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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318297a9d0
New Antibody/Techniques

Value of SOX10 Immunostaining in Tumor Diagnosis

Ordóñez, Nelson G. MD

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Author Information

Department of Pathology, M.D. Anderson Cancer Center, The University of Texas, Houston, TX

The author has no funding or conflicts of interest to disclose.

Reprints: Nelson G. Ordóñez, MD, Department of Pathology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: nordonez@mdanderson.org).

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Abstract

SOX10 is a transcription factor that is essential for the generation of neural crest cells, their survival, and maintenance of pluripotency. Recent studies have shown that, among tumors, SOX10 is commonly expressed in melanomas, including desmoplastic melanomas, tumors with Schwann cell differentiation, and some salivary gland neoplasms, particularly those with myoepithelial differentiation. Because of its restricted expression, SOX10 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed.

The testis-determinant gene SRY from the human Y chromosome is the name-given member of a class of genes known as SOX genes.1,2 The acronym SOX [SRY-related high-mobility group (HMG) box] indicates that this class of genes shares a common sequence motif, the HMG box. SOX proteins represent one of a number of families in the HMG domain superfamily, which also includes the TCF, MATA, and HMG/UBF families.3,4 The SOX gene family is characterized by the presence of the HMG box, which encodes a 79 amino acid, DNA-binding HMG domain. The HMG domains in all SOX proteins are highly conserved in primary structure and appear to be capable of binding to the same target DNA sequence AACAA(A/T)G.5,6 SOX proteins show restricted patterns of tissue-specific expression and are essential for many developmental processes, including nervous system development, skeletogenesis, pigment cell formation, development of the immune system, sex determination, and eye development.5,7 A total of 20 SOX proteins have been identified in mammals based on full-length protein sequence comparisons and these have been subdivided into 7 groups (A to G), each with between 1 and 5 members.5,6 Members of each group share >80% amino acid identity within the HMG domain.5 SOX10, together with SOX8 and SOX9, constitute the SOX E group of transcription factors.5,6

SOX10, also known as SRY (sex-determinant region Y) box 10, DOM, WS4, PCWH and WS2E, is a transcription factor that is essential for the survival of neural crest-derived cells and for the maintenance of the multipotency of neural crest cells.8,9 The cells derived from neural crest multipotential cells include neurons and glial cells in the peripheral nervous system, melanocytes of the skin, C-cells of the thyroid, catecholaminergic cells of the adrenal gland, and cartilage and bone of the face.10,11 SOX10 is required for normal central and peripheral nervous system myelination.12–15 In Schwann cells, SOX10 regulates the expression of myelin proteins, including protein zero (P0), peripheral myelin protein 22 (PMP-22), and connexin 32.12,16 In oligodendrocytes, myelin basic protein and proteolipid protein are under direct transcriptional control of SOX10.17SOX10 directly regulates the expression of microphthalmia transcription factor, which plays a critical role in promoting the differentiation of neural crest-derived melanocytes.18–20 It also has the ability to transcriptionally regulate the number of genes that are essential for melanin synthesis, including dopachrome tautomerase (Dct, also known as tyrosinase-related protein 2 or Tyrp2),21–23 tyrosinase,24,25 and tyrosinase-related protein 1 (Tyrp1).26 In addition, SOX10 directly regulates c-ret Tyr receptor kinase gene, which plays an important role in the development of the enteric nervous system.27 The SOX10 protein is comprised of 466 amino acids, has a molecular weight of ∼68 kDa, and is encoded by a gene located on chromosome 22q13.1. Mutations of the SOX10 gene are associated with Waardenburg-Shah syndrome type IV, which is dominantly inherited and is characterized by hypopigmentation of the skin, heterochromia irides, deafness, and aganglionic colon (Hirschsprung disease).28,29 Human SOX10 mutations are also associated with a more severe demyelination syndrome combined with the Waardenburg-Shah syndrome designated as PCWH (peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease)30–33 and with the Yemenite deaf-blind hypopigmentation syndrome, which consists of cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma, and severe hearing loss.28,34

To my knowledge, only 2 studies have been published in which the expression of SOX10 was investigated by immunohistochemistry in a wide variety of normal adult tissues.35,36 In those investigations, SOX10 expression was reported in Schwann cells of the peripheral nerves, melanocytes of the epidermis, oligodendrocytes of the cerebral cortex, mast cells, and myoepithelial cells of the submucosal bronchial glands and breast, and in acinar and myoepithelial cells of the salivary glands, but not in any of the other tissues and organs investigated. These findings indicate that, because of the restricted cell distribution of SOX10 expression, immunostaining for this protein could be potentially useful for assisting in the diagnosis of those tumors derived from cells in which SOX10 is expressed. With the recent commercial availability of highly specific anti-SOX10 antibodies that can be used on formalin-fixed, paraffin-embedded tissue specimens, several studies have been published on the expression of SOX10 in a wide variety of tumors. The purpose of this article is to present a review of the literature on the expression of SOX10 in tumors and its application as an immunohistochemical marker in diagnostic pathology.

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SOX10 AS A MELANOCYTIC MARKER

SOX10 is one of the most recently recognized melanocytic-associated immunohistochemical markers that has been reported as being useful for assisting in the diagnosis of melanocytic neoplasms. In 2005, Gershon et al37 was the first to investigate SOX10 expression by immunohistochemistry in melanomas. Using 2 anti-SOX10 antibodies that had recently become commercially available, these authors investigated the expression of this marker in a group of tumors that included 3 melanomas, all of which were reported to be SOX10 positive. Since then, a few other studies have been published indicating that SOX10 is a highly sensitive and specific melanocytic-associated marker that can be useful for assisting in the differential diagnosis of melanomas.35,38–42 SOX10 has been reported to be commonly expressed in cutaneous and capsular lymph node nevi (100%),35,38,39 as well as in both primary conventional (95% to 100%)35,39,42 and metastatic (97% to 100%) melanomas39,42 (Figs. 1A–D). All (100%) of the spindle cell35 and desmoplastic35,36,40,42 melanomas investigated in different studies were reported to express SOX10. Some reports also indicated that the staining for SOX10 was stronger than that for S100 in a high percentage of desmoplastic melanomas.35,36 When compared with other melanocytic-associated markers, SOX10 is a more sensitive immunohistochemical marker for these tumors (Table 1).35,36,40,42–63 The percentage of positivity reported in desmoplastic melanomas has ranged from 0% to 30% for HMB-45,44–50,52–57 0% to 33% for melan A (MART-1),47,49,50,52–56,58 0% to 55% for Tyrosinase,47,48,50,52,54,55,57–59 0% to 8% for PNL2,56,57,60 0% to 55% for microphthalmia transcription factor,48–50,52,57,61,62 85% to 100% for KBA.62,60,63 and 82% to 100% for CD146 (Mel-CAM).54,62 A recent study has also indicated that because of its high sensitivity for desmoplastic melanoma and its low or lack of reactivity in spindled fibrocytes and histiocytes, SOX10 immunostaining can be used in distinguishing this type of melanoma from excisional scar.40 Because of its high sensitivity for melanomas and due to the fact that, in contrast to S100, it is not expressed in dendritic cells in lymph nodes, SOX10 immunostaining has also been reported to be very useful in the detection of micrometastases in sentinel lymph nodes.38,41 Similar to other melanocytic-associated markers, SOX10 is commonly expressed in clear cell sarcomas (100%),35,36 but in contrast to some of these markers, it appears to be absent in angiomyolipomas.35 The results of some of the published studies on SOX10 expression in melanocytic tumors are shown in Table 2.35–40,42

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TABLE 1
TABLE 1
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TABLE 2
TABLE 2
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SOX10 EXPRESSION IN TUMORS OF THE NERVOUS SYSTEM

In the nervous system, SOX10 is required for the development of Schwann cells, as well as the terminal differentiation of oligodendrocytes in the brain and spinal cord.17 In the normal adult nervous system, SOX10 is expressed in oligodendrocytes, Schwann cells, and enteric, sensory, and sympathetic ganglia. Although the number of studies published on the expression of SOX10 in tumors of the nervous system is limited, the results of these investigations indicate that this protein is commonly expressed in Schwannomas (100%),35,37,42 neurofibromas (98% to 100%),35,37,42 and, less frequently, in malignant peripheral nerve sheath tumors (MPNSTs) (∼50% to 55%)35,64 (Figs. 1E, F). In a combined review of 182 MPNSTs from 4 published studies, 98 (54%) were reported as being SOX10 positive.35,37,42,64 S100 protein is a marker that traditionally has been used to assist in the diagnosis of the previously mentioned groups of tumors. Current information indicates that, although the percentage of SOX10 positivity reported in both Schwannomas and neurofibromas is comparable to that of S100 protein, it appears to be a more sensitive marker for MPNSTs than S100. This was recently shown in a comparative study in which expression for SOX10 and S100 was demonstrated in 38 (49%) and 23 (30%) of the 77 MPNSTs investigated, respectively.35 When the specificity of these 2 markers for MPNST is compared, SOX10 is more specific as it has been reported to be almost invariably absent in those tumors with which MPNST can be confused.36 In contrast to S100, which has been reported to be expressed in almost 40% of spindle cell monophasic synovial sarcomas,65–68 SOX10 positivity is rare in these tumors. In a combined review of 191 synovial sarcomas from 3 published studies, SOX10 expression was observed in 6 (3%) of the cases.35,36,64

Granular cell tumors are typically benign neoplasms that are characterized by being composed of polygonal or slightly elongated cells having well-defined cell borders and abundant, granular cytoplasm.69 Although controversy exists regarding the histogenesis of these neoplasms, true granular cell tumors are neoplasms that are believed to be related to Schwann cells.70 Two recent studies have investigated SOX10 expression in these tumors. All 31 (100%) of the granular cells tumors included in these investigations were found to be SOX10 positive.36,42 This finding supports the belief that granular cell tumors are related to nerve sheath tumors and have a neural crest derivation. None of the 4 cases of perineurioma that have been investigated for SOX10 expression were positive for this marker.35

Because it was found that, in adult normal brain, SOX10 is expressed in oligodendroglia but not in astrocytes, several studies have investigated the potential utility of this protein as an immunohistochemical marker for assisting in distinguishing astrocytomas from oligodendrogliomas.71–74 The results of these investigations indicate that because SOX10 was found to be expressed not only in the large majority of oligodendrogliomas but also in a large percentage of astrocytomas, immunostaining for this marker has no utility for assisting in the differential diagnosis between these 2 groups of neoplasms. The results of some of the published studies on SOX10 expression in tumors of the nervous system are shown in Table 3.35–37,42,64,72,74,75

TABLE 3
TABLE 3
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SOX10 EXPRESSION IN EPITHELIAL TUMORS

Only a few studies have investigated SOX10 expression in epithelial tumors.35,42 The results of these investigations demonstrate that, with the exception of salivary gland tumors, this marker is uncommonly expressed in these types of neoplasms. In normal and neoplastic salivary glands, SOX10 expression was first demonstrated in myoepithelial cells and in a few of the cases of myoepithelioma investigated.35 In a subsequent study, it was reported to be present in both normal acinar and myoepithelial cells,36 as well as in a variety of salivary gland tumors.76 In a recent investigation of a large series of salivary gland tumors, SOX10 was reported to be frequently expressed in pleomorphic adenomas (79%), monomorphic adenomas (100%), polymorphous low-grade adenocarcinomas (88%), adenoid cystic carcinomas (96%), and acinic cell carcinomas (96%), but virtually no staining was seen in other subtypes of salivary gland tumors, including oncocytomas, mucoepidermoid carcinomas, and salivary duct carcinomas. The conclusion of the study was that SOX10 could serve as a useful immunohistochemical marker for assisting in the differential diagnosis between some subtypes of salivary gland tumors.76 Among other epithelial tumors, SOX10 positivity has been reported in the sustentacular cells in some neuroendocrine carcinomas, including rare cases of carcinoid tumors of the lung, stomach, appendix and colon, and in neuroendocrine tumors of the pancreas.35 All other epithelial tumors that have been investigated for SOX10 expression have been consistently negative for this marker.35,42 These findings indicate that, because SOX10 is commonly expressed in melanomas, but not in carcinomas, immunostaining for this marker can be very useful for assisting in distinguishing between poorly differentiated carcinomas and melanomas in those instances in which the differential diagnosis is not apparent on routine histologic preparations. The results of some of the published studies on SOX10 expression in epithelial tumors are shown in Table 4.35,42,76

TABLE 4
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SOX10 EXPRESSION IN SOFT TISSUE AND MISCELLANEOUS TUMORS

Only 1 study has been published in which a large series of soft-tissue neoplasms were investigated for SOX10 expression. In that study, only 5 (0.7%) of 668 soft-tissue tumors of non-neural crest origin were reported as being SOX10 positive.36 The results of this investigation indicate that, with the exception of nerve sheath tumors and rare cases of synovial sarcomas,64 pleomorphic undifferentiated sarcomas, glomus tumors, and rhabdomyosarcomas,36 which have been reported to be SOX10 positive, this marker is almost invariably negative in soft-tissue tumors.36,42 More studies are needed, however, to fully determine the spectrum of SOX10 expression in this group of neoplasms. All mesotheliomas and lymphomas that have been investigated have been reported to be SOX10 negative.42 Because of its lack of expression in most soft-tissue sarcomas, as well as in mesotheliomas and lymphomas, SOX10 can serve as a useful immunohistochemical marker for assisting in distinguishing these groups of neoplasms from melanomas.

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ANTI-SOX10 ANTIBODIES

At present, several polyclonal and mouse monoclonal anti-SOX10 antibodies that can be used on routinely fixed, paraffin-embedded tissue specimens, including clones 1E6 and A-2, are commercially available. The one that has been used in most of the published studies on the expression of SOX10 in tumors is the N-20 goat polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA), which reacts with an epitope located between amino acids 2 and 29 at the N-terminus of the human SOX10 protein. Several rabbit polyclonal antibodies are also available and can be obtained from different commercial sources. To date, I am aware of only 2 published studies that utilized a rabbit polyclonal antibody and each was from a different commercial source (1 from Abcam, Cambridge, MA and the other from Cell Marque, Rocklin, CA).42,77 In the study in which the antibody from Cell Marque was employed, the authors investigated the expression of SOX10 in a wide variety of tumors.42 The results of that investigation indicated that the reactivity of this antibody is comparable to that of the N-20 goat polyclonal antibody from Santa Cruz. To my knowledge, no studies on SOX10 expression in tumors have been published using any of the mouse monoclonal antibodies that are commercially available.

Some controversy exists in the literature regarding the staining pattern for SOX10. Although most studies have indicated that the staining is nuclear or nuclear and weakly cytoplasmic,35,36,42,78 others have reported a perinuclear and cytoplasmic reactivity.77 These differences appear to be related, in part, to the type of anti-SOX10 antibody used in the individual investigations. While those studies in which the staining was described as nuclear or nuclear and weakly cytoplasmic used either the N-20 goat polyclonal antibody from Santa Cruz36,78 or the rabbit polyclonal antibody from Cell Marque,42 the study in which the staining was described as being perinuclear and cytoplasmic employed a rabbit polyclonal antibody obtained from Abcam (ab25978).77 The latter antibody was raised using a synthetic peptide corresponding to amino acids 178 to 227 of the human SOX10 protein. The authors of the study interpreted the staining seen in the perinuclear and cytoplasmic regions as meaning that SOX10 may also be present outside of the nucleus, but probably not in an activated state.77 In my opinion, nuclear reactivity is required in order to consider the staining for SOX10 as being positive. In addition, some investigators have indicated that any cytoplasmic staining should be considered as being background artifact.78

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CONCLUSIONS

Because of the restricted expression of SOX10 in tumors with melanocytic, Schwannian, or myoepithelial differentiation, immunostaining for this marker can assist in the diagnosis of these tumors. SOX10, when compared with S100 protein, another marker that is commonly expressed in these types of tumors, appears to have a higher sensitivity and/or specificity for these types of neoplasms, which seems to be the case in MPNSTs and desmoplastic melanomas. It should be emphasized, however, that the number of studies published on SOX10 expression in tumors is still very limited and the determination of its value as an immunohistochemical marker in diagnostic pathology is still subject to change as more information becomes available.

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ACKNOWLEDGMENTS

The author wishes to thank Janet Quiñones for technical assistance, Kim-Anh Vu for assistance with digital images, and Asuncion Moroi for secretarial assistance.

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Keywords:

SOX10; immunohistochemistry; melanocytic marker; peripheral nerve sheath tumor; Schwannoma; salivary gland tumor

Copyright © 2013 by Lippincott Williams & Wilkins

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