RNA-binding protein LIN28 is a marker for primary extragonadal germ cell tumors: an immunohistochemical study of 131 cases

Abstract

LIN28 has been shown to have an important role in primordial germ cell development and malignant transformation of germ cells in mouse. In this study, we examined the immunohistochemical profile of LIN28 in 131 primary human extragonadal germ cell tumors (central nervous system (CNS) 76, mediastinum 17, sacrococcygeal region 30, pelvis 3, vagina 2, liver 1, omentum 1, and retroperitoneum 1), including the following tumors and/or components: 57 seminomas/germinomas, 10 embryonal carcinomas, 74 yolk sac tumors, 6 choriocarcinomas, 15 mature, and 13 immature teratomas. We compared LIN28 with SALL4 to assess its diagnostic value. To determine its specificity, we examined LIN28 in 406 extragonadal-non-germ cell tumors (103 carcinomas, 91 sarcomas, 9 melanomas, 12 mesotheliomas, 83 lymphomas, 9 plasmacytomas, 82 CNS tumors, and 17 thymic epithelial tumors). The staining was semi-quantitatively scored as 0 (no cell stained), 1 þ (0-30%), 2 þ (31-60%), 3 þ (61-90%), and 4 þ (490%). LIN28 staining was seen in all seminomas/germinomas (3 þ in 1 and 4 þ in 56), embryonal carcinomas (4 þ in all 10), and yolk sac tumors (3 þ in 3 and 4 þ in 71). Variable LIN28 staining was seen in 5 of 6 choriocarcinomas (1 þ to 4 þ ), 8 of 13 immature teratomas (1 þ to 2 þ in immature elements), and in 1 of 15 mature teratomas (1 þ ). Only 11 of 406 non-germ cell tumors showed 1 þ LIN28 staining. Therefore, LIN28 is a sensitive (100% sensitivity) marker for primary extragonadal seminomas/germinomas, embryonal carcinomas, and yolk sac tumors with high specificity. Compared with SALL4, LIN28 demonstrated a similar level of diagnostic sensitivity for seminomas/ germinomas and embryonal carcinomas. For primary extragonadal yolk sac tumors, although SALL4 stained all tumors (1 þ in 1, 2 þ in 2, 3 þ in 10, and 4 þ in 61), LIN28 stained more tumor cells (mean 95 vs 90%, P ¼ 0.03) and was therefore more sensitive. For primary extragonadal yolk sac tumors, combining LIN28 and SALL4 can achieve a higher diagnostic sensitivity than either alone.

Immunohistochemistry in Undifferentiated Neoplasm/Tumor of Uncertain Origin

“…LIN28 is a highly sensitive and relatively specific cytoplasmic marker for primary extragonadal and testicular germ cell tumors, including intratubular germ cell neoplasias, seminomas, yolk sac tumors, and embryonal carcinomas. 114,115 The utility of LIN28 is similar to that of SALL4.…”

“…1,112,113 SALL4 and lin-28 homolog A (LIN28) are highly sensitive and specific markers for identifying a tumor of germ cell origin. [88][89][90][91][92][93][94][95]114,115 The markers for determinining many neoplasms are summarized in Table 3.…”

“…SALL4 and LIN28 are excellent screening markers for germ cell tumors, which are positive in nearly 100% of seminomas, embryonal carcinomas, and yolk sac tumors; 70% of choriocarcinomas; and 50% of teratomas. [88][89][90][91][92][93][94][95][96]114,115 D2-40 and CD117 are specific markers for seminoma; AFP and glypican-3 are specific markers for yolk sac tumors; SOX2, NANOG, and CD30 are relatively specific markers for embryonal carcinomas, although NANOG is also positive in seminomas and SOX2 may be positive in yolk sac tumors; and CD10 and b human chorionic gonadotropin (B-HCG) are specific markers for choriocarcinomas. The useful markers are summarized in Table 22.…”

Lin-28 Homologue A (LIN28A) Promotes Cell Cycle Progression via Regulation of Cyclin-dependent Kinase 2 (CDK2), Cyclin D1 (CCND1), and Cell Division Cycle 25 Homolog A (CDC25A) Expression in Cancer

“…Importantly, the expression of LIN28A/LIN28B is highly restricted to ES cells and developing tissues, and expression dramatically decreases as differentiation progresses (2,3,7,8,11,21,40,41). In human tumors, LIN28A/LIN28B expression is up-regulated/reactivated (4,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) and may function as an oncogene promoting malignant transformation (42,43,52,53), inducing metastasis (43,46,(52)(53)(54), regulating inflammation (5,43), and maintaining the cancer stem cells (43,45,(55)(56)(57). Clinical studies have indicated that higher levels of LIN28A/LIN28B expression are associated with poor clinical outcomes (44,58,59) and that LIN28 family polymorphisms may influence susceptibility to ovarian (60) and breast (61) cancers.…”

Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

“…The above-mentioned studies provided a range of markers that have been validated for the identification of GCNIS and seminoma/(dys)germinoma in tissue specimens by immunohistochemistry, including OCT4 [36,39,49,50], NANOG [51,52], LIN28 [47,53], AP-2γ [54][55][56], podoplanin (PDPN, M2A, D2-40, Aggrus) [57,58], and KIT [33]. The markers that are useful in clinical practice and research are listed in Table 1.…”