High-level expression of divergent endodermal lineage markers in gonadal and extra-gonadal yolk sac tumors

Yolk sac tumors occur at both gonadal and extra-gonadal sites. A recent case of ovarian endometrioid-pattern yolk sac tumor with strong diffuse expression of TTF-1 illustrated the potential for misdiagnosis due to divergent expression of endodermal lineage markers. The aim of this study was to investigate the expression of four divergent endodermal lineage markers, TTF-1, CDX2, Hep Par 1, and Napsin A, in gonadal and extra-gonadal yolk sac tumors of differing age, sex, and location (excluding foci of overt hepatoid differentiation). We identified 26 cases (5 ovarian, 15 testicular, and 6 extra-gonadal) containing yolk sac tumor as identified by typical histology and confirmed by positive immunohistochemical staining for alpha-fetoprotein and glypican-3. Mixed or ambiguous foci were confirmed by immunohistochemistry (SALL4 positive and Oct-4 negative). The relative proportion of three histologic patterns: reticular/cystic, solid/myxoid, and glandular was estimated. Percent positivity for the four divergent endodermal lineage markers was compared within yolk sac tumor areas according to site, age group, and histologic pattern. High-level (>25%) staining for one or more divergent endodermal lineage markers was seen in eleven cases: Hep Par 1 in seven cases, all post-pubertal, TTF-1 in four cases, two ovarian and two extra-gonadal, and CDX2 in three cases, with no age or site predilection. No case highly expressed all three divergent endodermal lineage markers, but four co-expressed high levels of two markers: two ovarian yolk sac tumors with TTF-1 and Hep Par 1, one testicular yolk sac tumor with CDX2 and Hep Par 1, and one extra-gonadal yolk sac tumors with TTF-1 and CDX2. While no absolute correlation of high-level divergent endodermal lineage marker expression with histologic subtype was observed, TTF-1 and CDX2 expression was predominantly seen in reticular/cystic and glandular areas while Hep Par 1 was most frequent in myxoid/solid and glandular areas.