Advances in Anatomic Pathology:
SATB2 is a Novel Marker of Osteoblastic Differentiation and Colorectal Adenocarcinoma
Ordóñez, Nelson G. MD
Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
The author has no funding or conflicts of interest to disclose.
Reprints: Nelson G. Ordóñez, MD, Department of Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: firstname.lastname@example.org).
SATB2 is a nuclear matrix-associated transcription factor and epigenetic regulator that is involved in osteoblastic differentiation and is also expressed in the glandular epithelial cells of the lower gastrointestinal tract. Recent studies have shown that, because of its relative specificity for osteoblastic differentiation, SATB2 immunostaining could potentially be a useful adjunct for assisting in the differential diagnosis of both benign and malignant osteogenic tumors. In addition, because SATB2 is also a highly sensitive and specific marker for colorectal adenocarcinomas, it could also serve as a complementary marker in the differential diagnosis of a carcinoma of unknown primary origin.
SATB2, also known as SATB homeobox 2, SATB family 2, special AT-rich sequence-binding protein 2, DNA-binding protein SATB2, KIAA1034, and FLJ21434, is an AT-rich DNA-binding protein that binds to nuclear matrix attachment regions involved in transcriptional regulation and chromatin remodeling. SATB2 interacts with transcription factors that regulate craniofacial development and cortical neuron differentiation.1–3 It also regulates skeletal development and osteoblast differentiation, and modulates immunoglobulin μ gene expression.4 The SATB2 protein is comprised of 733 amino acids, has a molecular weight of ∼83 kDa, and is encoded by a gene located on chromosome 2q33.1. This gene consists of 11 exons that span approximately for about 201 kb of genomic DNA. Haploinsufficiency of the SATB2 gene in humans is associated with a cleft palate syndrome.5 Animal experimental studies have shown that mice lacking the SATB2 gene display craniofacial abnormalities that resemble those observed in humans carrying a translocation in SATB2, and defects in osteoblastic differentiation and function.1
To the best of my knowledge, only 1 study has been published in which the expression of SATB2 was investigated by immunohistochemistry in a wide variety of normal adult tissues.6 In that investigation, strong positivity was reported in the epithelial cells of the lower gastrointestinal tract, including those of the appendix, colon, and rectum, and in a subset of neuronal cells of the cerebral cortex and hippocampus. Weak to moderate reactivity was seen in a subset of lymphoid cells and in cells of the seminiferous ducts and those lining the epididymis, whereas all other tissues/cells, including epithelial cells of the small intestine, stomach, esophagus, salivary gland, breast, lung, thyroid, and endometrium, exocrine glandular cells and islet cells of the pancreas, urothelial cells, hepatocytes, bile duct cells, renal tubular cells, trophoblastic cells of the placenta, and skeletal and smooth muscle cells were negative for this marker. The purpose of this article is to make pathologists aware of the potential diagnostic applications of SATB2 as a novel immunohistochemical marker of both osteoblastic differentiation and colorectal adenocarcinoma.
SATB2 AS AN OSTEOBLASTIC MARKER
One of the greatest challenges in bone and soft-tissue pathology is the accurate identification of osteoid. Since the late 1980s, a number of cytoplasmic proteins, such as osteonectin7 and osteocalcin,8 and osteoblast lineage restricted nuclear transcription factors, such as SP7,9 all of which are involved in the production of bone matrix, have been investigated as potential immunohistochemical markers of osteoblastic differentiation. Plasma membrane proteins, such as CADM1 (cell adhesion molecule 1),10 NDRG1,11 and CD51,12 have recently been identified by the use of proteomic techniques as potential markers of osteosarcoma, but their practical utility in the diagnosis of bone tumors is unclear. Osteonectin, also known as SPARC (secreted protein acid rich in cysteine), is a calcium-binding glycoprotein that plays a role in a wide variety of biological processes, including cell-matrix interactions during tissue remodeling, wound repair, morphogenesis, cellular differentiation and proliferation, cell migration, and angiogenesis.13–15 Early investigations suggested that osteonectin was a sensitive and specific marker of osteoblastic differentiation that could be helpful in the diagnosis of bone tumors, particularly osteosarcomas.7,8,16 Subsequent studies, however, have demonstrated that even though osteonectin is a very sensitive marker of osteoblastic neoplasms (90%), it has a low specificity for these tumors as expression has been reported in sarcomas other than osteosarcomas (eg, leiomyosarcomas, rhabdomyosarcomas, synovial sarcomas, and malignant fibrous histiocytomas),17,18 melanomas,18,19 and some carcinomas, including sarcomatoid carcinomas.18 Osteocalcin is a vitamin K-dependent, calcium-binding, noncollagenous protein that is predominantly synthesized by osteoblasts and it is thought to play a role in bone mineralization and calcium homeostasis. Similar to osteonectin, osteocalcin was one of the first markers that was considered to be useful for the identification of osteoblastic differentiation in bone and soft-tissue tumors. Osteocalcin, in contrast to osteonectin, is a highly specific marker of osteoblastic tumors, but its sensitivity is lower (70%) than that of osteonectin.17,18 SP7, also known as osterix, is a zinc finger–containing transcription factor that is essential for osteoblastic differentiation and bone formation.9 Although it has been suggested that SP7 could be a useful marker for assisting in the differential diagnosis of bone tumors, the number of immunohistochemical studies on the expression of this marker in these neoplasms is limited.20,21 At present, there is insufficient information available to determine whether SP7 has any practical use as an osteoblastic differentiation marker in the diagnosis of bone and soft-tissue tumors.
In 2013, Conner and Hornick22 investigated SATB2 as a potential marker for osteoblastic differentiation in bone and soft-tissue tumors. SATB2 expression was evaluated in whole sections from 215 tumors, including 52 osteosarcomas (43 skeletal and 9 extraskeletal), 86 other bone neoplasms, and 77 soft-tissue tumors (Table 1). All (100%) of the skeletal osteosarcomas, osteoid osteomas, and fibrous dysplasias, 83% of the giant cell tumors, and 50% of the chondromyxoid fibrous tumors exhibited nuclear positivity for SATB2 (Figs. 1A, B). Staining for SATB2 was described as being predominantly limited to areas of heterologous osteoblastic differentiation. Focal, weak staining was reported in 1 of 11 unclassified pleomorphic sarcomas and in 1 of 9 monophasic synovial sarcomas investigated. No reactivity was seen in any of the soft-tissue tumors with prominent sclerotic stromal collagen. The conclusion of this study was that SATB2 was a relatively specific marker for osteoblastic differentiation in both benign and malignant bone and soft-tissue tumors, and although it is not specific for osteosarcomas, it can potentially be useful in the distinction between hyalinized collagen and osteoid.
SATB2 AS A MARKER FOR COLONIC ADENOCARCINOMA
Although the diagnosis of colonic adenocarcinoma is usually straightforward, it can sometimes be difficult, especially in those cases that present as a metastasis in a patient with no known history of adenocarcinoma of the colon, or when the tumor is poorly differentiated or exhibits morphologic features that overlap with those of other carcinomas, such as mucinous or signet-ring cell. In these instances, the differential diagnosis can be greatly facilitated by the use of immunohistochemistry. Although a specific marker for colonic adenocarcinoma has not yet been recognized, a variety of immunohistochemical markers that are frequently and strongly expressed in this type of tumor have been proven to be useful in various differential diagnoses when used in conjunction with other relevant markers.
Over the past 2 decades, a number of markers have been recognized as being helpful for assisting in the diagnosis of colonic adenocarcinomas. Among these, carcinoembryonic antigen, villin, CDX2, cadherin 17, and keratin 20, alone or in combination with keratin 7, are the ones that have more frequently been recommended in published studies.23–25 Carcinoembryonic antigen was the first marker that was introduced to assist in the diagnosis of colonic adenocarcinomas; however, because its specificity is very low, it is, at present, rarely used as an immunohistochemical marker in the diagnosis of these tumors. Villin is an actin-binding cytoskeletal protein that is associated with the brush border microvilli of the intestine, proximal tubules of the kidney, and seminiferous ducts.26–28 It is commonly expressed in both primary and metastatic adenocarcinomas of the colon and its expression is not related to the degree of tumor differentiation.23,29–31 The specificity of villin for these tumors, however, is low as it can be commonly expressed in adenocarcinomas of the small intestine31,32 and stomach,29,31 enteric-type sinonasal adenocarcinomas,33 lung adenocarcinomas with enteric differentiation,29 adenocarcinomas of the pancreas29,31 and bladder,34 mucinous carcinomas of the ovary,31 and renal cell carcinomas.26,30,35 CDX2 is a Drosophila caudal-related homeobox transcription factor that is involved in the regulation of the development, proliferation, and homeostasis of intestinal epithelial cells and the maintenance of the intestinal phenotype.36 Currently, CDX2 is the intestinal-associated immunohistochemical marker that is most frequently used by surgical pathologists to determine the site of origin of a metastatic carcinoma of unknown primary. Despite its high sensitivity for adenocarcinomas of the gastrointestinal tract, CDX2, like villin, is not specific for colonic adenocarcinomas as it is also frequently positive in adenocarcinomas arising in the small intestine, stomach, and esophagus.31,37 In addition, it is also expressed in neuroendocrine carcinomas of intestinal origin,38 adenocarcinomas of the pancreas and biliary tree,31,37,39 enteric-type sinonasal adenocarcinomas,33 adenocarcinomas of the lung with enteric differentiation,40 and mucinous carcinomas of the ovary.31,37,39 The specificity of CDX2 for colonic adenocarcinomas can be increased when it is used in conjunction with keratin 20 and keratin 7. Keratin 20 is strongly expressed in adenocarcinomas of the colon (∼90% to 100%)41–46 and, although to a lesser degree, in adenocarcinomas of the stomach (∼30% to 80%)42,47–50 and pancreas (∼10% to 70%),42,45,47,51 mucinous carcinomas of the ovary (∼45% to 90%),42,47,52,53 and lung adenocarcinomas (up to 15%).41,42,45,54 Conversely, keratin 7 is uncommonly expressed in colonic adenocarcinomas (∼5% to 35%),43,46,47,55,56 but frequently expressed in adenocarcinomas of the stomach (55% to 90%)47–49,57 and pancreas (∼90% to 100%),45,47,58 mucinous carcinomas of the ovary (80% to 100%),43,47,53 and lung adenocarcinomas (∼95% to 100%).45,55 Cadherin 17, also known as liver-intestine cadherin, is one of the most recently recognized immunohistochemical markers that has been found to be useful in the diagnosis of adenocarcinomas of the digestive system. It is expressed in the intestinal epithelium and it is transcriptionally regulated by CDX2.59 Recent investigations have shown that, among adenocarcinomas of the gastrointestinal tract, cadherin 17 is expressed in the large majority of adenocarcinomas of the colon, stomach, and esophagus, and it is also present in about half of the adenocarcinomas of the pancreas and biliary tract.24,60 All other adenocarcinomas that have been investigated from other sites have been negative for this marker.60
In 2011, Magnusson et al6 investigated the expression of SATB2 by immunohistochemistry in a variety of colonic and noncolonic carcinomas using tissue microarrays. The results of that study demonstrated nuclear expression of this marker in 1336 (86%) of 1558 primary and 205 (81%) of 252 metastatic adenocarcinomas of the colon, whereas all 25 gastric adenocarcinomas investigated were negative (Figs. 1C, D). Of the noncolonic carcinomas investigated, weak positive staining was reported in 6 (4%) of 147 breast adenocarcinomas, 3 (6%) of 53 lung adenocarcinomas, 5 (3%) of 153 ovarian carcinomas, 1 (7%) of 15 cholangiocarcinomas, and 5 (57%) of 9 sinonasal carcinomas, whereas all other tumors included in the study were reported to be negative for this marker. The conclusion of the study was that SATB2 was a highly sensitive and specific marker for establishing the diagnosis of colorectal adenocarcinomas and that, when used in combination with keratin 20, it could be very useful for assisting in the differential diagnosis of metastatic carcinomas of unknown primary origin.
At present, several anti-SATB2 antibodies that can be used on formalin-fixed, paraffin-embedded tissue specimens are commercially available. These include several rabbit polyclonal antibodies, as well as the SATBA4B10 and CLO276 mouse monoclonal antibodies, and the EPNCIR130A and EPNCIR130B rabbit monoclonal antibodies. Published investigations have used a rabbit polyclonal antibody from Sigma (HPA001042; St Louis, MO).6,22
At present, an absolutely specific and sensitive marker of osteoblastic differentiation has not yet been identified. Because current information indicates that SATB2 is a highly sensitive marker of osteoblastic differentiation when it is used in conjunction with other osteoblast-associated markers (ie, osteocalcin), it may be useful for assisting in the diagnosis of osteosarcomas. In addition, as recent investigations have shown that SATB2 expression in carcinomas is highly restricted to colorectal adenocarcinomas and it is absent in other epithelial tumors with which they can be confused, it seems that this transcription factor has a higher specificity for these tumors than CDX2, a marker that, at present, is commonly used to assist in the differential diagnosis of adenocarcinomas of the colon.
The author thanks Dr Jason L. Hornick, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for providing the illustrations.
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SATB2; immunohistochemistry; bone tumors; osteosarcoma; colorectal adenocarcinoma
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