SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases

Abstract

The SALL4 transcription factor is associated with embryonic cell pluripotency and has been shown as a useful immunohistochemical marker for germ cell tumors. However, information of SALL4 distribution in normal human tissues and non-germ cell tumors is limited. In this study we examined normal human tissues and 3215 tumors for SALL4 expression using a monoclonal antibody 6E3 and automated immunohistochemistry. In a 10-week embryo, SALL4 was expressed in ovocytes, intestine, kidney, and some hepatocytes. In adult tissues, it was only detected in germ cells. SALL4 was consistently expressed in all germ cell tumors except some trophoblastic tumors and mature components of teratomas, in which it was selectively expressed in intestinal-like and some squamous epithelia. In non-germ cell carcinomas, SALL4 was detected in 20% of cases or more of serous carcinoma of the ovary, urothelial high-grade carcinoma, and gastric adenocarcinoma (especially the intestinal type). SALL4 was only rarely (≤ 5%) expressed in mammary, colorectal, prostatic, and squamous cell carcinomas. Many SALL4-positive carcinomas showed poorly differentiated patterns, and some showed positivity in most tumor cells mimicking the expression in germ cell tumors. SALL4 was commonly expressed in rhabdoid tumors of the kidney and extrarenal sites and in the Wilms tumor. Expression of SALL4 was rare in other mesenchymal and neuroendocrine tumors but was occasionally detected in melanoma, desmoplastic small round cell tumor, epithelioid sarcoma, and rhabdomyosarcoma. All hematopoietic tumors were negative. SALL4 is an excellent marker of nonteratomatous germ cell tumors, but it is also expressed in other tumors, sometimes extensively. Such expression may reflect stem cell-like differentiation and must be considered when using SALL4 as a marker for germ cell tumors. Observed lack of other pluripotency factors, OCT4 and NANOG, in SALL4-positive non-germ cell tumors can also be diagnostically helpful.

Fig. 1

SALL4 expression in a 10 week-old fetus. A. Ovarian germ cells are strongly positive. B-D. Non-germ cell elements, such as developing tubular and glomerular epithelia, intestinal epithelia, and a portion of hepatocytes, show weaker yet distinct positivity.

Fig. 2

SALL4 in germ cell tumors. A, Seminoma cells are strongly positive but lymphocyte-rich septa are negative. B. Yolk sac tumor epithelium is strongly positive. C. In a trophoblastic component of a testicular germ cell tumor, small trophoblasts are positive but the larger cells including syncytiotrophoblasts are negative. D. In mature components of teratoma, intestinal epithelia is uniformly positive and squamous epithelia focally positive.

Fig. 3

A. Ovarian serous tumor of low malignant potential, B. Urothelial high-grade in situ carcinoma, C. poorly differentiated endometrial carcinoma with a solid pattern, and D. Stroma of sarcomatoid endometrial carcinoma are SALL4-positive.

Fig. 4

SALL4-positive carcinomas. A. Gastric carcinoma of intestinal type. B. Gastric hepatoid carcinoma. C. Poorly differentiated pancreatic adenocarcinoma with a solid pattern. D. Pulmonary adenocarcinoma with acinar differentiation.

Fig 5

A, B. A renal rhabdoid tumor has inclusion-like eosinophilic cytoplasm. Tumor cells are partly SALL4-positive and they show loss of INI1.

Fig. 6

Two examples of Wilms tumor. A. A triphasic tumor with epithelial tubules, purple staining blastema, and pale staining stroma (middle up). B. A tumor predominantly consisting of epithelial tubules. C. The triphasic tumor shows SALL4-expression in the blastema, whereas the epithelial tubules and stroma are negative. D. In the example with tubular differentiation, tubular epithelia are positive.

Fig. 7

A. Metastatic melanoma and B. Desmoplastic stromal tumor are here strongly SALL4-positive, a rare event among these tumors. C. Uterine cervical embryonal rhabdomyosarcoma (botryoid rhabdomyosarcoma) has a high number of SALL4-positive cells in the subepithelial zone. D. An exceptionally SALL4-positive epithelioid sarcoma.