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Yolk Sac Surprise!Ovarian and Extraovarian Pelvic Yolk Sac Tumors in

WomenCharles Zaloudek, M.D.

Professor, Department of PathologyUniversity of California, San Francisco

505 Parnassus Ave., M563San Francisco, CA 94143

charles.zaloudek@ucsf.edu

Malignant Germ Cell Tumors in Females

9 SEER Registries, 1973-2002

Tumor N %Immature Teratoma 449 35Malignancy in Benign Teratoma 37 3Dysgerminoma 414 33Yolk Sac Tumor 183 15Embryonal Carcinoma 52 4Choriocarcinoma 27 2Mixed Germ Cell Tumor 100 8

Obstet Gynecol 2006;107:1075-1085

Yolk Sac Tumor• Most occur in girls and young women; average

age 19• Rare cases in elderly women associated with

endometrioid carcinoma• Clinical presentation: abdominal pain, palpable

mass• Stage

– 70% stage I (none bilateral)– 30% stage > I (peritoneum, distant)

• Differentiates toward yolk sac or vitelline structures ∴ secretes α-fetoprotein, AAT

Yolk Sac Tumor

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Yolk Sac Tumor

Yolk Sac Tumor Histologic Patterns

Microcystic (aka Reticular)Macrocystic

SolidEndodermal sinus (aka festoon)

PapillaryGlandular/alveolar (including intestinal,

endometrioid)Polyvesicular vitelline

Myxoid (aka myxomatous)Parietal

Hepatoid

Embryological Classification of Yolk Sac TumorHistologic patterns correspond to types of

differentiation of primitive endoderm

Site Tissue PatternExtraembryonal endoderm

Primary endoderm and secondary yolk sac

MicrocysticSolidEndodermal sinus

Allantois PVVMurine parietal yolk sac

Parietal

Somatic endoderm

Primitive intestine and lung

GlandularYolk sac tumor - reticular

pattern

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Yolk sac tumor - solid pattern

Yolk sac tumor - yolk sac, or festoon pattern

Yolk Sac Tumor – Schiller Duval Bodies

PASD

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Papillary YST

Glandular-alveolar pattern

Yolk sac tumor - polyvesicular vitelline pattern

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Myxoid YST Basement membrane material - Parietal pattern

Yolk Sac TumorSurvival Rates

Stage Pre-ChemoModernChemo

I 16% 100%

II-IV 8% > 60%

Yolk Sac Tumor Immunohistochemistry

Stain ResultCytokeratin AE1/AE3 + CytoplasmEMA, CK7 -OCT4, NANOG -SALL4 +Glypican 3 +Alpha-fetoprotein +CD30 -CD117 (c-kit) -D2-40, PLAP - or minimal

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CKAE1/AE3

α-fetoprotein

Glypican-3 SALL4

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Yolk Sac TumorUCSF Staining Panel

Stain Expected ResultCytokeratin AE1/AE3 + CytoplasmicEMA -CK7 -SALL4 +OCT4 -Glypican 3 +Alpha-fetoprotein +

Yolk Sac TumorDifferential Diagnosis

• Clear cell carcinoma• Endometrioid adenocarcinoma• Hepatoid carcinoma• Juvenile granulosa cell tumor• Embryonal carcinoma• Polyembryoma

Mesonephroma

Yolk Sac Tumor Clear Cell Carcinoma

Gonocytoma; homologous ovarian and testicular tumours. 1. With discussion of “mesonephroma ovarii” (Schiller: Am. J. Cancer, 1939) Teilum, G. Acta Pathol Microbiol Scand 1946;23:243-251.

“Mesonephroma” of the ovary: tumor of Mülleriannature related to endometrioid carcinoma. Scully RE, Barlow JF. Cancer 20: 1405-1417,1967.

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CK 7 Clear Cell Carcinoma vs YST

CK CK7 EMASALL

4GLY3 AFP

CCCa + + + - - -

YST + - - + + +

Yolk Sac Tumors in Older Women

• Ovarian epithelial tumors with a yolk sac tumor component

• First described by Rutgers and Scully• Most patients postmenopausal• Most carcinomas endometrioid, but

carcinosarcoma also described• Typical yolk sac tumor patterns• Usual immunohistochemical findings in

the two components• Poor response to chemotherapy

Nogales FF et al. Am J Surg Pathol 1996;20:1056-1066

Our Case

• 59 year old postmenopausal woman G4P4

• Abdominal distention, pressure.• Various GI symptoms• CT scan showed L adnexal mass

suggestive of malignancy• CA125 elevated at 531 IU/ml

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L

“Solid left adnexal mass with at least 4 implants.”

Surgery

• 2 liters of hemorrhagic ascites removed• 10 cm extensively necrotic tumor resected

from region of left adnexa; grew to involve the anterior abdominal wall, left side of uterus, anterior aspect of the bladder, the sigmoid colon, the cul de sac and the small bowel mesentery

• Did not involve the ovary or fallopian tube

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TIC

p53

Clear cell carcinoma, fallopian tube

Left pelvic tumor, with clear cells

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Hyaline globules HNF-1 β positive

What we learned later…

• Patient had an elevated alpha-fetoprotein

• Additional immunostains performed

Yolk Sac TumorUCSF Staining Panel

Stain Result in CaseCytokeratin AE1/AE3 + CytoplasmicEMA -CK7 -SALL4 +OCT4 -Glypican 3 +Alpha-fetoprotein +HNF 1-β +

Revised Diagnosis for Pelvic Tumor

Extraovarian Yolk Sac Tumor

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What did we learn from this case?

• Yolk sac tumors, in or out of the ovary, can occur in older women, and the diagnosis should not be dismissed ba sed only on the patient’s age without performing approp riate stains

• Hepatocyte nuclear factor 1 β staining cannot be used to differentiate between yolk sac tumor and clear cell carcinoma

• We have now stained about 20 yolk sac tumors for HN F-1βand all have been positive except one, which also d id not stain for AFP

• HNF-1β is a good marker for yolk sac tumor, helpful for identifying it and differentiating it from embryona l carcinoma and dysgerminoma, which are HNF-1 β-

HNF-1β positive in yolk sac tumors

HNF 1β Staining in Germ Cell Tumors

Yolk Sac Tumor +

Embryonal carcinoma

-

Dysgerminoma -

Teratoma+ in immature and

some mature endodermal glands

Immunohistochemistry in Yolk Sac Tumor Differential Diagnosis

Stain Embryonal CA YST Dysgerminoma

Cytokeratin + Membrane + Cytoplasm -EMA - - -OCT4, NANOG + - +SOX2 + - -SALL4 + + +HNF 1β - + -AFP -/+ + -Glypican 3 -/+ + -CD30 + - -CD117, D2-40 - - +

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• HNF-1β should be used with caution pending better delineation of its staining pattern

• Did this tumor originate from the fallopian tube carcinoma – should it be viewed as a combined clear cell carcinoma/yolk sac tumor?