Diagnostic Utility of Novel Stem Cell Markers SALL4, OCT4, NANOG, SOX2, UTF1, and TCL1 in Primary Mediastinal Germ Cell Tumors

Abstract

Primary mediastinal germ cell tumors (GCTs) are rare and sometimes they pose diagnostic difficulty without immunohistochemical studies. Here, we investigated the diagnostic utility of 6 stem cell markers (SCMs) SALL4, OCT4, NANOG, SOX2, UTF1, and TCL1 in 16 primary mediastinal seminomas, 3 embryonal carcinomas (ECs), 10 yolk sac tumors (YSTs), 7 teratomas (4 mature, 3 immature), and 1 choriocarcinoma. The percentage of tumor cells stained was scored as: 0 (no tumor cell staining), 1+ (< or =30%), 2+ (31% to 60%), 3+ (61% to 90%), and 4+ (>90%). The staining intensity of SCMs was scored as weak, moderate, or strong. We also compared them with currently used GCT markers placental-like alkaline phosphatase (PLAP), alpha-fetoprotein (AFP), c-KIT, CD30, and glypican-3. All 16 seminomas showed staining for SALL4 (4+ in 15, 2+ in 1) (15 strong, 1 moderate), OCT4 (4+ in 11, 3+ in 4, 2+ in 1) (13 strong, 3 moderate), and UTF1 (4+ in 13, 3+ in 2, 2+ in 1) (7 strong, 5 moderate, 4 weak). Positive staining was shown by 9/9 seminomas tested for NANOG (4+ in 7, 2+ in 2) (8 strong, 1 weak), TCL1 (4+ strong in all), c-KIT (4+ in all), and PLAP (4+ in 5, 3+ in 1, 2+ in 2, 1+ in 1), but SOX2 staining was negative in all these tumors. All 3 ECs showed 4+ strong staining for SALL4, OCT4, and UTF1 but negative for TCL1. SOX2 staining was seen in 3/3 ECs (4+ strong in 1, 3+ weak to moderate in 2) whereas NANOG staining was seen in 2/3 ECs (2+ weak, 1+ moderate). CD30 staining was seen in 3/3 ECs (1+, 2+, 4+). Strong SALL4 staining was seen in 10/10 YSTs (4+ in 9, 2+ in 1). All 10 YSTs showed AFP (1+ in 7, 2+ in 1, 3+ in 2) and glypican-3 (1+ in 3, 2+ in 1, 3+ in 5, 4+ in 1) staining but only 4/10 YSTs showed PLAP staining (1+ in all 4). The mean percentage of YST cells stained with SALL4 was 92%, whereas it was 23% for AFP, 50% for glypican-3, and 4% for PLAP (P<0.01). Focal (1+) SALL4 (weak) and SOX2 (weak to moderate) staining was seen in 2/7 and 4/7 teratomas, respectively. The choriocarcinoma was negative for all 6 SCMs. Eleven thymomas and 6 thymic carcinomas were negative for 6 SCMs. No staining of NANOG and SOX2 was seen in 20 lymphomas (5 Hodgkin, 5 large B cell, 5 lymphoblastic, 5 anaplastic large cell) (other 4 SCMs in lymphomas earlier studied). Our study indicates that SALL4, OCT4, NANOG, SOX2, UTF1, and TLC1 are novel sensitive diagnostic markers for primary mediastinal GCTs, with high specificity. Of these 6 SCMs, SALL4 is the only 1 expressed in YST. These novel SCMs are more sensitive than the currently used markers for mediastinal GCTs.

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

“…Primary extragonadal germ cell tumors are uncommon tumors that most often occur in the midline structures and mediastinum, but they can also occur in many other organs, not only in children but also in adults. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Morphologically, primary extragonadal germ cell tumors can mimic many types of non-germ cell tumors. For example, mediastinal seminomas may mimic type B thymomas and embryonal carcinoma may mimic other types of carcinomas.…”

“…The result of SALL4 in these germ cell tumors was previously reported. [10][11][12] To determine its specificity, we also examined LIN28 in 82 primary non-germ cell tumors of the CNS and in 17 primary mediastinal epithelial tumors (thymomas and thymic carcinomas). The immunohistochemical status of LIN28 in other extragonadal non-germ cell tumors (103 carcinomas, 91 sarcomas, 83 lymphomas, 9 plasmacytomas, 12 mesotheliomas, and 9 melanomas) was previously reported.…”

ZNF797 plays an oncogenic role in gastric cancer

“…In adults, SALL4 expression is normally restricted to CD34+ hematopoietic stem/ progenitor cells , and in adult mice, SALL4 is also predominantly expressed in testes and ovaries (Kohlhase et al, 2002b). Nonetheless, SALL4 expression is reported in numerous malignancies, such as precursor B-cell lymphoblastic lymphoma , myelodysplastic syndromes , acute myeloid leukemia (Shuai et al, 2009), endometriotic samples (Forte et al, 2009), ovarian germ cell tumors (Cao et al, 2009a), all types of testicular germ cell tumors (GCTs) (Cao et al, 2009c), all metastatic seminomas/ dysgerminomas and embryonal carcinomas (Cao et al, 2009b), and primary mediastinal yolk sac tumors (Liu et al, 2010). It is suggested that SALL4 may not only be important in the pathogenesis of GCTs, especially to maintain their poorly differentiated status, but can also be used as a highly specific marker to confirm the germ cell origin of a metastatic tumor, due to its sensitivity and specificity (Cao et al, 2009a,b,c).…”

Induced Pluripotency and Oncogenic Transformation Are Related Processes

“…However, Nanog, Sox2, and Oct4 (also known as Pou5f1) are linked to tumorigenesis as well ( [8][9][10] and reviewed in ref. [11]).…”