Yolk Sac Tumor of the Testis

This is a germ cell neoplasm of the testis. Like embryonal carcinoma, it is classified as a non-seminomatous germ cell neoplasm. It most commonly presents as a painless testicular mass.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLGY	CHARACTERIZATION
SYNONYMS	Endodermal sinus tumor
INCIDENCE	Most common testicular tumor of children 82% of all prepubertal germ cell tumors
AGE-RANGE AND MEDIAN	Newborn to 8 years with 50-75% occurring <2 years In adults, occurs in 17-40 years
GEOGRAPHIC DISTRIBUTION	Whites=Blacks in childhood cases Whites:Blacks 4-5:1 in adult cases

DISEASE ASSOCIATIONS	CHARACTERIZATION
Cryptorchidsim	No association with childhood tumors Common in adult tumors

PATHOGENESIS

CHARACTERIZATION

Role of IGCNU

ICGNU is present in most adult cases but only rarely seen in childhood cases suggesting that childhood tumors result from an oligoclonal intrabular malignant transformation

CHROMOSOMAL ABNORMALITIES

Anomalies of 1p, 6q, 3p

Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants. Kato N, Tamura G, Fukase M, Shibuya H, Motoyama T. Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan.

Am J Pathol. 2003 Aug;163(2):387-91. Abstract quote Testicular yolk sac tumor (YST) of infants is biologically distinct from its adult counterpart. Cytogenetically, YSTs in infants generally lack i(12p), which is highly characteristic of adult germ cell tumors (GCTs), whereas they frequently show a deletion of 1p36, indicating that the loss of a certain gene(s) in this region is an important event in the pathogenesis of infantile YSTs. In the present study, we examined 10 testicular YSTs from infants for promoter methylation status of the RUNX3 gene, localizing in 1p36.1, and loss of heterozygosity (LOH) in this region, on the presumption that RUNX3 acts as a tumor suppressor. Methylation of RUNX3 and LOH at 1p36.1 were detected in 8 of 10 (80%) and 6 of 8 (75%) infantile YSTs examined, respectively. All six cases harboring LOH showed RUNX3 methylation. In contrast, 0 of 12 adult GCTs showed RUNX3 methylation, and LOH at 1p36.1 was less frequent (1 of 6 cases: 16%) in adult GCTs. There is a significant difference in RUNX3 methylation between these 2 groups (P < 0.001). In normal testes of the young group, RUNX3 methylation was not detected. These results strongly suggest that RUNX3 is one of the tumor suppressors involved in the pathogenesis of testicular YSTs in infants.

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
Serum AFP	Elevated levels

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
Gray-white to tan yellow tumors with glistening mucoid cut sruface Hemorrhage and necrosis may be extensive
Extratesticular extension	Rarely occurs

HISTOLOGICAL TYPES

CHARACTERIZATION

Reticular (microcystic, vacuolated, honeycomb)

Most common pattern
Prominent cytoplasmic vacuoles creating a sieve-like appearance and microcysts

Macrocystic

Coalescing of microcysts

Endodermal sinus

Most distinctive with Schiller-Duval bodies characterized by a papillary cord of fibrous tissue containing a central small vessel and ringed by malignant cuboidal and columnar cells

Papillary

Solid

Glandular-alveolar (Intestinal and endometrioid-like)

Myxomatous

Sarcomatoid (Spindle cell)

Polyvesicular vitelline

Hepatoid

Occurs in 20% of tumors
Cells indistinguishable from hepatocytes

Parietal

Eosinophilic bands of basement membrane material recapitulating the parietal layer of the embryonic yolk sac

ADDITIONAL VARIANTS

MICROLITHIASIS

Yolk sac tumor and testicular microlithiasis. Drut R. Servicio de Patologia, Hospital de Ninos Superiora Sor Maria Ludovica, La Plata, Buenos Aires, Argentina.

Pediatr Pathol Mol Med. 2003 Jul-Aug;22(4):343-7. Abstract quote Yolk sac tumor (YST) of prepubertal testis is a peculiar neoplasm with overall good prognosis. There are no known conditions associated with the development of this tumor. The case of a 2-year-old boy with testicular YST and presence of testicular microlithiasis (TM) in the adjacent-still-recognizable testicular tissue is reported. Concentrically laminated microliths were clearly extratubular structures. Ultrasound of the remaining testis revealed microlithiasis. Bilateral TM is being recognized with increasing frequency due to the extensive use of ultrasound. The exact meaning of its finding has not been definitively elucidated, but the association of TM with cryptorchidism, intratubular germ cell neoplasia and germ cell tumors either of the testis or mediastinum is on record. The combination of prepubertal YST and bilateral TM has not been reported previously. Finding of TM at this early age suggests a congenital deranged Sertoli cell function and/or an abnormal gonadal embryogenesis in its pathogenesis.

SPECIAL STAINS/ IMMUNOPEROXIDASE	CHARACTERIZATION
AFP	74-100% positive
Alpha-1-antitrypsin	50%
Cytokeratin	Nearly all cases
EMA	Negative

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Juvenile granulosa cell tumors	Usually <3 months of age Cells are less primitive AFP negative
Immature teratoma	Enteric appearing glands usually are encircle with smooth muscle Usually weak and diffuse AFP staining

PROGNOSIS AND TREATMENT

CHARACTERIZATION

Prognostic Factors

Stage is most important

In mixed germ cell tumors, it is thought that a yolk sac component may convey a relatively better prognosis

Childhood

Overall good prognosis though some find that presentation over 2 years of age may be associated with a poorer prognosis
No difference in survival between histologic patterns
Stage I presentation in 84-94% of cases

Metastasis

Retroperitoneal lymph nodes
Lungs

Treatment

If tumor is limited to testis, some advocate retroperitoneal lymph node dissection (RPLND)

If there is relapse after initial negative nodes, cisplatin-based chemotherapy may be started, with 98-100% survival

If nodes are positive (6 cm or less of total nodal involvement) with chemotherapy, 98% survival

Advanced stage bulky disease

Defined as:
Mediastinal mass >50% intrathoracic diameter
>10 pulmonary metastases per lung field, largest >3cm
Palpable abdominal mass with lung, liver, bone, or brain metastases

Chemotherapy achieves clinical remission in 57%

Childhood disease

If tumor is limited to testis, conservative management with orchiectomy without RPLND has been followed
May have lower rates of lymph node metastases compared to adults
50% cure with chemotherapy in patients with metastatic disease
Lungs are frequent site of relapse

CHEMOTHERAPY/
SURGERY

Risk-adapted treatment for patients with clinical stage I nonseminomatous germ cell tumor of the testis. Amato RJ, etal.
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA

Urology. 2004 Jan;63(1):144-8; discussion 148-9. Abstract quote OBJECTIVES: To evaluate whether two courses of chemotherapy after orchiectomy in patients with clinical Stage I nonseminomatous germ cell testicular tumor at high risk of relapse will spare patients additional chemotherapy or surgery. METHODS: High-risk patients had one or more of the following: preorchiectomy alpha-fetoprotein level of 80 ng/dL or greater, 80% embryonal cell carcinoma or greater, or vessel invasion in the primary tumor. Low-risk patients had none of these factors or had 50% teratoma or more without vessel invasion. High-risk patients were offered two 21-day courses of outpatient chemotherapy consisting of carboplatin, etoposide, and bleomycin. Low-risk patients and high-risk patients not receiving chemotherapy were observed. RESULTS: Of 99 patients, we classified 76 as high risk and 23 as low risk of relapse. All but eight of the high-risk patients received chemotherapy. No patient who underwent chemotherapy developed relapse, although 1 patient with normal biomarkers and a late-appearing mass underwent retroperitoneal lymphadenectomy for mature teratoma. Two of the 23 low-risk patients had disease relapse; both successfully underwent chemotherapy. The nonhematologic toxicity was mild in patients receiving chemotherapy, and no patient required hospitalization. The median follow-up was 38 months (range 9 to 69). CONCLUSIONS: Two courses of postorchiectomy adjuvant chemotherapy were safe and well tolerated and markedly decreased the relapse rate in high-risk patients with clinical Stage I nonseminomatous germ cell testicular tumor without additional surgery or more protracted chemotherapy. This approach may avoid potential problems with compliance and diminish the cost of scrupulous follow-up. Our results support that surveillance for carefully selected patients at a low risk of relapse is appropriate.

Two cycles of carboplatin-based adjuvant chemotherapy for high-risk clinical stage I and stage IM non-seminomatous germ cell tumours of the testis: a HECOG trial. Pectasides D, Skarlos D, Dimopoulos AM, Farmakis D, Pectasides M, Fountzilas G, Aravantinos G. 2nd Department of Medical Oncology, Metaxas Memorial Cancer Hospital, 51 Botassi St, 18537 Piraeus, Greece.

Anticancer Res. 2003 Sep-Oct;23(5b):4239-44. Abstract quote BACKGROUND: We investigated the efficacy and safety of 2 cycles of adjuvant chemotherapy with carboplatin, etoposide and bleomycin (CEB90) in patients with high-risk clinical stage I or stage IM non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: A total of 52 consecutive patients (22 patients with high-risk histological features [vascular invasion, presence of embryonal carcinoma, absence of yolk sac tumour] and 30 with tumour marker activity post-orchidectomy-stage IM) were entered into this prospective study. Chemotherapy consisted of carboplatin 400 mg/m2 or AUC 5 (day 1), etoposide 165 mg/m2 (days 1-3) and bleomycin 30 mg (days 1, 8, 15). Chemotherapy was repeated every 3 weeks. RESULTS: During a median follow-up of 112 months (range, 10 to 174 months), two patietns with stage IM relapsed. These cases had a disseminated, marker-positive germ cell tumour (GCT), extensively involving both liver and lungs in the first case and para-aortic lymph nodes and lung in the second one; both patients died of the tumour after a number of salvage chemotherapy (including high-dose therapy) regimens. Fifty patients (96%) are alive and disease-free. Two cycles of CEB90 were well tolerated and the only side-effects were myelotoxicity and alopecia. CONCLUSION: Despite the general consensus that ciplatin-based chemotherapy is superior to carboplatin-containing regimens in testicular cancer, 2 cycles of CEB90 may be an equally effective treatment option as adjuvant therapy for high-risk clinical stage I and IM patients.

Clinical stage I nonseminomatous germ cell tumors of the testis in childhood and adolescence: an analysis of 31 cases.

Terenziani M, etal.
Pediatric Oncology Unit, Istituto Nazionale Tumori, Milan, Italy.

J Pediatr Hematol Oncol. 2002 Aug-Sep;24(6):454-8. Abstract quote A 20-year single-institution experience of clinical stage I nonseminomatous germ cell tumors of the testis (NSGCTT) in childhood and adolescents was reviewed in relation to clinical characteristics, treatment modalities, and survival. Thirty-one patients with clinical stage I NSGCTT were seen between 1980 and 2000: 14 children and 17 adolescents. Yolk sac tumors and/or teratomas occurred in the children, whereas mixed histologies, including embryonal carcinoma, were predominant in the adolescents. After orchiectomy, the children were assigned to surveillance and the adolescents to active treatment: 16 underwent retroperitoneal lymph node dissection (RPLND) and 1 had adjuvant cisplatin-based chemotherapy because of a high-risk histology. Three of the 14 children (21.4%) relapsed 3, 7, and 8 months after orchiectomy: all 3 had yolk sac tumors and presented with increased alpha-fetoprotein levels. No patients had retroperitoneal relapse; two recurred locally and one in the lung. All three children were treated with cisplatin-based chemotherapy with or without surgery. Among the 16 adolescents undergoing RPLND, 4 (25%) had nodal metastases. Three of the 12 patients (25%) who had negative nodes at RPLND relapsed in the lung 3, 7, and 8 months after RPLND. All were treated with cisplatin-based chemotherapy with or without surgery. Five-year relapse-free and overall survival rates for the whole series were 80.6% and 100%, respectively. This series enabled the authors to pinpoint several important aspects of stage I NSGCTT in children and adolescents. In particular, almost all the childhood cases had the same yolk sac tumor histology, the children tended to have localized disease, and an increased alpha-fetoprotein level had a very high predictive value, suggesting that follow-up should include AFP measurements. A conservative approach is the best option in children, while adolescent NSGCTT behaves like the adult disease and management must include similar treatment strategies.

Comparison of surveillance and retroperitoneal lymph node dissection in Stage I nonseminomatous germ cell tumors
Spermon JR, etal. Department of Urology, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Urology. 2002 Jun;59(6):923-9. Abstract quote OBJECTIVES: To compare retrospectively the treatment results of surveillance and primary retroperitoneal lymph node dissection (RPLND) of patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT) in two institutions in The Netherlands. METHODS: From 1982 to 1994, 90 consecutive patients with clinical Stage I NSGCT were prospectively entered in a surveillance protocol in Amsterdam (group 1). In the same period, 101 patients with clinical Stage I NSGCT underwent primary RPLND in Nijmegen (group 2). Both patient populations were comparable for patient age, presence of vascular invasion, and embryonal cell components in the primary tumor. All patients in group 1 with relapse, except for 2, were treated with cisplatin-based chemotherapy. All patients in group 2 with vital tumor in the RPLND specimen were treated with two adjuvant courses of combined chemotherapy (cisplatin, etoposide, and bleomycin). RESULTS: In group 1, at a median follow-up of 7.7 years, 23 patients (26%) had relapse. The median time to relapse was 12 months. Relapses were located retroperitoneally (n = 18, 78%), in the lung (n = 3, 13%), scrotally (n = 1, 4%), and combined in the liver, lung, and pleura (n = 1, 4%). After treatment of relapses (chemotherapy in 21 and/or surgery in 11), only 1 patient died of disseminated disease. A disease-free survival rate of 98.5% was achieved at the median follow-up. The main toxicities consisted of short-lasting leukopenia, accompanied by infection (13%). Four patients reported cardiovascular and four neuropathy complaints. In group 2, the median follow-up was 6.9 years. In 31 patients (30.7%), vital tumor was found retroperitoneally; after two courses of combined chemotherapy, none of them had a relapse. Seven patients with pathologic Stage I disease (6.4%) had a pulmonary relapse within 1 year after surgery. No retroperitoneal relapses were found. After chemotherapy, 6 patients with relapse were salvaged, and 1 died of disseminated disease. The disease-specific survival rate in group 2 was 98% at the median follow-up. The most frequent surgical complications were lymphocele (n = 3), small bowel obstruction (n = 3), and abdominal pain (n = 3). The antegrade ejaculation rate was 94%. CONCLUSIONS: Excellent treatment results in terms of disease-free survival can be achieved in Stage I NSGCT with both surveillance and primary RPLND. Patients with pathologic Stage II disease adjuvantly treated with chemotherapy did not have any relapse and consequently all survived. Most complications after both treatment strategies are reversible. The choice of treatment should be based on balanced information and not on dogmatic principles.

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