Reviewing vulvar Paget’s disease molecular bases. Looking forward to personalized target therapies: a matter of CHANGE

Mantovani, Giulia; Fagotti, Anna; Franchi, Massimo Piergiuseppe; Scambia, Giovanni; Garganese, Giorgia

doi:10.1136/ijgc-2018-000080

Cited by 16 publications

(14 citation statements)

References 48 publications

(33 reference statements)

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“…Selected cases of EMPD (with amplified ERBB2/HER2 gene) have been successfully treated with trastuzumab alone or in combinations with chemotherapy. 4,[15][16][17][18][19][20][21] In contrast to MPD, we found overexpression and HER2 gene amplification in a minority of cases, and a co-amplification with TOPO2 in a single case of vulvar disease. Amplification of TOPO2 gene and expression of Topo2 protein in several cases of EMPD is a novel finding in our cohort.…”

Section: Discussionmentioning

confidence: 91%

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

et al. 2020

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Background Primary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known. Methods Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers). Results Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable. Conclusions EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD‐L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations.

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Section: Discussionmentioning

confidence: 91%

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

et al. 2020

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“…After a systematic review of the literature and in the light of the experience of our previous study on the molecular characterization of vulvar Paget’s disease [ 31 , 32 ], we focused our research on four main pathways, considering their influence on carcinogenesis: (1) tumor immune microenvironment, (2) activation of oncogenic growth factor receptors, (3) hormonal environment, and (4) neo-angiogenesis. From each of these areas, we selected the main biological markers, chosen on the basis of their relevance as potential prognostic/therapeutic factors, as already known from the study of squamous tumors in other anatomical regions.…”

Section: Introductionmentioning

confidence: 99%

The Vulvar Immunohistochemical Panel (VIP) Project: Molecular Profiles of Vulvar Squamous Cell Carcinoma

Garganese

Inzani

Fragomeni

et al. 2021

Cancers

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Introduction: The study’s aim was to investigate the immunohistochemical (IHC) expression of biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma (VSCC). Methodology: A series of 101 patients surgically treated at our center from 2016 to 2020 were retrospectively enrolled: 53 node-negative (Group A) and 48 node-positive (Group B). A total of 146 samples, 101 from primary tumor (T) and 45 from nodal metastases (N), were investigated. The IHC panel included: p16, p53, MLH1, MSH2, MSH6, PMS2, PD-L1, CD3, HER2/neu, ER, PR, EGFR, VEGF, and CD31. The reactions were evaluated on qualitative and semi-quantitative scales. Generalized Linear Model (GLM) and cluster analysis were performed in R statistical environment. A distance plot compared the IHC panel of T with the correspondent N. Results: In Group A: p16-positive expression (surrogate of HPV-dependent pathway) was significantly higher (20.8% vs. 6.2%, p = 0.04). In Group B: PD-L1 positivity and high EGFR expression were found, respectively, in 77.1% and 97.9% patients (T and/or N). Overall, p16-negative tumors showed a higher PD-L1 expression (60.9% vs. 50.0%). In both groups: tumoral immune infiltration (CD3 expression) was mainly moderate/intense (80% vs. 95%); VEGF showed strong/moderate-diffuse expression in 13.9% of T samples; CD31, related to tumoral microvessel density (MVD), showed no difference between groups; a mutated p53 and over-expressed PD-L1 showed significant association with nodal metastasis, with Odds Ratios (OR) of 4.26 (CI 95% = 1.14–15.87, p = 0.03) and 2.68 (CI 95% = 1.0–7.19, p < 0.05), respectively; since all mismatch repair proteins (MMR) showed a retained expression and ER, PR, and HER2/neu were negative, they were excluded from further analysis. The cluster analysis identified three and four sub-groups of molecular profiles, respectively, in Group A and B, with no difference in prognosis. The molecular signature of each N and corresponding T diverged significantly in 18/41 (43.9%) cases. Conclusions: Our results support a potential role of immune checkpoint inhibitors and anti-VEGF and anti-EGFR drugs especially in patients with worse prognosis (metastatic, HPV-independent). A panel including EGFR, VEGF, PDL1, p16, and p53 might be performed routinely in primary tumor and repeated in case of lymph node metastases to identify changes in marker expression.

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“…Median overall time to perform fusion imaging was 32 (range, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] min. Median duration of Step 1 (acquisition of 3D volumes and target identification on CT and SPECT) was 10 (range, 8-12) min; of Step 2 (coregistration and synchronization of SPECT/CT and ultrasound) was 10 (range, 7-10) min; and of Step 3 (fine tuning and SPECT/CT and ultrasound fusion imaging navigation) was 12 (range, [8][9][10][11][12][13][14][15][16][17][18][19] min. Time spent performing Steps 1 and 2 was similar in all 10 cases, whereas the time spent performing Step 3 reduced significantly from the first to the last examination (19 vs 12 min; Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…Vulvar carcinoma is the fourth most common gynecological cancer, with an incidence of 1-3 per 100 000 women [1][2][3][4][5][6][7][8] . The initial spread usually occurs to the inguinofemoral lymph nodes 9 , and lymph-node surgical staging is required in early-stage disease.…”

Section: Introductionmentioning

confidence: 99%

Fusion of ultrasound and 3D single‐photon‐emission computed tomography/computed tomography to identify sentinel lymph nodes in vulvar cancer: feasibility study

Garganese

Bove

Zagaria

et al. 2019

Ultrasound in Obstet & Gyne

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Objective To evaluate the feasibility of fusion of ultrasound imaging and three‐dimensional (3D) single‐photon‐emission computed tomography/computed tomography (SPECT/CT) in detecting sentinel lymph nodes in women with vulvar cancer. Methods This was a prospective pilot single‐center study. Patients with vulvar cancer who were candidates for sentinel lymph‐node biopsy were enrolled between December 2018 and February 2019. Fusion imaging virtual navigation using 3D SPECT/CT and ultrasound was performed to investigate the tumor‐draining lymph node. All clinical, imaging, surgical and histological information was collected prospectively and entered into a dedicated Excel file. Feasibility and success of fusion imaging virtual navigation and time needed to perform the three steps of fusion imaging were evaluated. Results Ten lymph‐node sites were evaluated in five consecutive women with a histological diagnosis of vulvar cancer. Fusion imaging virtual navigation was feasible and completed successfully for all (10/10) draining sites. Median overall time to perform fusion imaging was 32 (range, 25–40) min and the time decreased from the first to the last examination. Conclusions The present study demonstrated that fusion imaging virtual navigation using 3D SPECT/CT and ultrasound is feasible and able to detect sentinel lymph nodes in women with vulvar carcinoma. Fusion imaging using ultrasound for detection of sentinel lymph nodes opens up multiple diagnostic and therapeutic opportunities in gynecological oncology. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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Reviewing vulvar Paget’s disease molecular bases. Looking forward to personalized target therapies: a matter of CHANGE

Cited by 16 publications

References 48 publications

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

The Vulvar Immunohistochemical Panel (VIP) Project: Molecular Profiles of Vulvar Squamous Cell Carcinoma

Fusion of ultrasound and 3D single‐photon‐emission computed tomography/computed tomography to identify sentinel lymph nodes in vulvar cancer: feasibility study

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