac tumor is typically seen in the very young is the sacrococcygeal region. Other well-known extragonadal sites, such as the retroperitoneum, mediastinum, and pineal, are usually involved in somewhat older patients. Rare locations of yolk sac tumor include various sites in the head and neck and the stomach and liver, among others, as reviewed in detail elsewhere.51 In the literature, boys with this testicular neoplasm typically have presented with an asymptomatic mass at an average age of 16 to 17 months,52,53 similar to our figure of 20.7 months. Only about 6% occur after 5 years of age.11 In young adults, yolk sac tumor is again seen with some frequency in the testis, but almost always as a component
within a malignant mixed germ cell tumor.20–22 AFP levels are elevated in the majority of childhood cases (90%).52 As testicular yolk sac tumors are not hormonally active, these patients lack endocrine-related symptoms, a contrast with ovarian examples, which occasionally are hormonally active due to stromal luteinization (so-called ovarian tumors with functioning stroma), a phenomenon that does not have a testicular counterpart.54 The tumors have ranged from 1 to 12 cm in maximum dimension, but most often are circa 4 cm, and are pale gray to yellow and solid, with a mucoid cut surface.41,43,52 In some cases, particularly in large tumors, hemorrhage and necrosis may be present.41,52 When considering the differential diagnosis of the yolk sac tumor, it is crucial to emphasize the importance of the age in formulating the differential diagnosis of a testicular mass.1 The common neoplasms of the young adult male (seminoma, embryonal carcinoma, and mixed forms) are almost never seen in the first 5 years of life (old cases of infantile embryonal carcinoma are yolk sac tumors according to current
FIGURE 10. Prominent growth of cells in ribbons, sometimes forming drape-like formations (festoons) and communications with each other (labyrinthine).
FIGURE 11. Primitive-appearing tumor cells with pale to clear cytoplasm, enlarged nuclei with irregular borders, prominent nucleoli, and brisk mitotic activity.
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FIGURE 12. Numerous intracellular and extracellular hyaline globules.
knowledge).1 More realistic than the differential with other germ cell tumors is that with the JGCT, as it is typically a tumor of the young, and some microscopic overlap exists. Although there is age overlap as well, the JGCT typically occurs within the first 6 months of life (90%), with the majority (51%) occurring in the first month, followed by a minority in the second (12%), third (12%), 4 to 6 months (15%), 6 to 12 months (4%), and >12 months (6%).25 JGCTs are rare after the first year, in contrast to the mean age of 16 to 17 months for yolk sac tumors, with only 3 of the later in our series being from a child 6 months or less.24,52,55–57 A few JGCTs may be associated with an abnormal karyotype and ambiguous genitalia but lack the elevated serum AFP levels seen in the majority of patients with yolk sac tumors, unless in the neonatal period, when some elevation may be seen.24,52,55–57 Therefore, males above 6 months of age with elevated AFP > 100 ng/mL should be evaluated for a yolk sac tumor.3,58,59 Macroscopically, JGCTs are tan to yellow, with usually a mixture of solid and cystic components.52,60 They may be uniformly solid and indistinguishable from a yolk sac tumor. The cysts are variable in size and may measure up to 6.5 cm.60 Microscopically, JGCTs typically contain follicles with mucinous material and solid areas with granulosa cells that have abundant eosinophilic to vacuolated cytoplasm and round nuclei.24,56,57 When follicles are absent or few in number in a JGCT and some separation of tumor cells is seen, the reticular pattern of yolk sac tumor may be mimicked to a degree. Brisk mitotic activity is a shared, potentially confusing aspect of the 2 tumors. In the largest series of testicular JGCTs, necrosis was an uncommon feature, present in only 1 of 70 cases evaluated and may help in differentiating these 2 entities.25 Immunohistochemical stains are helpful in differentiating these 2 neoplasms, as JGCTs are positive for inhibin and FOXL2 and negative for AFP, glypican-3, and SALL4, whereas yolk sac tumors have the opposite immunoprofile.25,61 Yolk sac tumors are typically diagnosed on routine sections. However, in certain instances immunohistoCopyright
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chemical markers may aid in the diagnosis. The most widely known marker used to diagnose yolk sac tumor historically has been AFP. However, immunoreactivity for AFP, although found in the majority of tumors, is often variable and weak in intensity, and a negative AFP immunostain does not exclude the diagnosis.42,52,62,63 Glypican-3, an oncofetal protein found to regulate cell growth and differentiation during embryogenesis is also positive in yolk sac tumors, with a better sensitivity than AFP.64,65 Similar to AFP, immunoreactivity has been reported in some studies to be weak and patchy.47,63 SALL4, which is a newer immunohistochemical marker, has also been found to be strongly positive in yolk sac tumors, including metastases, and appears to be a more sensitive marker than glypican-3 and AFP.63,66,67 However, comparable to the other immunohistochemical stains, it can stain other types of tumors and is not specific for yolk sac tumors.63,67 Additional immunohistochemical markers that may be helpful are cytokeratin, which is positive, and EMA and OCT3/4, which are typically negative in yolk sac tumors.47,68 Therefore, it is best to use a panel of immunostains. The few cases in our study that underwent immunohistochemical evaluation revealed reactivity for AFP (75%) and cytokeratin (50%) in the majority of cases. GATA-4 and GATA-6 immunostains have also been reported to be positive in yolk sac tumors, although studies are limited.69,70 The majority (80% to 85%) of prepubertal patients with testicular yolk sac tumors have cStage I disease, with metastasis at presentation in only about 20% of the cases.3,10,52,54,71–73 In our series, all of the patients presented with pStage I disease except for 2 (6%), which were cStage III. Orchiectomy alone with observation (the watch and wait or active surveillance strategy) will cure the majority of patients.74–78 Earlier studies noted the unexpectedly favorable prognosis of these neoplasms despite their histology.17,46 Magner et al16 and Teoh et al17 both noted that approximately 70% of patients were without evidence of disease with orchiectomy and minimal adjuvant therapy (2 patients received radiotherapy). The group I experience similarly taught us that some patients could be cured with orchiectomy and minimal adjuvant therapy, but this was less than half of the patients (3 of 8, 38%). Historically, RPLNDs were included in surgical protocols for therapeutic and staging purposes.54 When chemotherapy and radiation therapy with radical surgery developed, these modalities were applied to yolk sac tumors.26 The group II patients (n = 12) were treated very intensively with all forms of available adjuvant therapy. All patients were treated with orchiectomy and staged with RPLND at the time of presentation. Ten received radiation, and all 12 received chemotherapy. All 12 patients survived. Two required salvage chemotherapy and/ or radiation therapy to treat pulmonary metastasis. Survival improved from 38% for group I cases to 100% with the aggressive adjuvant therapy given in group II. This had its price, as the detrimental effects of radiation therapy of that period became evident, especially with regard
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to bone growth and scoliosis. Concern about long-term effects of radiation therapy in children as well as the efficacy of actinomycin-D led to omission of radiotherapy from the routine treatment protocol of yolk sac tumors in 1975. The group III patients were treated with orchiectomy, RPLND, and chemotherapy, and all 4 were cured of their tumor. One child died of bleomycin pulmonary toxicity 8 months after treatment with no evidence of disease. The omission of radiation therapy in this group did not affect disease-free survival. Similarly, a study analyzing treatment modalities in yolk sac tumors revealed a mortality rate of 36% with orchiectomy alone compared with 39% with orchiectomy and radiation, which also supports there being no role for radiotherapy.79 The role of RPLND eventually became controversial. Young and colleagues reported 18 cases of yolk sac tumors all treated with orchiectomy and 8 with lymph node dissections, none of which were positive. There was no difference in survival between the patients who underwent lymphadenectomy (75%) and those who did not (83%).41 Roth and Panganiban reported 6 patients, 2 of whom underwent RPLND. One patient died postoperatively secondary to complications and was found to have only 1 positive lymph node. The second patient had 45 negative lymph nodes.80 Conversely, Kaplan and Firlit reported 12 patients, all of whom underwent RPLND, and 4 (33%) had nodal disease.81 Treatment regimens subsequently changed, with a shift away from radiotherapy and RPLND; the latter were discontinued given that: (1) the morbidity was associated with abdominal surgery in children; (2) most RPLND were negative; and (3) yolk sac tumors commonly metastasized hematogenously and less commonly through lymphatics.12,44,54,73,74,82–84 In our series, all 18 patients who underwent RPLND had negative nodes. RPLND currently has a minimal role in both the prechemotherapy and postchemotherapy setting. RPLND is rarely offered before chemotherapy as a therapeutic and prognostic procedure, as chemotherapy has been found to be superior in patients with cStage I disease in a randomized trial.85–87 RPLND is limited mainly to postchemotherapy patients with persistent retroperitoneal involvement after chemotherapy, persistent elevated serum AFP levels after chemotherapy without evidence of metastasis on imaging studies, or normal or unknown serum AFP levels at the time of diagnosis, as it cannot be dependably followed as an indicator of recurrence or metastasis.10,12,45,54,72,77,88 In addition, it may be offered to patients who are unwilling to participate in active surveillance or chemotherapy.77,88 Although we previously advocated chemotherapy in pStage I disease, the literature no longer supports this practice. Flamant et al89 studied 24 patients with cStage I yolk sac tumors. None underwent RPLND, and 12 did not receive chemotherapy. The remaining 12 were treated with multidrug chemotherapy. No statistically significant difference in survival or relapse-free survival was demonstrated between those receiving chemotherapy and the
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group with orchiectomy alone. The 3-year survival rate was 96%, and the 3-year relapse-free survival rate was 84%.89 Similarly, Carroll et al72 prospectively treated 5 cStage I patients with orchiectomy alone, and they were all without evidence of disease at a median follow-up period of 46 months, supporting that RPLND and adjuvant therapy are not indicated as long as serum AFP levels return to normal. Protocols for adjuvant therapy have changed to avoid overtreatment and to minimize drug toxicity to patients.75 Therefore, with active surveillance, most children will be spared chemotherapy exposure. Multidrug chemotherapy protocols using platinum-based regimens have improved survival in prepubertal patients with yolk sac tumor, similar to group 4 in our series with a survival rate of 100%.10,54,84,88,90 Patients on active surveillance will undergo close follow-up with routine CT examination of the chest, abdomen, and pelvis and testing for serum AFP levels to assess for metastasis and/or recurrence.10,54,74 Approximately 20% of patients will recur, but most can be salvaged with chemotherapy with cure rates near 100%.12,74–76,88 Metastasis typically occurs through hematogenous spread in up to 40% of cases to sites such as the kidney and lungs but also through the lymphatics in up to 27% of cases to the retroperitoneal lymph nodes.52,72,82,84 Metastasis typically occurs within 2 years of diagnosis.43,45,73 All 8 patients with metastasis in our series either presented with spread or developed it within 11 months. Therefore, after 2 to 3 years of follow-up, recurrence is unlikely, and follow-up visits can be tailored accordingly. Although rare, pure yolk sac tumors of the adult testis have been reported with the largest series comprising 12 cStage I tumors.91,92 Similar to cStage I nonseminoma germ cell tumors (30%), retroperitoneal lymph node metastases occurred in 33% of patients.91 Therefore, it was proposed that pure yolk sac tumors of the adult behaved differently from its juvenile counterpart, and comparable to other nonseminoma germ cell tumors in the adult testis. Adult yolk sac tumors were also more likely to spread through the lymphatics, in contrast to the more common hematogenous spread in juvenile tumors, indicating that RPLND may be reasonable in adult patients.91,92 One of the main predictors of relapse in cStage I tumors on active surveillance is lymphovascular invasion, and in some instances the patient may be offered adjuvant chemotherapy on the basis of this finding despite the tumor being confined to the testis.85,86,88,93 In our study, lymphovascular invasion was identified in 78% of cases, so this approach may potentially expose a considerable number of patients to unnecessary chemotherapy. Histologic features such as tumor size >4.5 cm, invasion of the rete testis and/or epididymis, and presence of necrosis may help in identifying the small subset of tumors that may behave aggressively, as all tumors that spread had 2 or more of these features. In contrast, the presence of 2 or more unfavorable features occurred in only 3 of 24 tumors (13%) in the nonmetastasizing group with Copyright
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follow-up, which was statistically significant (P = 0.0001). However, most of the data were collected in the era of suboptimal staging and therapy. It is unclear as to whether these factors remain relevant in the era of effective chemotherapy. The only patient from group 4 with 2 of the histologic features was lost to follow-up. Genetic studies have revealed recurrent anomalies in prepubertal yolk sac tumors of the testis. The most common recurrent findings were gains of 20q and loss of 1p and 6q. Additional chromosomal aberrations such as gains of chromosomes 1q, 11q, and 22 and loss of chromosome 16q have also been reported.52,94 Gains of chromosome 12p, which is characteristic of postpubertal and adult germ cell tumors, are not identified in these neoplasms, with the exception of a rare case, suggesting an alternative pathogenetic pathway.94–98 Little is known about the genes involved in the development of yolk sac tumors. The recurrent chromosomal anomalies in yolk sac tumors, such as the loss of 1p, indicate that the deletion of certain genes may play a role in its pathogenesis. The runt-related transcription factor 3 (RUNX3) gene found on chromosome 1p36.1 has been implicated as a tumor-suppressor gene associated with gastric cancer.99–101 Hypermethylation of the RUNX3 gene promoter was identified in 8 of 10 (80%) infantile yolk sac tumors, whereas it was not identified in any of the adult germ cell tumors and normal infantile testes analyzed. In addition, loss of heterozygosity in 1p36.1 was identified in 6 of 8 (75%) infantile yolk sac tumors and infrequently in adult germ cell tumors (16%), suggesting that the RUNX3 gene plays a role in the development of prepubertal yolk sac tumors.99 These new insights into the genetic pathways involved in the development of yolk sac tumors appear promising and may eventually identify possible targets for therapy. In conclusion, our series of pure yolk sac tumors of the prepubertal testis highlights the clinicopathologic features and prognosis of these neoplasms. Although most yolk sac tumors of the testis are cStage I and have a good prognosis, a small subset metastasizes. Pathologic features such as tumor size >4.5 cm, necrosis, and invasion of the rete testis and/or epididymis may help identify tumors with aggressive behavior and a need for chemotherapy in addition to orchiectomy, rather than surveillance only, which is associated with a good outcome in most cases. REFERENCES 1. Ulbright TM, Young RH. Testicular tumors in the young. Semin Diagn Pathol. 2014;31:323–381. 2. Brosman SA. Testicular tumors in prepubertal children. Urology. 1979;13:581–588. 3. Kay R. Prepubertal Testicular Tumor Registry. J Urol. 1993;150: 671–674. 4. Bujons A, Sfulcini JC, Pascual M, et al. Prepubertal testicular tumours and efficacy of testicular preserving surgery. BJU Int. 2011;107:1812–1816. 5. Coppes MJ, Rackley R, Kay R. Primary testicular and paratesticular tumors of childhood. Med Pediatr Oncol. 1994;22: 329–340.
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6. Taskinen S, Fagerholm R, Aronniemi J, et al. Testicular tumors in children and adolescents. J Pediatr Urol. 2008;4:134–137. 7. Alanee S, Shukla A. Paediatric testicular cancer: an updated review of incidence and conditional survival from the Surveillance, Epidemiology and End Results database. BJU Int. 2009;104:1280–1283. 8. Nerli RB, Ajay G, Shivangouda P, et al. Prepubertal testicular tumors: our 10 years experience. Indian J Cancer. 2010;47:292–295. 9. Marulaiah M, Gilhotra A, Moore L, et al. Testicular and paratesticular pathology in children: a 12-year histopathological review. World J Surg. 2010;34:969–974. 10. Ross JH, Rybicki L, Kay R. Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the Prepubertal Testis Tumor Registry. J Urol. 2002;168:1675– 1678; discussion 1678-1679. 11. Walsh TJ, Grady RW, Porter MP, et al. Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000. Urology. 2006;68:402–405; discussion 405. 12. Agarwal PK, Palmer JS. Testicular and paratesticular neoplasms in prepubertal males. J Urol. 2006;176:875–881. 13. Pohl HG, Shukla AR, Metcalf PD, et al. Prepubertal testis tumors: actual prevalence rate of histological types. J Urol. 2004;172:2370–2372. 14. Magner D, Bryant JS. Adenocarcinoma of the testis occurring in infants; report of two cases. AMA Arch Pathol. 1951;51:82–89. 15. Magner D, Campbell JS, Wiglesworth FW. Testicular adenocarcinoma with clear cells, occurring in infancy: a distinctive tumour. Can Med Assoc J. 1962;86:485–488. 16. Magner D, Campbell JS, Wiglesworth FW. Testicular adenocarcinoma with clear cells, occurring in infancy. Cancer. 1956;9:165–175. 17. Teoh TB, Steward JK, Willis RA. The distinctive adenocarcinoma of the infant’s testis: an account of 15 cases. J Pathol Bacteriol. 1960;80:147–156. 18. Young RH, Teilum D, Talerman A. History of gynecological pathology XXV. Dr Gunnar Teilum. Int J Gynecol Pathol. 2013; 32:520–527. 19. Teilum G. Endodermal sinus tumors of the ovary and testis. Comparative morphogenesis of the so-called mesoephroma ovarii (Schiller) and extraembryonic (yolk sac-allantoic) structures of the rat’s placenta. Cancer. 1959;12:1092–1105. 20. Talerman A. Yolk sac tumor associated with seminoma of the testis in adults. Cancer. 1974;33:1468–1473. 21. Talerman A. The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults. Cancer. 1975;36:211–215. 22. Talerman A. Endodermal sinus (yolk sac) tumor elements in testicular germ-cell tumors in adults: comparison of prospective and retrospective studies. Cancer. 1980;46:1213–1217. 23. Crump WD. Juvenile granulosa cell (sex cord-stromal) tumor of fetal testis. J Urol. 1983;129:1057–1058. 24. Lawrence WD, Young RH, Scully RE. Juvenile granulosa cell tumor of the infantile testis. A report of 14 cases. Am J Surg Pathol. 1985;9:87–94. 25. Kao CS, Cornejo KM, Ulbright TM, et al. Juvenile granulosa cell tumors of the testis: a clinicopathologic study of 70 cases with emphasis on its wide morphologic spectrum. Am J Surg Pathol. 2015. (In press). 26. Tefft M, Vawter GF, Mitus A. Radiotherapeutic management of testicular neoplasms in children. Radiology. 1967;88:457–465. 27. Hopkins TB, Jaffe N, Colodny A, et al. The management of testicular tumors in children. J Urol. 1978;120:96–102. 28. Edge SB, Byrd DR, Compton CC, et al. Testis. In: Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual (7th ed). New York: Springer; 2010:471–488. 29. Hawkins EP. Pathology of germ cell tumors in children. Crit Rev Oncol Hematol. 1990;10:165–179. 30. Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64:83–103. 31. Weissbach L, Altwein JE, Stiens R. Germinal testicular tumors in childhood. Report of observations and literature review. Eur Urol. 1984;10:73–85. 32. Nogales FF. The Human Yolk Sac and Yolk Sac Tumors. New York: Springer-Verlag; 1993.
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33. Nogales FF, Preda O, Nicolae A. Yolk sac tumours revisited. A review of their many faces and names. Histopathology. 2012;60: 1023–1033. 34. Gonzalez-Crussi F. The human yolk sac and yolk sac (endodermal sinus) tumors. A review. Perspect Pediatr Pathol. 1979;5:179–215. 35. Brown NJ. Yolk sac tumor (orchioblastoma) and other testicular tumours of childhood. In: Pugh RCB, ed. Pathology of the Testis. Oxford: Blackwell; 1976:346–370. 36. Young RH. The yolk sac tumor: reflections on a remarkable neoplasm and two of the many intrigued by it-Gunnar Teilum and Aleksander Talerman-and the bond it formed between them. Int J Surg Pathol. 2014;22:677–687. 37. White CP. A case of carcinoma myxomatodes of the testis occurring in infancy. J Pathol Bacteriol. 1910;14:522–544. 38. Schiller W. Mesonephroma ovarii. Am J Cancer. 1939;35:1–21. 39. Abell MR, Holtz F. Testicular neoplasms in infants and children. I. Tumors of germ cell origin. Cancer. 1963;16:965–981. 40. Mostofi FK. Infantile testicular tumors. Bull N Y Acad Med. 1952; 28:684–687. 41. Young PG, Mount BM, Foote FW Jr, et al. Embryonal adenocarcinoma in the prepubertal testis. A clinicopathologic study of 18 cases. Cancer. 1970;26:1065–1075. 42. Wold LE, Kramer SA, Farrow GM. Testicular yolk sac and embryonal carcinomas in pediatric patients: comparative immunohistochemical and clinicopathologic study. Am J Clin Pathol. 1984;81:427–435. 43. Woodtli W, Hedinger C. Endodermal sinus tumor or orchioblastoma in children and adults. Virchows Arch. 1974;364:93–110. 44. Griffin GC, Raney RB Jr, Snyder HM, et al. Yolk sac carcinoma of the testis in children. J Urol. 1987;137:954–957. 45. Sabio H, Burgert EO Jr, Farrow GM, et al. Embryonal carcinoma of the testis in childhood. Cancer. 1974;34:2118–2121. 46. Huntington RW Jr, Morgenstern NL, Sargent JA, et al. Germinal tumors exhibiting the endodermal sinus pattern of Teilum in young children. Cancer. 1963;16:34–47. 47. Kao CS, Idrees MT, Young RH, et al. Solid pattern yolk sac tumor: a morphologic and immunohistochemical study of 52 cases. Am J Surg Pathol. 2012;36:360–367. 48. Clement PB, Young RH, Scully RE. Endometrioid-like variant of ovarian yolk sac tumor. A clinicopathological analysis of eight cases. Am J Surg Pathol. 1987;11:767–778. 49. 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;10:151–164. 50. Young RH, Scully RE. Endodermal sinus tumor of the vagina: a report of nine cases and review of the literature. Gynecol Oncol. 1984;18:380–392. 51. Clement PB, Young RH. Pathology of extragonadal yolk sac tumors. In: Nogales FF, ed. The Human Yolk Sac and Yolk Sac Tumors. New York: Springer-Verlag; 1993:285–308. 52. Woodward PJ, Mostofi FK, Talerman A, et al. Germ cell tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. WHO Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: International Agency for Research on Cancer (IARC); 2004:221–249. 53. Brown NJ. Teratomas and yolk-sac tumours. Journal of Clinical Pathology. 1976;29:1021–1025. 54. Grady RW. Current management of prepubertal yolk sac tumors of the testis. Urol Clin North Am. 2000;27:503–508, ix. 55. Sesterhenn IA, Cheville J, Woodward PJ, et al. Sex cord/gonadal stromal tumours. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. WHO Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: International Agency for Research on Cancer (IARC); 2004:250–258. 56. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol. 2005;18(suppl 2):S81–S98. 57. Young RH, Lawrence WD, Scully RE. Juvenile granulosa cell tumor—another neoplasm associated with abnormal chromosomes and ambiguous genitalia. A report of three cases. Am J Surg Pathol. 1985;9:737–743.
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58. Lee SD. Korean Society of Pediatric U. Epidemiological and clinical behavior of prepubertal testicular tumors in Korea. J Urol. 2004;172:674–678. 59. Hisamatsu E, Takagi S, Nakagawa Y, et al. Prepubertal testicular tumors: a 20-year experience with 40 cases. Int J Urol. 2010;17:956–959. 60. Fagin R, Berbescu E, Landis S, et al. Juvenile granulosa cell tumor of the testis. Urology. 2003;62:351. 61. Bai S, Wei S, Ziober A, et al. SALL4 and SF-1 are sensitive and specific markers for distinguishing granulosa cell tumors from yolk sac tumors. Int J Surg Pathol. 2013;21:121–125. 62. 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;88:328–332. 63. Cao D, Li J, Guo CC, et al. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009;33:1065–1077. 64. Zynger DL, McCallum JC, Luan C, et al. Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: immunohistochemical investigation with analysis of histological growth patterns. Histopathology. 2010;56:750–757. 65. Zynger DL, Dimov ND, Luan C, et al. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30:1570–1575. 66. Cao D, Humphrey PA. Yolk sac tumor of the testis. J Urol. 2011;186:1475–1476. 67. Cao D, Humphrey PA, Allan RW. SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors, with particular utility in detection of metastatic yolk sac tumors. Cancer. 2009;115: 2640–2651. 68. Niehans GA, Manivel JC, Copland GT, et al. Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer. 1988;62: 1113–1123. 69. Siltanen S, Anttonen M, Heikkila P, et al. Transcription factor GATA-4 is expressed in pediatric yolk sac tumors. Am J Pathol. 1999;155:1823–1829. 70. Siltanen S, Heikkila P, Bielinska M, et al. Transcription factor GATA-6 is expressed in malignant endoderm of pediatric yolk sac tumors and in teratomas. Pediatr Res. 2003;54:542–546. 71. Fernandes ET, Etcubanas E, Rao BN, et al. Two decades of experience with testicular tumors in children at St Jude Children’s Research Hospital. J Pediatr Surg. 1989;24:677–681; discussion 682. 72. Carroll WL, Kempson RL, Govan DE, et al. Conservative management of testicular endodermal sinus tumor in childhood. J Urol. 1985;133:1011–1014. 73. Kaplan GW, Cromie WC, Kelalis PP, et al. Prepubertal yolk sac testicular tumors—report of the testicular tumor registry. J Urol. 1988;140:1109–1112. 74. Ross JH, Kay R. Prepubertal testis tumors. Rev Urol. 2004;6: 11–18. 75. Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin oncol. 2000;18:3809–3818. 76. Schlatter M, Rescorla F, Giller R, et al. Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children’s Cancer Group/Pediatric Oncology Group. J Pediatr Surg. 2003;38:319–324; discussion 319-324. 77. Heidenreich A, Pfister D. Retroperitoneal lymphadenectomy and resection for testicular cancer: an update on best practice. Ther Adv Urol. 2012;4:187–205. 78. De Backer A, Madern GC, Wolffenbuttel KP, et al. Testicular germ cell tumors in children: management and outcome in a series of 20 patients. J Pediatr Urol. 2006;2:197–201. 79. Jeffs RD. Management of embryonal adenocarcinoma of the testis in childhood: an analysis of 164 cases. In: Godden JO, ed. Cancer in Childhood. New York: Plenum Press; 1973:68–77. 80. Roth LM, Panganiban WG. Gonadal and extragonadal yolk sac carcinomas: a clinicopathologic study of 14 cases. Cancer. 1976; 37:812–820. 81. Kaplan WE, Firlit CF. Treatment of testicular yolk sac carcinoma in the young child. J Urol. 1981;126:663–664.
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82. Grady RW, Ross JH, Kay R. Patterns of metastatic spread in prepubertal yolk sac tumor of the testis. J Urol. 1995;153: 1259–1261. 83. Green DM. The diagnosis and treatment of yolk sac tumors in infants and children. Cancer Treat Rev. 1983;10:265–288. 84. Wu HY, Snyder HM III. Pediatric urologic oncology: bladder, prostate, testis. Urol Clin North Am. 2004;31:619–627, xi. 85. Oldenburg J, Aparicio J, Beyer J, et al. Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer. Ann Oncol. 2014. pii:mdu514. [Epub ahead of print]. 86. Vaughn DJ. Primum non nocere: active surveillance for clinical stage I testicular cancer. J Clin Oncol. 2015;33:9–12. 87. Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol. 2008;26:2966–2972. 88. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer. Eur Urol. 2005;48:885–894. 89. Flamant F, Nihoul-Fekete C, Patte C, et al. Optimal treatment of clinical stage I yolk sac tumor of the testis in children. J Pediatr Surg. 1986;21:108–111. 90. Tandstad T, Stahl O, Hakansson U, et al. One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann Oncol. 2014;25:2167–2172. 91. Foster RS, Hermans B, Bihrle R, et al. Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor. J Urol. 2000;164:1943–1944.
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92. Medica M, Germinale F, Giglio M, et al. Adult testicular pure yolk sac tumor. Urol Int. 2001;67:94–96. 93. Cost NG, Lubahn JD, Adibi M, et al. Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors. J Urol. 2014;191: 1485–1490. 94. Perlman EJ, Hu J, Ho D, et al. Genetic analysis of childhood endodermal sinus tumors by comparative genomic hybridization. J Pediatr Hematol Oncol. 2000;22:100–105. 95. Perlman EJ, Cushing B, Hawkins E, et al. Cytogenetic analysis of childhood endodermal sinus tumors: a Pediatric Oncology Group study. Pediatr Pathol. 1994;14:695–708. 96. Bussey KJ, Lawce HJ, Olson SB, et al. Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences—a Children’s Cancer Group study. Genes Chromosomes Cancer. 1999;25:134–146. 97. van Echten J, Timmer A, van der Veen AY, et al. Infantile and adult testicular germ cell tumors. a different pathogenesis? Cancer Genet Cytogenet. 2002;135:57–62. 98. Reuter VE. Origins and molecular biology of testicular germ cell tumors. Mod Pathol. 2005;18(suppl 2):S51–S60. 99. Kato N, Tamura G, Fukase M, et al. Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants. Am J Pathol. 2003;163:387–391. 100. Li QL, Ito K, Sakakura C, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002;109: 113–124. 101. Fan XY, Hu XL, Han TM, et al. Association between RUNX3 promoter methylation and gastric cancer: a meta-analysis. BMC Gastroenterol. 2011;11:92.
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Yolk Sac Tumor of the Testis in Infants and Children A Clinicopathologic Analysis of 33 Cases Kristine M. Cornejo, MD,*w Lindsay Frazier, MD, ScM,z Richard S. Lee, MD,y8 Harry P.W. Kozakewich, MD,wz and Robert H. Young, MD*w
Abstract: We report 33 pure yolk sac tumors of the testis from boys 5 to 71 months of age (mean 20.7 mo) diagnosed from 1918 to 2014. All except 1 underwent orchiectomy, with lymph node dissections (all negative) performed in 18; 21 also received chemotherapy and 12 radiotherapy. The tumors were 1.6 to 7.0 cm (mean 3.7 cm) and were nonencapsulated, with a gray to yellow, often mucoid, cut surface. The commonest pattern was reticularmicrocystic, but macrocystic, papillary, endodermal sinus (Schiller-Duval bodies), labyrinthine, myxomatous, glandular, and solid patterns were also observed. Follow-up was available for 32 patients (mean 100.5 mo; range, 3 to 456 mo). Twentyfour patients (including 4 who did not receive adjuvant therapy) were without evidence of disease, 8 had metastatic disease; 5 of the latter died of tumor and 1 of treatment complications. Two patients with metastasis were cured with radiation with or without chemotherapy. Two or more of the following were associated with a poor outcome in patients presenting with stage I cases: tumor size >4.5 cm (4/6 tumors [67%]), invasion of rete testis and/or epididymis (3/7 tumors [43%]), and necrosis (6/17 tumors [35%]). In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3/24 tumors (13%) (P = 0.0001). It is crucial that this tumor be distinguished from the juvenile granulosa cell tumor, which occurs at a slightly younger age and has distinctive features, although there may be some morphologic overlap. The survival of young boys with testicular yolk sac tumor is very good because of both effective chemotherapy and likely, the inherent characteristics of the tumor in this age group. Key Words: yolk sac tumor, endodermal sinus tumor, prepubertal, testis, germ cell tumor, prognosis, treatment (Am J Surg Pathol 2015;39:1121–1131)
From the *James Homer Wright Pathology Laboratories, Massachusetts General Hospital; Department of wPathology; yUrology, Harvard Medical School; zDepartment of Pediatric Oncology, Dana-Farber Cancer Institute; Department of 8Urology; and zPathology, Boston Children’s Hospital, Boston, MA. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Kristine M. Cornejo, MD, Department of Pathology, UMass Memorial Healthcare, One Innovation Drive, Biotech 3, Worcester, MA 01605 (e-mail: kristine.cornejo@umassmemorial. org). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
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T
esticular tumors in the young (below 20 y of age) have a number of characteristics that differ from those seen in older patients,1 and account for 1% to 2% of neoplasms in the pediatric population.2–5 Benign lesions represent the majority, with most that are malignant being yolk sac tumor.4,6–13 The features of testicular yolk sac tumor, focusing on pediatric examples, were first elaborated in detail in 4 papers published from 1950 to 1962,14–17 shortly after the germ cell nature of this neoplasm was established by Dr Gunnar Teilum, a story recently reviewed in detail elsewhere.18,19 Subsequently, the majority of the focus on testicular yolk sac tumor from the pathology perspective has been with regard to its frequent presence in mixed germ cell tumors in older male individuals.20–22 There has been limited focus on pediatric testicular yolk sac tumors in the era of modern adjuvant therapy, which either did not exist or was not as developed as it is now, at the time of early reports. Those contributions were also undertaken before recent elaboration of some aspects of the histopathology of yolk sac tumors and the description of one important entity in its differential diagnosis, the juvenile granulosa cell tumor (JGCT).23–25 To investigate both its clinical and pathologic aspects, including differential diagnosis, we undertook a review of 33 cases and report our experience with pure yolk sac tumors in prepubertal boys.
MATERIALS AND METHODS Case Selection A search of the surgical pathology and consultation files of the Boston Children’s Hospital from 1918 to 2014 revealed 33 prepubertal pure yolk sac tumors of the testis with hematoxylin and eosin–stained slides available for review; the tumors were diagnosed from 1923 to 2012. Fifteen patients have been previously reported in prior studies from Boston Children’s Hospital.26,27 Ten cases were excluded from the study, as slides were not available for review. The number of slides per case ranged from 1 to 18 slides (mean 4.7). Immunohistochemical stains were reviewed if performed, or results were documented per the original pathology report. Clinical data including presentation, gross description and characteristics, and treatment were recorded. Follow-up was available in all but 1 case. The neoplasms were evaluated for gross aspects, histologic patterns, and
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cytologic features including mitotic count, lymphovascular invasion, and necrosis.
Statistical Analysis Tumors from the metastasizing and nonmetastasizing groups were compared using a Fisher exact test for the histologic features of size >4.5 cm, presence of necrosis, and invasion of the rete testes and/or epididymis. A 2-sided P value of 1980)
1
8
NA
6.0
Orch
NP
No
No
17
Yes
Yes
No
No
2 3 4 5
13 14 15 16
Left NA NA Right
4.0 4.0 4.0 7.0
Orch Orch Orch Orch
NP NP NP NP
Yes No Yes No
No No No No
26 6 42 37
Yes Yes Yes Yes
Yes No No Yes
No No No Yes
No No No No
6
17
NA
6.0
Orch
NP
No
Yes
27
Yes
Yes
No
No
7
20
Right
6.0
NP
NP
No
No
30
Yes
Yes
No
No
8
24
NA
5.0
Orch
NP
No
No
30
Yes
Yes
No
No
9 10 11 12
6 9 13 15
NA Right Right Left
2.5 2.5 3.0 4.0
Orch Orch Orch Orch
Bilat Right Right Left
Yes Yes Yes Yes
Yes Yes Yes Yes
20 21 27 45
Yes Yes No Yes
Yes No Yes Yes
No No No Yes
No No No No
13 14 15
18 18 22
Left Right Right
2.5 4.5 2.5
Orch Orch Orch
Left Right Bilat
Yes Yes Yes
Yes Yes Yes
53 33 31
Yes Yes Yes
Yes No Yes
No No Yes
No No Yes
16 17 18 19 20 21 22
22 23 25 46 71 19 41
NA Right Right Right Left NA Right
2.3 2.0 2.3 3.0 3.0 5.0 4.8
Orch Orch Orch Orch Orch Orch Orch
Bilat Right Bilat Bilat Left Yes Yes
Yes No Yes No Yes No No
Yes Yes Yes Yes Yes Yes Yes
30 47 31 14 42 43 17
No Yes No Yes Yes Yes Yes
Yes No No Yes Yes Yes Yes
No No Yes Yes No No Yes
No No No Yes No No Yes
23 24 25 26 27 28 29 30 31 32 33
42 54 5 6 6.5 7 10 13 16 21 27
Left NA Right Right Left Left Right Left Right Right Left
3.5 5.0 2.8 4.0 2.3 1.6 5.3 3.5 2.5 2.5 3.5
Orch Orch Orch Orch Orch Orch Orch Orch Orch Orch Orch
Yes Yes NP Right NP NP NP NP Right NP NP
No No No No No No No No No No No
Yes Yes Yes Yes No Yes No No No Yes Yes
63 27 15 33 32 13 30 50 48 27 37
Yes No No Yes No Yes No Yes No Yes Yes
Yes Yes No No No No Yes Yes No No No
Yes No No No No Yes NA No No No No
No No No No No No NA No No No No
Follow-up DOD at 3 mo, lung metastasis NED at 456 mo NED at 264 mo NED at 17 mo DOD at 12 mo, lung metastasis at 8 mo s/p rads+chemo DOD at 12 mo, metastasis to retroperitoneum at 11 mo s/p rads DOD at 11 mo, mets to retroperitoneum, liver, lymph nodes DOD at 18 mo, lung metastasis at 4 mo s/p rads+chemo NED at 192 mo NED at 252 mo NED at 72 mo NED at 180 mo, lung metastasis at 8 mo s/p rads+chemo NED at 132 mo NED at 192 mo NED at 168 mo, lung metastasis at 7 mo s/p rads NED at 144 mo NED at 192 mo NED at 144 mo NED at 72 mo NED at 240 mo NED at 72 mo DOOD at 8 mo, metastasis NED at 24 mo NED at 36 mo NED at 121 mo NED at 93 mo NED at 22 mo NED at 12 mo LTF NED at 24 mo NED at 16 mo NED at 12 mo NED at 4 mo
I, orchiectomy alone with minimal to no radiation or chemotherapy; II, combined modality of orchiectomy, RPLND, chemotherapy, and radiation; III, orchiectomy, RPLND and chemotherapy without radiation; IV, orchiectomy and chemotherapy only. Adj indicates adjuvant; chemo, chemotherapy; DOD, died of disease; DOOD, died of other disease; epidid, epididymal; inv, invasion; LTF, lost to follow-up; NA, not available; NED, no evidence of disease; NP, not performed; orch, orchiectomy; rads, radiation; rete, rete testis; s/p, status post; YST, yolk sac tumor.
count ranged from 6 to 63/10 high-power fields (HPF) (mean 31.6/10 HPF, 400). Adjacent testicular parenchyma was negative for intratubular germ cell neoplasia in all cases. Copyright
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Tumor invaded the tunica albuginea in 5 cases, the rete testis in 8, and epididymis in 3 cases. Tumor necrosis was observed in 20 (61%) cases, and lymphovascular invasion was seen in 25 (76%) cases. Immunostaining of 8
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FIGURE 3. Lobulated growth with solid pattern centrally and more typical patterns at the periphery.
FIGURE 1. Macroscopic image of a yolk sac tumor revealing a lobular tan to yellow neoplasm with a mucoid sectioned surface.
The following features correlated with an unfavorable outcome (ie, metastasis and/or death) in patients with pathologic stage (pStage) I disease at diagnosis: 4 of 6 tumors (67%) that were >4.5 cm in largest diameter (P = 0.007); 3 of 7 tumors (43%) in which rete testis and/or epididymal invasion occurred (P = 0.12); 6 of 17 tumors (35%) in which necrosis was identified (P = 0.02). Every tumor in the metastasizing group had 2 or more unfavorable features (6 of 6, 100%).
In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3 of 24 tumors (13%) (P = 0.0001), excluding the patient lost to follow-up. We compared the various treatment regimens with patient outcome. Of the 8 patients in group 1 who underwent orchiectomy alone, with minimal to no radiation or chemotherapy, 5 died of disease (63%). Of the 12 patients in group 2 who underwent orchiectomy with RPLND and chemoradiation, 2 died of disease (17%). Of the 4 patients who underwent orchiectomy with RPLND and chemotherapy alone in group 3, only 1 died, secondary to a complication of chemotherapy without disease. Lastly, of the 10 patients who underwent orchiectomy with or without RPLND and chemotherapy in group 4, all 9 patients with follow-up were alive without disease. Three of these patients underwent orchiectomy alone, 1 of whom had both lymphovascular invasion and necrosis, and a second with a tumor >4.5 cm and necrosis.
FIGURE 2. Lobular growth showing a typical microcystic pattern.
FIGURE 4. Classic reticular-microcystic appearance. A few solid aggregates are also seen.
neoplasms revealed cytoplasmic positivity for a-fetoprotein (AFP) in 6 (75%) tumors and cytokeratin in 4 (50%) tumors. All 8 tumors stained were negative for HCG (0%).
Prognostic Features and Outcome
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FIGURE 5. Several macrocysts are present in the background of reticular-microcystic morphology.
Yolk Sac Tumor of Testis in Infants and Children
DISCUSSION
FIGURE 7. Striking glandular pattern. Even at this low-power magnification, the cells are not as pleomorphic as typically seen in embryonal carcinoma. Also note the prominent myxoid stroma.
Malignant germ cell tumors of the testis are rare in children, and in contrast to postpubertal adolescents and adults in whom the majority are seminomas, embryonal carcinomas, and mixed germ cell tumors, yolk sac tumors and teratomas are the most common.1,10,29,30 The yolk sac tumor is by far the most frequently malignant, as prepubertal testicular teratomas rarely metastasize and have a good prognosis after orchiectomy alone.6–8,10–12,31 The yolk sac tumor is one of the most fascinating human neoplasms.19,32–36 The first recognizable case was a testicular example reported in 1910.37 Although Teilum likely saw examples of pure testicular yolk sac tumor, most of his early experience was based on yolk sac tumor as a component of mixed germ cell tumors of the adult testis.38 Although other early writers had recognized a distinctive aspect to the testicular yolk sac tumor as we know it today,39,40 Magner and colleagues first clearly delineated the tumor as a pure neoplasm occurring in young boys.14–16 The work of a British group in 196017
was a further significant, early contribution on the topic. As noted in the introduction, since the time the tumor was established as an entity, there has been relatively little focus overall on pediatric testicular yolk sac tumor, which accounts for the vast majority of pure examples, and its behavior in the contemporary clinical setting.41–46 Furthermore, early descriptions preceded detailed elaborations of morphologic variants of yolk sac tumor, such as hepatoid, glandular, and solid.47–49 Before discussing yolk sac tumor of the prepubertal testis, it is merited to briefly place its features in context with those of human yolk sac tumor overall. The yolk sac tumor occurs at diverse sites and has interesting features that differ from site to site. For example, in the ovary the tumors occur at significantly older age than in the testis, peaking at around 19 years of age, being uncommon in the age group when the pure testicular form is dominantly seen. In females, however, one does see a very similar
FIGURE 6. Admixture of reticular-microcystic and glandular patterns.
FIGURE 8. High-power view of a solid pattern. Note the lack of a lymphocytic infiltrate (in contrast to seminoma).
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TABLE 2. Pathologic Data of Testicular YST Cases (n = 33) Morphologic Feature Patterns Reticular/microcystic Glandular Solid Macrocystic Papillary Endodermal sinus (Schiller-Duval bodies) Myxomatous Labyrinthine Hyaline globules Mitotic count/10 HPF < 10 Z10-19 Z20 LVI Necrosis
FIGURE 9. Papillary pattern, largely endodermal sinus type with Schiller-Duval bodies. Note the presence of papillae with several blood vessels, best seen at the 3:00 to 5:00 position. Some papillae do not show vessels, likely because of the plane of section.
Cases (%) 31 28 21 19 13 7 7 5 24
(94) (85) (64) (58) (39) (21) (21) (15) (73)
1 5 27 25 20
(3) (15) (82) (76) (61)
LVI indicates lymphovascular invasion; YST, yolk sac tumor.
predilection to the early years of life in the case of the yolk sac tumor of the vagina,50 almost all of which occur in the first 2 years of life. Another site where yolk sac tumor is typically seen in the very young is the sacrococcygeal region. Other well-known extragonadal sites, such as the retroperitoneum, mediastinum, and pineal, are usually involved in somewhat older patients. Rare locations of yolk sac tumor include various sites in the head and neck and the stomach and liver, among others, as reviewed in detail elsewhere.51 In the literature, boys with this testicular neoplasm typically have presented with an asymptomatic mass at an average age of 16 to 17 months,52,53 similar to our figure of 20.7 months. Only about 6% occur after 5 years of age.11 In young adults, yolk sac tumor is again seen with some frequency in the testis, but almost always as a component
within a malignant mixed germ cell tumor.20–22 AFP levels are elevated in the majority of childhood cases (90%).52 As testicular yolk sac tumors are not hormonally active, these patients lack endocrine-related symptoms, a contrast with ovarian examples, which occasionally are hormonally active due to stromal luteinization (so-called ovarian tumors with functioning stroma), a phenomenon that does not have a testicular counterpart.54 The tumors have ranged from 1 to 12 cm in maximum dimension, but most often are circa 4 cm, and are pale gray to yellow and solid, with a mucoid cut surface.41,43,52 In some cases, particularly in large tumors, hemorrhage and necrosis may be present.41,52 When considering the differential diagnosis of the yolk sac tumor, it is crucial to emphasize the importance of the age in formulating the differential diagnosis of a testicular mass.1 The common neoplasms of the young adult male (seminoma, embryonal carcinoma, and mixed forms) are almost never seen in the first 5 years of life (old cases of infantile embryonal carcinoma are yolk sac tumors according to current
FIGURE 10. Prominent growth of cells in ribbons, sometimes forming drape-like formations (festoons) and communications with each other (labyrinthine).
FIGURE 11. Primitive-appearing tumor cells with pale to clear cytoplasm, enlarged nuclei with irregular borders, prominent nucleoli, and brisk mitotic activity.
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FIGURE 12. Numerous intracellular and extracellular hyaline globules.
knowledge).1 More realistic than the differential with other germ cell tumors is that with the JGCT, as it is typically a tumor of the young, and some microscopic overlap exists. Although there is age overlap as well, the JGCT typically occurs within the first 6 months of life (90%), with the majority (51%) occurring in the first month, followed by a minority in the second (12%), third (12%), 4 to 6 months (15%), 6 to 12 months (4%), and >12 months (6%).25 JGCTs are rare after the first year, in contrast to the mean age of 16 to 17 months for yolk sac tumors, with only 3 of the later in our series being from a child 6 months or less.24,52,55–57 A few JGCTs may be associated with an abnormal karyotype and ambiguous genitalia but lack the elevated serum AFP levels seen in the majority of patients with yolk sac tumors, unless in the neonatal period, when some elevation may be seen.24,52,55–57 Therefore, males above 6 months of age with elevated AFP > 100 ng/mL should be evaluated for a yolk sac tumor.3,58,59 Macroscopically, JGCTs are tan to yellow, with usually a mixture of solid and cystic components.52,60 They may be uniformly solid and indistinguishable from a yolk sac tumor. The cysts are variable in size and may measure up to 6.5 cm.60 Microscopically, JGCTs typically contain follicles with mucinous material and solid areas with granulosa cells that have abundant eosinophilic to vacuolated cytoplasm and round nuclei.24,56,57 When follicles are absent or few in number in a JGCT and some separation of tumor cells is seen, the reticular pattern of yolk sac tumor may be mimicked to a degree. Brisk mitotic activity is a shared, potentially confusing aspect of the 2 tumors. In the largest series of testicular JGCTs, necrosis was an uncommon feature, present in only 1 of 70 cases evaluated and may help in differentiating these 2 entities.25 Immunohistochemical stains are helpful in differentiating these 2 neoplasms, as JGCTs are positive for inhibin and FOXL2 and negative for AFP, glypican-3, and SALL4, whereas yolk sac tumors have the opposite immunoprofile.25,61 Yolk sac tumors are typically diagnosed on routine sections. However, in certain instances immunohistoCopyright
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chemical markers may aid in the diagnosis. The most widely known marker used to diagnose yolk sac tumor historically has been AFP. However, immunoreactivity for AFP, although found in the majority of tumors, is often variable and weak in intensity, and a negative AFP immunostain does not exclude the diagnosis.42,52,62,63 Glypican-3, an oncofetal protein found to regulate cell growth and differentiation during embryogenesis is also positive in yolk sac tumors, with a better sensitivity than AFP.64,65 Similar to AFP, immunoreactivity has been reported in some studies to be weak and patchy.47,63 SALL4, which is a newer immunohistochemical marker, has also been found to be strongly positive in yolk sac tumors, including metastases, and appears to be a more sensitive marker than glypican-3 and AFP.63,66,67 However, comparable to the other immunohistochemical stains, it can stain other types of tumors and is not specific for yolk sac tumors.63,67 Additional immunohistochemical markers that may be helpful are cytokeratin, which is positive, and EMA and OCT3/4, which are typically negative in yolk sac tumors.47,68 Therefore, it is best to use a panel of immunostains. The few cases in our study that underwent immunohistochemical evaluation revealed reactivity for AFP (75%) and cytokeratin (50%) in the majority of cases. GATA-4 and GATA-6 immunostains have also been reported to be positive in yolk sac tumors, although studies are limited.69,70 The majority (80% to 85%) of prepubertal patients with testicular yolk sac tumors have cStage I disease, with metastasis at presentation in only about 20% of the cases.3,10,52,54,71–73 In our series, all of the patients presented with pStage I disease except for 2 (6%), which were cStage III. Orchiectomy alone with observation (the watch and wait or active surveillance strategy) will cure the majority of patients.74–78 Earlier studies noted the unexpectedly favorable prognosis of these neoplasms despite their histology.17,46 Magner et al16 and Teoh et al17 both noted that approximately 70% of patients were without evidence of disease with orchiectomy and minimal adjuvant therapy (2 patients received radiotherapy). The group I experience similarly taught us that some patients could be cured with orchiectomy and minimal adjuvant therapy, but this was less than half of the patients (3 of 8, 38%). Historically, RPLNDs were included in surgical protocols for therapeutic and staging purposes.54 When chemotherapy and radiation therapy with radical surgery developed, these modalities were applied to yolk sac tumors.26 The group II patients (n = 12) were treated very intensively with all forms of available adjuvant therapy. All patients were treated with orchiectomy and staged with RPLND at the time of presentation. Ten received radiation, and all 12 received chemotherapy. All 12 patients survived. Two required salvage chemotherapy and/ or radiation therapy to treat pulmonary metastasis. Survival improved from 38% for group I cases to 100% with the aggressive adjuvant therapy given in group II. This had its price, as the detrimental effects of radiation therapy of that period became evident, especially with regard
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to bone growth and scoliosis. Concern about long-term effects of radiation therapy in children as well as the efficacy of actinomycin-D led to omission of radiotherapy from the routine treatment protocol of yolk sac tumors in 1975. The group III patients were treated with orchiectomy, RPLND, and chemotherapy, and all 4 were cured of their tumor. One child died of bleomycin pulmonary toxicity 8 months after treatment with no evidence of disease. The omission of radiation therapy in this group did not affect disease-free survival. Similarly, a study analyzing treatment modalities in yolk sac tumors revealed a mortality rate of 36% with orchiectomy alone compared with 39% with orchiectomy and radiation, which also supports there being no role for radiotherapy.79 The role of RPLND eventually became controversial. Young and colleagues reported 18 cases of yolk sac tumors all treated with orchiectomy and 8 with lymph node dissections, none of which were positive. There was no difference in survival between the patients who underwent lymphadenectomy (75%) and those who did not (83%).41 Roth and Panganiban reported 6 patients, 2 of whom underwent RPLND. One patient died postoperatively secondary to complications and was found to have only 1 positive lymph node. The second patient had 45 negative lymph nodes.80 Conversely, Kaplan and Firlit reported 12 patients, all of whom underwent RPLND, and 4 (33%) had nodal disease.81 Treatment regimens subsequently changed, with a shift away from radiotherapy and RPLND; the latter were discontinued given that: (1) the morbidity was associated with abdominal surgery in children; (2) most RPLND were negative; and (3) yolk sac tumors commonly metastasized hematogenously and less commonly through lymphatics.12,44,54,73,74,82–84 In our series, all 18 patients who underwent RPLND had negative nodes. RPLND currently has a minimal role in both the prechemotherapy and postchemotherapy setting. RPLND is rarely offered before chemotherapy as a therapeutic and prognostic procedure, as chemotherapy has been found to be superior in patients with cStage I disease in a randomized trial.85–87 RPLND is limited mainly to postchemotherapy patients with persistent retroperitoneal involvement after chemotherapy, persistent elevated serum AFP levels after chemotherapy without evidence of metastasis on imaging studies, or normal or unknown serum AFP levels at the time of diagnosis, as it cannot be dependably followed as an indicator of recurrence or metastasis.10,12,45,54,72,77,88 In addition, it may be offered to patients who are unwilling to participate in active surveillance or chemotherapy.77,88 Although we previously advocated chemotherapy in pStage I disease, the literature no longer supports this practice. Flamant et al89 studied 24 patients with cStage I yolk sac tumors. None underwent RPLND, and 12 did not receive chemotherapy. The remaining 12 were treated with multidrug chemotherapy. No statistically significant difference in survival or relapse-free survival was demonstrated between those receiving chemotherapy and the
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group with orchiectomy alone. The 3-year survival rate was 96%, and the 3-year relapse-free survival rate was 84%.89 Similarly, Carroll et al72 prospectively treated 5 cStage I patients with orchiectomy alone, and they were all without evidence of disease at a median follow-up period of 46 months, supporting that RPLND and adjuvant therapy are not indicated as long as serum AFP levels return to normal. Protocols for adjuvant therapy have changed to avoid overtreatment and to minimize drug toxicity to patients.75 Therefore, with active surveillance, most children will be spared chemotherapy exposure. Multidrug chemotherapy protocols using platinum-based regimens have improved survival in prepubertal patients with yolk sac tumor, similar to group 4 in our series with a survival rate of 100%.10,54,84,88,90 Patients on active surveillance will undergo close follow-up with routine CT examination of the chest, abdomen, and pelvis and testing for serum AFP levels to assess for metastasis and/or recurrence.10,54,74 Approximately 20% of patients will recur, but most can be salvaged with chemotherapy with cure rates near 100%.12,74–76,88 Metastasis typically occurs through hematogenous spread in up to 40% of cases to sites such as the kidney and lungs but also through the lymphatics in up to 27% of cases to the retroperitoneal lymph nodes.52,72,82,84 Metastasis typically occurs within 2 years of diagnosis.43,45,73 All 8 patients with metastasis in our series either presented with spread or developed it within 11 months. Therefore, after 2 to 3 years of follow-up, recurrence is unlikely, and follow-up visits can be tailored accordingly. Although rare, pure yolk sac tumors of the adult testis have been reported with the largest series comprising 12 cStage I tumors.91,92 Similar to cStage I nonseminoma germ cell tumors (30%), retroperitoneal lymph node metastases occurred in 33% of patients.91 Therefore, it was proposed that pure yolk sac tumors of the adult behaved differently from its juvenile counterpart, and comparable to other nonseminoma germ cell tumors in the adult testis. Adult yolk sac tumors were also more likely to spread through the lymphatics, in contrast to the more common hematogenous spread in juvenile tumors, indicating that RPLND may be reasonable in adult patients.91,92 One of the main predictors of relapse in cStage I tumors on active surveillance is lymphovascular invasion, and in some instances the patient may be offered adjuvant chemotherapy on the basis of this finding despite the tumor being confined to the testis.85,86,88,93 In our study, lymphovascular invasion was identified in 78% of cases, so this approach may potentially expose a considerable number of patients to unnecessary chemotherapy. Histologic features such as tumor size >4.5 cm, invasion of the rete testis and/or epididymis, and presence of necrosis may help in identifying the small subset of tumors that may behave aggressively, as all tumors that spread had 2 or more of these features. In contrast, the presence of 2 or more unfavorable features occurred in only 3 of 24 tumors (13%) in the nonmetastasizing group with Copyright
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follow-up, which was statistically significant (P = 0.0001). However, most of the data were collected in the era of suboptimal staging and therapy. It is unclear as to whether these factors remain relevant in the era of effective chemotherapy. The only patient from group 4 with 2 of the histologic features was lost to follow-up. Genetic studies have revealed recurrent anomalies in prepubertal yolk sac tumors of the testis. The most common recurrent findings were gains of 20q and loss of 1p and 6q. Additional chromosomal aberrations such as gains of chromosomes 1q, 11q, and 22 and loss of chromosome 16q have also been reported.52,94 Gains of chromosome 12p, which is characteristic of postpubertal and adult germ cell tumors, are not identified in these neoplasms, with the exception of a rare case, suggesting an alternative pathogenetic pathway.94–98 Little is known about the genes involved in the development of yolk sac tumors. The recurrent chromosomal anomalies in yolk sac tumors, such as the loss of 1p, indicate that the deletion of certain genes may play a role in its pathogenesis. The runt-related transcription factor 3 (RUNX3) gene found on chromosome 1p36.1 has been implicated as a tumor-suppressor gene associated with gastric cancer.99–101 Hypermethylation of the RUNX3 gene promoter was identified in 8 of 10 (80%) infantile yolk sac tumors, whereas it was not identified in any of the adult germ cell tumors and normal infantile testes analyzed. In addition, loss of heterozygosity in 1p36.1 was identified in 6 of 8 (75%) infantile yolk sac tumors and infrequently in adult germ cell tumors (16%), suggesting that the RUNX3 gene plays a role in the development of prepubertal yolk sac tumors.99 These new insights into the genetic pathways involved in the development of yolk sac tumors appear promising and may eventually identify possible targets for therapy. In conclusion, our series of pure yolk sac tumors of the prepubertal testis highlights the clinicopathologic features and prognosis of these neoplasms. Although most yolk sac tumors of the testis are cStage I and have a good prognosis, a small subset metastasizes. Pathologic features such as tumor size >4.5 cm, necrosis, and invasion of the rete testis and/or epididymis may help identify tumors with aggressive behavior and a need for chemotherapy in addition to orchiectomy, rather than surveillance only, which is associated with a good outcome in most cases. REFERENCES 1. Ulbright TM, Young RH. Testicular tumors in the young. Semin Diagn Pathol. 2014;31:323–381. 2. Brosman SA. Testicular tumors in prepubertal children. Urology. 1979;13:581–588. 3. Kay R. Prepubertal Testicular Tumor Registry. J Urol. 1993;150: 671–674. 4. Bujons A, Sfulcini JC, Pascual M, et al. Prepubertal testicular tumours and efficacy of testicular preserving surgery. BJU Int. 2011;107:1812–1816. 5. Coppes MJ, Rackley R, Kay R. Primary testicular and paratesticular tumors of childhood. Med Pediatr Oncol. 1994;22: 329–340.
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58. Lee SD. Korean Society of Pediatric U. Epidemiological and clinical behavior of prepubertal testicular tumors in Korea. J Urol. 2004;172:674–678. 59. Hisamatsu E, Takagi S, Nakagawa Y, et al. Prepubertal testicular tumors: a 20-year experience with 40 cases. Int J Urol. 2010;17:956–959. 60. Fagin R, Berbescu E, Landis S, et al. Juvenile granulosa cell tumor of the testis. Urology. 2003;62:351. 61. Bai S, Wei S, Ziober A, et al. SALL4 and SF-1 are sensitive and specific markers for distinguishing granulosa cell tumors from yolk sac tumors. Int J Surg Pathol. 2013;21:121–125. 62. 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;88:328–332. 63. Cao D, Li J, Guo CC, et al. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol. 2009;33:1065–1077. 64. Zynger DL, McCallum JC, Luan C, et al. Glypican 3 has a higher sensitivity than alpha-fetoprotein for testicular and ovarian yolk sac tumour: immunohistochemical investigation with analysis of histological growth patterns. Histopathology. 2010;56:750–757. 65. Zynger DL, Dimov ND, Luan C, et al. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006;30:1570–1575. 66. Cao D, Humphrey PA. Yolk sac tumor of the testis. J Urol. 2011;186:1475–1476. 67. Cao D, Humphrey PA, Allan RW. SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors, with particular utility in detection of metastatic yolk sac tumors. Cancer. 2009;115: 2640–2651. 68. Niehans GA, Manivel JC, Copland GT, et al. Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer. 1988;62: 1113–1123. 69. Siltanen S, Anttonen M, Heikkila P, et al. Transcription factor GATA-4 is expressed in pediatric yolk sac tumors. Am J Pathol. 1999;155:1823–1829. 70. Siltanen S, Heikkila P, Bielinska M, et al. Transcription factor GATA-6 is expressed in malignant endoderm of pediatric yolk sac tumors and in teratomas. Pediatr Res. 2003;54:542–546. 71. Fernandes ET, Etcubanas E, Rao BN, et al. Two decades of experience with testicular tumors in children at St Jude Children’s Research Hospital. J Pediatr Surg. 1989;24:677–681; discussion 682. 72. Carroll WL, Kempson RL, Govan DE, et al. Conservative management of testicular endodermal sinus tumor in childhood. J Urol. 1985;133:1011–1014. 73. Kaplan GW, Cromie WC, Kelalis PP, et al. Prepubertal yolk sac testicular tumors—report of the testicular tumor registry. J Urol. 1988;140:1109–1112. 74. Ross JH, Kay R. Prepubertal testis tumors. Rev Urol. 2004;6: 11–18. 75. Mann JR, Raafat F, Robinson K, et al. The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin oncol. 2000;18:3809–3818. 76. Schlatter M, Rescorla F, Giller R, et al. Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children’s Cancer Group/Pediatric Oncology Group. J Pediatr Surg. 2003;38:319–324; discussion 319-324. 77. Heidenreich A, Pfister D. Retroperitoneal lymphadenectomy and resection for testicular cancer: an update on best practice. Ther Adv Urol. 2012;4:187–205. 78. De Backer A, Madern GC, Wolffenbuttel KP, et al. Testicular germ cell tumors in children: management and outcome in a series of 20 patients. J Pediatr Urol. 2006;2:197–201. 79. Jeffs RD. Management of embryonal adenocarcinoma of the testis in childhood: an analysis of 164 cases. In: Godden JO, ed. Cancer in Childhood. New York: Plenum Press; 1973:68–77. 80. Roth LM, Panganiban WG. Gonadal and extragonadal yolk sac carcinomas: a clinicopathologic study of 14 cases. Cancer. 1976; 37:812–820. 81. Kaplan WE, Firlit CF. Treatment of testicular yolk sac carcinoma in the young child. J Urol. 1981;126:663–664.
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Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Am J Surg Pathol
Volume 39, Number 8, August 2015
82. Grady RW, Ross JH, Kay R. Patterns of metastatic spread in prepubertal yolk sac tumor of the testis. J Urol. 1995;153: 1259–1261. 83. Green DM. The diagnosis and treatment of yolk sac tumors in infants and children. Cancer Treat Rev. 1983;10:265–288. 84. Wu HY, Snyder HM III. Pediatric urologic oncology: bladder, prostate, testis. Urol Clin North Am. 2004;31:619–627, xi. 85. Oldenburg J, Aparicio J, Beyer J, et al. Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer. Ann Oncol. 2014. pii:mdu514. [Epub ahead of print]. 86. Vaughn DJ. Primum non nocere: active surveillance for clinical stage I testicular cancer. J Clin Oncol. 2015;33:9–12. 87. Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol. 2008;26:2966–2972. 88. Albers P, Albrecht W, Algaba F, et al. Guidelines on testicular cancer. Eur Urol. 2005;48:885–894. 89. Flamant F, Nihoul-Fekete C, Patte C, et al. Optimal treatment of clinical stage I yolk sac tumor of the testis in children. J Pediatr Surg. 1986;21:108–111. 90. Tandstad T, Stahl O, Hakansson U, et al. One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group. Ann Oncol. 2014;25:2167–2172. 91. Foster RS, Hermans B, Bihrle R, et al. Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor. J Urol. 2000;164:1943–1944.
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