The SRY-related HMG-box (SOX) family of transcription factors are important in determining the differentiation of a cell during embryogenesis. SOX transcription factors get their name because these proteins share greater than, or equal to 50% similarity of their high-mobility-group (HMG) domain to the SRY gene.1 There have been 20 different SOX genes discovered in mice and humans and these 20 genes are further subclassified into groups. Sox8, Sox9 and Sox10 belong to the SoxE subclass of the Sox family of transcription factors.2 Together, the SoxE subclass is responsible for neural crest migration and differentiation, chondrogenesis, gliogenesis and sex determination (figure 1).3

Sox10 structure

The SOX10 gene encodes an open reading frame of 466 amino acids that display 92% DNA and 98% amino-acid sequence identities.4 Due to an incomplete description of the human gene 5’-UTR non-coding exon, the most common exon coding system used is non-coding exons 1 and 2, a start codon (ATG) in exon 3 and a stop codon (TAA) in exon 5.4 The SOX10 gene consists of a dimerisation domain (Dim), an HMG, a K2 domain and a transactivation (TA) domain.

Function of SOX10

Sox10 is a key transcription factor for neural-crest development and is crucial for survival and the maintenance of the pluripotency as the neural-crest progenitor cells migrate.5 A mutation in SOX10 can manifest with peripheral demyelination, defective pigmentation, deafness and Hirschsprung disease. This constellation of symptoms is often referred to as ‘PCWH’ (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease).5 Due to its importance in neural-crest cell transportation, Sox10 immunohistochemistry has become an important diagnostic marker to classify a cell lineage.

Role of Sox10 immunostain in diagnostic histopathology

Sox10 expression can be seen in a variety of neoplasms including cutaneous adnexal neoplasms, salivary gland neoplasms, breast neoplasms, melanocytic lesions, and peripheral nerve sheath tumours.

Cutaneous adnexal neoplasms

Of normal adnexal structures, Sox10 stains the eccrine glands but not the eccrine ducts, apocrine glands and hair follicles.6 Sox10 expression can be seen in a variety of cutaneous adnexal neoplasms (table 1).6–8 Sox10 expression is more frequently seen in benign eccrine and apocrine neoplasms (table 1).6–8 Cylindroma, spiradenoma, syringocystadenoma papilliferum, chondroid syringoma, and apocrine adenoma are typically positive for Sox10. In contrast, the malignant eccrine and apocrine neoplasms, as well as sebaceous neoplasms and follicular neoplasms, rarely express Sox10 (table 1).6–8

Table 1

Frequency of Sox10 expression in cutaneous adnexal neoplasms6–8

Salivary gland neoplasms

Hsieh et al 9 studied Sox10 expression in 14 different types of salivary gland neoplasms. The authors reported Sox10 positivity in acinic cell carcinoma, adenoid cystic carcinoma, mammary analogue secretory carcinoma, epithelial-myoepithelial carcinoma, low-grade salivary duct carcinoma, sialoblastoma, basal cell adenocarcinoma, basal cell adenoma and pleomorphic adenoma. Sox10 staining was not observed in salivary duct carcinoma, lymphoepithelial carcinoma, hyalinising clear cell carcinoma and oncocytoma (table 2) (figure 2A,B).9–11 In another study by Lee et al,10 Sox10 expression was observed in all pleomorphic adenoma (48/48), and basal cell adenoma (3/3), but not in other benign neoplasms. Sox10 positivity was observed in 9 of 31 (29.0%) malignant neoplasms (table 2).9–11

Figure 2

Acinic cell carcinoma of the parotid (A, ×100) is highlighted by Sox10 (B, ×200). An infiltrating ductal carcinoma of the breast (C, ×200) is positive for Sox10 (D, ×200). A spindle cell proliferation in dermis (E, ×100) is strongly highlighted by Sox10 immunostain (F, ×200) supporting the diagnosis of melanoma. A granular cell tumour (G, ×100) is positive for Sox10 (H, ×200).

Table 2

Frequency of Sox10 expression in salivary gland neoplasms9–11

Breast neoplasms

SOX10 is thought to play a role in mammary epithelial cell growth through the NOTCH4 PBP (peroxisome-proliferative-activated receptor-binding protein) signalling pathway.12 While Sox10 immunohistochemistry has not been shown to be positive in lobular carcinomas, it is expressed in 12% of ductal carcinomas and in 38–77% of triple negative breast carcinomas (table 3) (figure 2C,D).13–19 Sox10 staining can be useful when GATA3 labelling is negative.14 Of note, 69% of basal-like breast carcinomas and 46% of metaplastic carcinomas also stain positive for Sox10. Both entities tend to also be triple-negative. A cytokeratin should always be included in the diagnostic panel since metastatic melanoma would express Sox10 and this can be a diagnostic pitfall.

Table 3

Sox10 expression in breast carcinomas and mimics13–19

Melanocytic lesions

Nuclear Sox10 expression is similarly sensitive but with better specificity in comparison to S100 in the diagnosis of melanocytic lesions (figure 2E,F).13 20–22 Sox10 expression is seen in 90–100% of primary and metastatic melanomas, all spindle cell melanomas, 78–100% desmoplastic melanomas and 57–100% clear cell sarcomas (table 4).13 16 20 21 23 Sox10 exhibits better specificity than Melan-A in detecting melanocytes on sun-damaged skin.22 Evaluation of excision margins with Sox10 immunostain has been shown to be helpful since one can quantify the melanocytes density as well as assessing the nuclear size of the melanocytes.24 Sox10 immunostain has also been shown to be helpful in diagnosing metastatic melanoma in lymph node in the cytology specimens.25 Of potential diagnostic pitfall, Sox10 expression can be frequently seen in scar tissue, representing staining of fibrohistiocytes in scar.26 In the differential diagnosis for spindle cell melanocytic lesions, Sox10 expression was negative in dermatofibrosarcoma protuberans, Ewing sarcoma, leiomyosarcoma and synovial sarcoma (table 4).13 20 23

Table 4

Sox10 expression in melanocytic, peripheral nerve sheath and representative soft tissue neoplasms13 16 20 21 23

Peripheral nerve sheath tumours

Sox10 transcription factor is necessary for the development of neural crest-derived cells. These include not just melanocytes, but neurons of autonomic and enteric systems, as well as peripheral glial cells.27 For this reason, Sox10 is a useful diagnostic marker for many peripheral nerve sheath tumours including schwannoma, neurofibroma, malignant peripheral nerve sheath tumours (MPNST) and granular cell tumours.13 Sox10 stains positive in 99–100% of schwannoma, 98–100% of neurofibromas, up to 100% of granular cell tumours that are S100-positive and 48–49% of MPNST (table 4) (figure 2GH).13 20 21 23

Take away messages

Sox10 expression can be seen in a variety of neoplasms including cutaneous adnexal neoplasms, salivary gland neoplasms, breast neoplasms, melanocytic lesions and peripheral nerve sheath tumours.

Sox10 has similar sensitivity but with better specificity in comparison to S100 in the diagnosis of melanocytic lesions.

While Sox10 expression is frequently seen in benign eccrine and apocrine neoplasms, the malignant eccrine and apocrine neoplasms, as well as sebaceous neoplasms and follicular neoplasms, rarely express Sox10.

Sox10 immunostain can be helpful in distinguishing triple-negative breast carcinoma from gynaecological carcinoma.