The vulvar immunohistochemical panel (VIP) project: molecular profiles of vulvar Paget’s disease
To investigate the expression of biological markers in primary vulvar Paget’s disease (VPD).
Forty-one patients referred to a single major Center for Gynecologic Oncology from January 2008 to June 2018 were enrolled retrospectively: 30 non-invasive-VPD and 11 invasive-VPD. A total number of 60 samples, from all the 41 vulvar sites (VS), 8 metastatic lymph node sites (MLS) and 11 successive recurrent disease in vulvar site (RVS), were tested for an immunohistochemical panel, including the following markers: PD-L1, CD3, MSH2, MSH6, MLH1, PMS2, HER2/neu, EGFR, p16, p53, Ki67, ER, PR, AR, VEGF and CD31.
We found a positive PD-L1 in 10% of non-invasive-VPD and 27% of invasive-VPD (18% VS; 38% MLS). ER and AR were expressed respectively in more than 70% and 75% of all specimens. HER2/neu amplification was found in 21% of non-invasive-VPD and 45% of invasive-VPD (40% VS; 38% MLS). A machine learning cluster analysis identified three groups among non- invasive-VPD: cluster-1 with higher median ER expression (40%); cluster-3 with more frequent HER2/neu overexpression (46%). Among invasive-VPD, two clusters were found: the second with more frequent HER2/neu overexpression (67% vs. 0%) and nodal metastases (100% vs. 25%). Repeating the IHC panel on the correspondent MLS and RVS, it significantly changed, respectively, in 50% and 27%.
This study reveals the expression of PDL-1 and ER and confirms the expression of HER2/AR in VPD; new bases are provided to design multicenter clinical trials on personalized target therapies.
KeywordsGynecological cancers Biostatistics Molecular targets Vulvar cancer Immunohistochemistry
Study conception and design: GG, FI, MF, AF, GS, GFZ, GB. Acquisition of data: GM, GP, AS, MV, SMF, SB, SG, GA. Analysis and interpretation of data: GB, GG, FI, GM, GP, AS, MV, SMF, SB, GA. Drafting of manuscript: GG, FI, GM, GP, AS, MV, SMF, SB, GA. Critical revision: MF, AF, GS, GFZ, SG, GG, FI, GB. Final approval: GG, FI, GM, AS, MV, GB, GP, SMF, SG, SB, MF, AF, GS, GFZ, GA.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Al-Obaidy KI, Kao C-S, Idrees MT (2018) P16 expression in extramammary Paget’s disease of the vulva and scrotum is not human papillomavirus related. Int J Surg Pathol 1:1066896918775513Google Scholar
- Edey KA, Allan E, Murdoch JB, Cooper S, Bryant A (2013) Interventions for the treatment of Paget’s disease of the vulva. Cochrane Database Syst Rev 26(10):CD009245Google Scholar
- Ellis PE, Wong Te Fong LF, Rolfe KJ, Crow JC, Reid WMN, Davidson T et al (2002b) The role of vascular endothelial growth factor-A (VEGF-A) and platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) in Paget’s disease of the vulva and breast. Anticancer Re 22(2A):857–861Google Scholar
- Ellis PE, MacLean AB, Wong Te Fong LF, Crow JC, Perrett CW (2012) Angiogenesis in Paget’s disease of the Vulva and the Breast: correlation with microvessel density. J Oncol [Internet] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321467/
- Garganese G, Collarino A, Fragomeni SM, Rufini V, Perotti G, Gentileschi S et al (2017) Groin sentinel node biopsy and 18F-FDG PET/CT-supported preoperative lymph node assessment in cN0 patients with vulvar cancer currently unfit for minimally invasive inguinal surgery: the GroSNaPET study. Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol 43(9):1776–1783Google Scholar
- Gentileschi S, Servillo M, Garganese G, Fragomeni S, De Bonis F, Cina A et al (2017) The lymphatic superficial circumflex iliac vessels deep branch perforator flap: a new preventive approach to lower limb lymphedema after groin dissection-preliminary evidence. Microsurgery 37(6):564–573CrossRefGoogle Scholar
- Hummel M, Edelmann D, Kopp-Schneider A (2017) Clustering of samples and variables with mixed-type data. PLoS One [Internet] 12(11). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705083/
- Inoguchi N, Matsumura Y, Kanazawa N, Morita K, Tachibana T, Sakurai T et al (2007) Expression of prostate-specific antigen and androgen receptor in extramammary Paget’s disease and carcinoma. Clin Exp Dermatol 32(1):91–94Google Scholar
- Larbouret C, Gaborit N, Chardès T, Coelho M, Campigna E, Bascoul-Mollevi C et al (2012) In pancreatic carcinoma, dual EGFR/HER2 targeting with cetuximab/trastuzumab is more effective than treatment with trastuzumab/erlotinib or lapatinib alone: implication of receptors’ down-regulation and dimers’ disruption. Neoplasia 14(2):121–130CrossRefGoogle Scholar
- Liegl B, Horn L-C, Moinfar F (2005) Androgen receptors are frequently expressed in mammary and extramammary Paget’s disease. Mod Pathol Off J U S Can Acad Pathol Inc 18(10):1283–1288Google Scholar
- Mantovani G, Fagotti A, Franchi M, Scambia G, Garganese G (2019) Reviewing vulvar Paget’s disease molecular bases. Looking forward to personalized target therapies: a matter of CHANGE. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc 29:422–429Google Scholar
- Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol Off J Am Soc Clin Oncol 31(31):3997–4013CrossRefGoogle Scholar
- Xu X, Shao N, Qiao D, Wang Z, Song N, Song N (2015) Expression of vascular endothelial growth factor and basic fibroblast growth factor in extramammary Paget disease. Int J Clin Exp Pathol 8(3):3062–3068Google Scholar
- Zhou S, Zhong W, Mai R, Zhang G (2017) Mammary and extramammary Paget’s disease presented different expression pattern of steroid hormone receptors. Biomed Res Int 2017:3768247Google Scholar