SALL4 as a Useful Marker for the Distinction of Various Gestational Trophoblastic Disease Subtypes: Choriocarcinoma From Other Trophoblastic Lesions and Early Complete Hydatidiform Mole From Partial Mole and NonMolar Villi

Abstract

The distinction between choriocarcinoma and residual trophoblastic cell proliferation from a complete hydatidiform mole/invasive mole (CHM/IM) without villi is challenging on curettage materials. We investigated whether SALL4 immunostaining could help differentiate various gestational trophoblastic diseases. Placental site nodules (PSN; n=10), atypical PSN (APSN; n=8), placental site trophoblastic tumors (PSTT; n=9), epithelioid trophoblastic tumors (ETT; n=5), gestational choriocarcinomas (n=31), partial hydatidiform moles (PHM; n=13), CHM/IM (n=47), and nonmolar products of conception (POC) (n=26) were included. SALL4 immunostaining was quantified (0 [1% to 10%], [11% to 100%]) and characterized (scattered single-cell or clustered nuclear positivity) in 2 locations: cytotrophoblast/intermediate trophoblast and villous stromal fibroblasts. A diffuse (11% to 100%) and clustered pattern of SALL4 immunostaining in cytotrophoblast/intermediate trophoblast was statistically associated with choriocarcinomas (74.2%, 23/31) as compared with PSN (0/10; P <0.0001), APSN (0/8; P =0.0002), PSTT (0/9; P <0.0001), ETT (0/5; P =0.0034), PHM (0/13; P <0.0001), CHM/IM (0/47; P <0.0001), and nonmolar POC (0/26; P <0.0001). Most nonchoriocarcinoma samples showed no SALL4 expression; when present, it was of low level (1% to 10%) and with a scattered single-cell staining in 3/9 PSTT (33%), 1/13 PHM (7.7%), 19/47 CHM/IM (40%), and 1/26 nonmolar POC (1.7%). These results were confirmed using a validation cohort. In addition, 66% (31/47) of CHM/IM villous stromal fibroblasts showed SALL4 expression (11% to 100%) (all before 14 gestational weeks), whereas this level of expression was never observed in PHM (0/13), nor in nonmolar POC (0/26; P <0.0001). Finally, a clustered and >10% SALL4 immunostaining in cytotrophoblast/intermediate trophoblast favors choriocarcinoma diagnosis. SALL4 expression in >10% villous stromal fibroblasts before 14 gestational weeks favors CHM/IM rather than PHM and nonmolar POC.

Keywords: SALL4; gestational trophoblastic disease; gestational trophoblastic neoplasia; hydatidiform mole; immunohistochemistry.

FIGURE 1

SALL4 immunostaining in cytotrophoblast/intermediate trophoblast of choriocarcinomas. A (hematoxylin-eosin-saffron [HES]) and B (SALL4): gestational choriocarcinoma with >10% SALL4 expression and clustered nuclear positivity in cytotrophoblast/intermediate trophoblast on a hysterectomy specimen. C (SALL4): clustered nuclear positivity in an intraplacental choriocarcinoma (tumor on the right and normal villi on the left). D (SALL4): clustered nuclear positivity in a curettage material.

FIGURE 2

SALL4 immunostaining in cytotrophoblast/intermediate trophoblast of CHM/IM and PHM. A (hematoxylin-eosin-saffron [HES]) and B (SALL4): a complete hydatidiform mole with scattered single-cell nuclear positivity in cytotrophoblast/intermediate trophoblast. C (HES) and D (SALL4): invasive hydatidiform mole with absence of SALL4 expression in cytotrophoblast/intermediate trophoblast. E (HES) and F (SALL4): partial hydatidiform mole without any SALL4 positivity in cytotrophoblast/intermediate trophoblast. CHM/IM indicates complete hydatidiform mole/invasive hydatidiform mole; PHM, partial hydatidiform mole.

FIGURE 3

SALL4 immunostaining in cytotrophoblast/intermediate trophoblast of PSTT and ETT. A (hematoxylin-eosin-saffron [HES]) and B (SALL4): placental site trophoblastic tumor showing a scattered <10% SALL4 expression. C (HES) and D (SALL4): epithelioid trophoblastic tumor showing absence of SALL4 expression. ETT indicates epithelioid trophoblastic tumor; PSTT, placental site trophoblastic tumor.

FIGURE 4

SALL4 immunostaining in villous stroma: example of a twin pregnancy with a coexisting CHM and nonmolar POC of a normal fetus. A (hematoxylin-eosin-saffron [HES]): twin pregnancy with a coexisting CHM (green frame, corresponding to C) and nonmolar villi (black frame, corresponding to B) of a normal fetus. B (HES): nonmolar villi component. C (HES): CHM component. D (p57): expression of p57 by villous stromal cells and cytotrophoblast/intermediate trophoblast of the nonmolar villi component. E (p57): absence of p57 expression by villous stromal cells and cytotrophoblast of the CHM component. F (SALL4): absence of SALL4 expression by villous stromal fibroblasts and cytotrophoblast/intermediate trophoblast of the nonmolar villi component, but expression of SALL4 in endothelial cells (box). G (SALL4): SALL4 expression by villous stromal fibroblasts, but the absence of SALL4 expression by cytotrophoblast/intermediate trophoblast of the CHM component. CHM indicates complete hydatidiform mole; HES, hematoxylin-eosin-saffron.