Interesting Cases in Surgical Pathology a Malignant Neoplasm in the Brain

Interesting cases in surgical pathology

A malignant neoplasm in the brain

Ashley Cimino‐Mathews, MD Assistant Professor of Pathology and Oncology The Johns Hopkins Hospital

24 March 2013 Case Presentation

A 54 year‐old female presented to the emergency department with mental status changes and was found to have a large dural‐ based brain mass. The patient had a reported history of melanoma and breast cancer (ER 1%, PR‐, Her2‐). The patient underwent resection of the brain tumor. Brain lesion Brain lesion Brain lesion Brain lesion Brain lesion Brain lesion: Sox10 Positive Brain lesion: GATA3 negative (lymphocytes are positive internal control) Is this a metastatic melanoma? Metastatic melanoma?

• Diffuse Sox10 immunoreactivity is typically used to support a diagnosis of melanoma or a nerve sheath tumor. • The morphology of this brain lesion in keeping with malignant melanoma. However…diffuse Sox10 immunoreactivity has also been documented in other neoplasms: primary brain tumors (most often astrocytomas), salivary gland neoplasms, and breast carcinoma. The patient’s prior lumpectomy slides were retrieved and additional immunostains performed Breast tumor Breast tumor Breast tumor Breast tumor: CK7 positive Breast tumor: HMB45 negative Breast tumor: Sox10 positive Additional immunostains were performed on the brain lesion Brain lesion Brain lesion: CK7 positive Brain lesion: ER focally positive Final diagnosis: Metastatic breast carcinoma to the brain Case lessons learned

1. Sox10 can be expressed in primary breast carcinomas, primarily triple‐negative carcinomas 2. Sox10 can be expressed in metastatic breast carcinomas – Potential diagnostic utility as triple negative breast carcinomas may not label for traditional markers of mammary differentiation 3. Sox10 labeling in breast carcinomas is a potential diagnostic pitfall for metastatic melanoma Case lessons learned

1. Sox10 can be expressed in primary breast carcinomas, primarily basal‐like carcinomas 2. Sox10 can be expressed in metastatic breast carcinomas – Potential diagnostic utility as triple negative breast carcinomas may not label for traditional markers of mammary differentiation 3. Sox10 labeling in breast carcinomas is a potential diagnostic pitfall for metastatic melanoma What is Sox10? What is Sox10?

• Sox10 is a transcription factor in the Sox (Sry‐related HMG box) gene family, which have HMG DNA‐binding domains and play a role in many developmental processes including the development of the immune, nervous and skeletal systems. • Sox10 has a role in the survival, maturation and differentiation of neural‐crest derived melanocytes and glial cells. • In the breast, Sox10 is required for Notch4‐PBP mediated cell growth of mammary epithelial cells in in vitro mouse models. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues

• Normal tissues that demonstrated Sox10+ labeling: – Schwann cells, melanocytes and the myoepithelial cells of the salivary glands, bronchial mucosa, and breast. • Neoplastic tissues that demonstrated Sox10+ labeling: – 97% of melanomas, 100% of schwannomas and neurofibromas, 100% of salivary gland myoepitheliomas, as well as a subset of malignant peripheral nerve sheath tumors, paragangliomas, carcinoids and astrocytomas. • In this study, none of the 25 epithelial tumors (including 8 breast carcinomas) labeled for Sox10.

Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Sox10 Immunohistochemistry: initial utility in neural‐crest derived tissues

Nonaka D, et al. Am J Surg Pathol. 2008;32:1291‐1298. Melanocytes: Sox10+ Melanoma: Sox10+ Peripheral nerve Schwann cells: Sox10+ Nerve sheath‐derived granular cell tumor: Sox10+ Breast lobule: myoepithelial and luminal cells Sox10+ Breast ductule: myoepithelial and luminal cells Sox10+ Sox10 labels a subset of breast carcinomas

• We first reported Sox10 positivity in breast carcinomas: – Overall, 40% of primary invasive breast ductal carcinomas – Specifically 66% of all triple negative carcinomas • 69% of basal‐like triple negative carcinomas • 45% metaplastic carcinomas – In contrast, 5% of estrogen receptor (ER)‐positive or Her2‐positive carcinomas labeled for Sox10 – Focal labeling in ER‐negative ductal carcinoma in situ.

Cimino‐Mathews A, et al. Hum Pathol. 2013;44:959‐965. Sox10 labels a subset of breast carcinomas

• We reported Sox10 positivity in breast carcinomas: – Overall, 40% of primary invasive breast ductal carcinomas – Specifically 66% of all triple negative carcinomas • 69% of basal‐like triple negative carcinomas • 45% metaplastic carcinomas – In contrast, 5% of estrogen receptor (ER)‐positive or Her2‐positive carcinomas labeled for Sox10 – Focal labeling in ER‐negative ductal carcinoma in situ.

Cimino‐Mathews A, et al. Hum Pathol. 2013;44:959‐965. Basal‐like triple negative breast carcinoma (ER‐/PR‐/Her2‐ and CK5/6+) Basal‐like triple negative breast carcinoma: Sox10+ Metaplastic Carcinoma: 45% are Sox10 positive

ER+ Ductal Carcinoma: Sox10 negative Sox10 positivity in breast ductal carcinomas has been confirmed in subsequent studies

• 12%‐17% breast carcinomas are Sox10+ in subsequent studies; if reported, the majority are ER negative or basal‐like in phenotype • Gene expression profiling data has also identified overlapping Sox10 gene signatures in breast basal‐like breast carcinoma and salivary adenoid cystic carcinoma

Mohamed, et al. Appl Immunohistochem Mol Morphol. 2013;21:506‐51. Ivanov SV, et al. Br J Cancer. 2013;109:444‐451. Tacha, et al. Arch Pathol Lab Med. 2014. [Epub ahead of print]. Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]. Sox10 positivity in breast ductal carcinomas has been confirmed in subsequent studies

• 12%‐17% breast carcinomas are Sox10+ in subsequent studies; if reported, the majority are ER negative or basal‐like in phenotype • Gene expression profiling data has also identified overlapping Sox10 gene signatures in breast basal‐like carcinoma and salivary gland adenoid cystic carcinoma

*Asch‐Kendrick, et al. Mod Pathol. 2015.28(S2):14A. (USCAP 2015 Poster Wednesday 1pm) What other epithelial neoplasms label for Sox10?

• Salivary gland neoplasms (adenoid cystic carcinoma, acinic cell carcinoma, epithelial‐myoepithelial carcinoma, myoepitheliomas, myoepithelial carcinoma, pleomorphic adenoma) • Breast adenoid cystic carcinoma* • Skin adnexal neoplasms (eccrine spiradenoma/ cylindroma) • Soft tissue myoepitheliomas and carcinomas • Rarely: – embryonal carcinoma (25%) – pulmonary small cell carcinoma (7%) – lung or head and neck squamous cell carcinoma (5%) – pulmonary adenocarcinoma (fetal type) (1%) – Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print].

*Asch‐Kendrick, et al. A broad survey of neural crest transcription factor Sox10 in benign and neoplastic tissues. Mod Pathol. 2015.28(S2):14A. (USCAP 2015 Poster Wednesday 1pm) What other epithelial neoplasms label for Sox10?

• In addition to clear cell sarcomas and nerve sheath tumors, there is very rare labeling reported in: – Leiomyosarcoma – Rhabdomyosarcoma – Ossifying fibromyxoid tumor – Nodular fasciitis

Karamchandani JR, et al.Appl Immunohistochem Mol Morphol. 2012;20:445‐450. Tacha, et al. Arch Pathol Lab Med. 2014. [Epub ahead of print]. Miettinen, et al. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]. Sox10 labeling in adenocarcinomas is largely specific to breast and salivary gland neoplasms with basal‐like or myoepithelial differentiation, and adenocarcinomas of most other organs are consistently negative or rarely positive. Case lessons learned

• In a study of paired primary and metastatic breast carcinoma in 36 patients, we found: – Sox10 positivity in 38% metastatic triple negative carcinomas – compared to 0% ER‐positive or Her2‐positive metastases.

Nelson E, et al. Mod Pathol. 2015.28(S2):58A. (USCAP 2015 Poster Monday am) Metastatic triple negative ductal carcinoma to the lung Metastatic triple negative ductal carcinoma to the lung: Sox10+ Triple negative breast carcinomas typically do not label for traditional breast‐specific markers such as GCDFP or mammaglobin GCDFP, mammaglobin and GATA3 labeling in triple negative breast carcinomas

• GCDFP labels 5‐12% of primary basal‐like carcinomas • Mammaglobin labels 21‐24% of primary basal‐ like carcinomas • GATA3 labels 43% of primary triple negative carcinomas (basal type unspecified)

Lewis GH, et al. Am J Clin Pathol. 2011;135:587‐91. Luo MH, et al. Hum Pathol. 2013;44:1241‐50. Cimino‐Mathews A, et al. Hum Pathol. 2013;44:1341‐1349. GCDFP, mammaglobin and GATA3 labeling in triple negative breast carcinomas

Lewis GH, et al. Am J Clin Pathol. 2011;135:587‐91. Luo MH, et al. Hum Pathol. 2013;44:1241‐50. Cimino‐Mathews A, et al. Hum Pathol. 2013;44:1341‐1349. Case example #1: Triple negative breast carcinoma GCDFP‐, GATA3‐, Sox10+ Triple negative breast carcinoma Triple negative breast carcinoma Triple negative breast carcinoma: Cam5.2+ Triple negative breast carcinoma: GCDFP‐ Triple negative breast carcinoma: GATA3‐ Triple negative breast carcinoma: Sox10+ Case example #2: Triple negative breast carcinoma GCDFP‐, GATA3 focal+, Sox10+ Triple negative breast carcinoma Triple negative breast carcinoma: GCDFP‐ Triple negative breast carcinoma: rare focal GATA3+ Triple negative breast carcinoma: Sox10+ Case lessons learned

Sox10 positivity is typically used to support a diagnosis of malignant melanoma

But, since Sox10 labels triple negative breast carcinomas: Not all ER‐, S100+, Sox10+ lesions are MELANOMA This potential pitfall may arise in several settings:

1. Evaluation of a lesion in the breast or axilla: is it a primary breast carcinoma or metastatic melanoma 2. Evaluation of a tumor of unknown primary: is it metastatic breast carcinoma or metastatic melanoma? 3. Evaluation of a tumor in a patient with a known history of both breast carcinoma and melanoma. In the work‐up of an ER‐, S100+, Sox10+ neoplasm, additional lineage‐ specific markers should be included:

cytokeratins for carcinoma

HMB45, MelanA or MITF for melanoma Case example: Sox10+ neoplasm in the breast on core needle biopsy

Sox10+ Cam5.2‐ MITF+ Diagnosis: Metastatic melanoma to the breast In summary In summary

• Sox10 immunoreactivity alone cannot be used to support a diagnosis of metastatic melanoma, and metastatic breast carcinoma must be considered in the differential of an ER‐, S100+, Sox10+ malignant neoplasm • More lineage‐ specific immunomarkers—such as cytokeratins for carcinoma or HMB45 for melanoma— should be employed in the work‐up of a ER‐,S100+, Sox10+ neoplasm • Sox10 immunolabeling has particular utility in supporting breast origin of metastatic triple negative carcinomas References

1. Nonaka D, Chiriboga L, Rubin BP. Sox10: a pan‐schwannian and melanocytic marker. Am J Surg Pathol. 2008;32:1291‐1298. 2. Karamchandani JR, Nielsen TO, van de Rijn M, et al. Sox10 and S100 in the diagnosis of soft‐tissue neoplasms. Appl Immunohistochem Mol Morphol. 2012;20:445‐450. 3. Shin J, Vincent JG, Cuda JD, et al. Sox10 is expressed in primary melanocytic neoplasms of various histologies but not in fibrohistiocytic proliferations and histiocytoses. J Am Acad Dermatol. 2012;67:717‐726. 4. Tacha D, Qi W, Ra S, et al. A Newly Developed Mouse Monoclonal SOX10 Antibody Is a Highly Sensitive and Specific Marker for Malignant Melanoma, Including Spindle Cell and Desmoplastic Melanomas. Arch Pathol Lab Med. 2014. 5. Ohtomo R, Mori T, Shibata S, et al. SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis. Mod Pathol. 2013;26:1041‐1050. 6. Ivanov SV, Panaccione A, Nonaka D, et al. Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal‐like carcinomas. Br J Cancer. 2013;109:444‐451. 7. Cimino‐Mathews A, Subhawong AP, Elwood H, et al. Neural crest transcription factor Sox10 is preferentially expressed in triple‐ negative and metaplastic breast carcinomas. Hum Pathol. 2013;44:959‐965. 8. Mohamed A, Gonzalez RS, Lawson D, et al. SOX10 expression in malignant melanoma, carcinoma, and normal tissues. Appl Immunohistochem Mol Morphol. 2013;21:506‐510. 9. Cimino‐Mathews A, Subhawong AP, Illei PB, et al. GATA3 expression in breast carcinoma: utility in triple‐negative, sarcomatoid, and metastatic carcinomas. Hum Pathol. 2013;44:1341‐1349. 10. Lewis GH, Subhawong AP, Nassar H, et al. Relationship between molecular subtype of invasive breast carcinoma and expression of gross cystic disease fluid protein 15 and mammaglobin. Am J Clin Pathol. 2011;135:587‐591. 11. Miettinen M, McCue PA, Sarlomo‐Rikala M, et al. Sox10‐A Marker for Not Only Schwannian and Melanocytic Neoplasms But Also Myoepithelial Cell Tumors of Soft Tissue: A Systematic Analysis of 5134 Tumors. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print]rs of Soft Tissue: A Systematic Analysis of 5134 Tumors. Am J Surg Pathol. 2015 Feb 25. [Epub ahead of print] 12. Luo MH, Huang YH, Ni YB, et al.Expression of mammaglobin and gross cystic disease fluid protein‐15 in breast carcinomas. Hum Pathol. 2013 Jul;44(7):1241‐50. 13. Nelson ER, Sharma R, Argani P, Cimino‐Mathews A. Nuclear Transcription Factor Sox10 is Expressed in a Subset of Metastatic Triple Negative Breast Carcinomas. Mod Pathol. 2015;28(S2):58A. 14. Asch‐Kendrick R, Anders R, Argani P, et al. A Broad Survey of Neural Crest Transcription Factor Sox10 in Benign and Neoplastic Tissues. Mod Pathol. 2015;28(S2):14A. Thank you