(Sal-like protein 4)

Nature: Zing finger protein, transcription factor for maintenance of pluripotency, encoded by chromosome 20q13.
Function and occurrence: SALL4 is expressed in germ cells and fetal gut cells. It is a master regulator of embryonal pluripotency together with the other pluripotency-related transcription factors such as OCT4 and NANOG.


+ SALL4 is consistently expressed in germ cell tumors (except some trophoblast tumours). In seminoma, embryonal carcinoma and yolk sac tumour, the expression is strong and uniform. In teratomas, SALL4 may be expressed in intestinal-like and squamous epithelia. Intratubular germ cell neoplasia (ITGCN) and spermatocytic seminomas are generally positive. Hepatoid carcinoma in e.g., stomach is generally positive.
+/- SALL4 is expressed in most cases rhabdoid tumors of the kidney and extrarenal sites and in the Wilms tumor.
-/+ SALL4 is less frequently expressed in serous carcinoma of the ovary (30%), urothelial high-grade carcinoma (20%), and tubular gastric adenocarcinoma.
-(+) SALL4 is rarely expressed in mammary, lung, colorectal, pancreatic, prostatic, endometrioid and squamous cell carcinomas, particularly those showing poorly differentiated patterns. SALL4 has also been detected in few cases of rhabdoid tumour, malignant melanoma, desmoplastic small round cell tumor, epithelioid sarcoma, and rhabdomyosarcoma.
- SALL4 is not expressed in sarcomas (apart from the above mentioned) and haematolymphoid neoplasms.


SALL4 is a highly sensitive marker for germ cell tumours but as it is not entirely specific, SALL4 should be used in panels with e.g., OCT4 and NANOG.


Normal testis is recommended as positive tissue control for SALL4. The majority of spermatogonia lining the basement membrane in seminiferous tubules must show an at least weak to moderate but distinct nuclear staining reaction. A dot-like staining of nucleoli in dispersed spermatocytes may be seen. No staining of stromal cells, including Leydig cells, should be seen. Appendix can be used as negative tissue control. No staining reaction should be seen.

Selected references

Agackiran Y, Ozcan A, Akyurek N, Memis L, Findik G, Kaya S. Desmoglein-3 and Napsin A double stain, a useful References Cao D, Guo S, Allan RW, et al..SALL4 is a novel sensitive and specific marker of ovarian primitive germ cell tumors and is particularly useful in distinguishing yolk sac tumor from clear cell carcinoma.Am J Surg Pathol.2009;33:894–904. Cao D, Li J, Guo CC, et al..SALL4 is a novel diagnostic marker for testicular germ cell tumors.Am J Surg Pathol.2009;33:1065–1077. Gonzalez-Roibon N, Katz B, Chaux A, et al..Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors.Hum Pathol.2013;44:1293–1299. Ikeda H, Sato Y, Yoneda N, et al..[alpha]-Fetoprotein-producing gastric carcinoma and combined hepatocellular and cholangiocarcinoma show similar morphology but different histogenesis with respect to SALL4 expression.Hum Pathol.2012;43:1955–1963. Kobayashi D, Kuribayashi K, Tanaka M, et al.Overexpression of SALL4 in lung cancer and its importance in cell proliferation.Oncol Rep.2011;26:965–970. Kobayashi D, Kuribayshi K, Tanaka M, et al..SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer.Int J Oncol.2011;38:933–939. Liu A, Cheng L, Du J, et al..Diagnostic utility of novel stem cell markers SALL4, OCT4, NANOG, SOX2, UTF1, and TCL1 in primary mediastinal germ cell tumors.Am J Surg Pathol.2010;34:697–706. Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS. SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases. Am J Surg Pathol. 2014 Mar;38(3):410-20. Ushiku T, Shinozaki A, Shibahara J, et al..SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma.Am J Surg Pathol.2010;34:533–540. Wang F, Liu A, Peng Y, et al..Diagnostic utility of SALL4 in extragonadal yolk sac tumors: an immunohistochemical study of 59 cases with comparison to placental-like alkaline phosphatase, alpha-fetoprotein, and glypican-3.Am J Surg Pathol.2009;33:1529–1539. Warren M, Wang W, Spiden S, et al..A SALL4 mutant mouse model useful for studying the role of SALL4 in early embryonic development and organogenesis.Genesis.2007;45:51–58. Yang J, Chai L, Fowles TC, et al..Genome-wide analysis reveals SALL4 to be a major regulator of pluripotency in murine-embryonic stem cells.Proc Natl Acad Sci USA.2008;105:19756–19761. Zhang J, Tam WL, Tong GQ, et al..SALL4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1.Nat Cell Biol.2006;8:1114–1123.

22.04.15 - MV/LE