• One of four members of the SALL (spalt-like, sal-like) family of transcription factors
• Involved in the maintenance of embryonic stem cell pluripotency and self renewal
• Novel oncogene important in the initiation and progression of cancers

• Spalt-like transcription factor 4
• Sal-like protein 4

• Master regulator of embryonic stem cell pluripotency
• Zinc finger transcriptional factor at 20q13.2
• In mice, essential for neural tube closure, anogenital tract formation, and limb and heart development; loss of SALL4 expression causes differentiation along trophectoderm lineage (Development 2006;133:3005, Nat Cell Biol 2006;8:1114)
• In cancers, interacts with many oncogenic partners as a transcriptional regulator including PTEN/AKT and Wnt/B-catenin pathways, DNMT, OCT 3/4, SOX2, MYC, others (Gene 2016;584:111)
• Impacts cancer cell proliferation, invasion, and chemoresistance (Cancer Lett 2015;357:55)

• SALL4 related disorders: Okihiro / Duane radial ray syndrome, acro-renal-ocular syndrome, thalidomide embryopathy (J Med Genet 2003;40:473)

• Nuclear staining
• Germ cell tumors: strong, uniform nuclear staining (Am J Surg Pathol 2009;33:1065, Am J Surg Pathol 2014;38:410, Cancer 2009;115:2640)
• Hepatocellular carcinoma: punctate / clumped nuclear staining pattern in 94% of cases (Hum Pathol 2013;44:1293)

• General marker of germ cell tumors (SALL4+) and differentiation from sex cord stromal tumors (SALL4-) (Int J Gynecol Pathol 2015;34:528, Int J Surg Pathol 2013;21:121)
• Distinguishes ovarian yolk sac tumor (SALL4+) from clear cell carcinoma (SALL4-) (Am J Surg Pathol 2009;33:894)
• Sensitive (~100%) marker for extragonadal yolk sac tumor with strong diffuse staining (Am J Surg Pathol 2009;33:1529)
• Rhabdoid tumor (SALL4+) versus epithelioid sarcoma (SALL4-) (Hum Pathol 2015;46:225)

• Unfavorable prognosis
  • Hepatocellular carcinoma (N Engl J Med 2013;368:2266, World J Gastro 2016;22:2837)
  • Metastatic colorectal cancer (J Biomed Sci 2013;20:6)
  • Endometrial carcinoma (Oncogene 2015;34:63)
  • Gastric carcinoma (Oncogene 2014;33:5491)
  • Esophageal squamous cell carcinoma (Med Oncol 2014;31:922)

Contributed by Derek Hoerres, M.D.

• Embryonic oocytes, intestine, kidney, hepatocytes (Am J Surg Pathol 2014;38:410)
• Adult germ cells, CD34+ hematopoietic stem cells (Transfusion 2013;53:1037)

• Nearly all non trophoblastic germ cell tumors (seminoma, embryonal carcinoma, yolk sac tumor) and germ cell neoplasia in situ (Am J Surg Pathol 2014;38:410)
• Malignant rhabdoid tumors (88%), Wilms tumor (50%) (Am J Surg Pathol 2011;35:1463, Pathol Oncol Res 2011;17:639)
• Acute myeloid leukemia (Blood 2006;108:2726)
• Diffuse large B cell lymphoma (Am J Surg Pathol 2016;40:950)
• Hepatocellular carcinoma (56%) (N Engl J Med 2013;368:2266)

SALL4 immunohistochemistry is most likely to be positive in which of the following tumor types?


1. Clear cell carcinoma
2. Epithelioid carcinoma
3. Granulosa cell tumors
4. Yolk sac tumor

D. Yolk sac tumor. SALL4 is expressed in most germ cell tumors (except some trophoblastic tumors) and nearly 100% sensitive for gonadal and extragonadal yolk sac tumors. The other answers are typically negative for SALL4, which can be used to differentiate from histologically similar diagnoses which are SALL4 positive.

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Reference: SALL4