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Chae YK, Corthell L, Patel SP, Edwards R, Scalici JM, Kim HS, Chung LIY, Othus M, McLeod CM, Chen HX, Sharon E, Streicher H, Ryan CW, Blanke CD, Kurzrock R. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors SWOG S1609: Vulvar Cancers. Clin Cancer Res 2025; 31:308-315. [PMID: 39561273 PMCID: PMC11804806 DOI: 10.1158/1078-0432.ccr-24-1957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/17/2024] [Accepted: 11/14/2024] [Indexed: 11/21/2024]
Abstract
PURPOSE Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial presents initial results of ipilimumab/nivolumab in vulvar cancers. PATIENTS AND METHODS DART is a prospective/open-label/multicenter (1,016 US sites)/multicohort phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR; confirmed complete response and partial response (PR)] per RECISTv1.1, whereas progression-free survival (PFS), overall survival, clinical benefit rate (CBR; ORR plus stable disease ≥6 months), and toxicity were secondary endpoints. RESULTS Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. The ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); the PFS was 34.1, 16.7. 15.5, 7.2, and 7.0 months for these five patients, respectively. The median PFS and overall survival were 2.2 and 7.6 months, respectively. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3 to 4 adverse events occurred in 25% of patients (n = 4). There was one grade 1 to 2 adverse event (6.7%) that led to discontinuation and one (6.7%) grade 5 death adverse event. CONCLUSIONS Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in 3 of 16 patients, all of whom had durable responses lasting over 1 year. Notably, two additional patients experienced durable stable disease and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.
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Affiliation(s)
| | - Lucy Corthell
- SWOG Statistics and Data Management Center, Seattle, WA
| | | | - Robert Edwards
- University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, PA
| | | | - Hye Sung Kim
- Northwestern University, Chicago, IL
- Temple University Hospital, Philadelphia, PA
| | | | - Megan Othus
- SWOG Statistics and Data Management Center, Seattle, WA
| | | | - Helen X. Chen
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD
| | - Elad Sharon
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD
| | - Howard Streicher
- National Cancer Institute, Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD
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Buchholz A, Vattai A, Fürst S, Vilsmaier T, Zati Zehni A, Steger A, Kuhn C, Schmoeckel E, Dannecker C, Mahner S, Jeschke U, Heidegger HH. Prostaglandin E2 receptor EP1 expression in vulvar cancer. J Cancer Res Clin Oncol 2023; 149:5369-5376. [PMID: 36436093 PMCID: PMC10349743 DOI: 10.1007/s00432-022-04487-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/15/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic targets are essential. Chronic inflammation plays an important role in carcinogenesis and COX-2, and its product prostaglandin E2 and its receptors EP1-4 are known to be important mediators in cancer initiation and progression. METHODS EP1 expression in vulvar cancer specimens (n = 129) was investigated via immunohistochemistry and evaluated using the well-established immunoreactive score (IRS). Subsequently, the values were correlated with clinicopathological parameters. RESULTS Our analysis did not reveal EP1 expression as a negative prognostic factor in overall and disease-free survival. However, in the subgroup of patients with lymph-node metastasis, overall survival was significantly shorter in tumors with high EP1 expression. Moreover, EP1 expression correlated positively with good differentiation of the tumor, but not with p16 status or COX-2 expression. CONCLUSIONS This study shed first light on EP1 expression in vulvar carcinoma. EP1 expression correlated significantly with the grading of the tumor, suggesting that it influences cell differentiation. Further research on EP1 signaling may lead to a deeper understanding of the molecular mechanisms of carcinogenesis.
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Affiliation(s)
- Anna Buchholz
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Aurelia Vattai
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Sophie Fürst
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Theresa Vilsmaier
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alaleh Zati Zehni
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Alexander Steger
- Klinik und Poliklinik für Innere Medizin I, University Hospital, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany
| | - Christina Kuhn
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Elisa Schmoeckel
- Department of Pathology, LMU Munich, Thalkirchner Str. 142, 80337, Munich, Germany
| | - Christian Dannecker
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.
- Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany.
| | - Helene H Heidegger
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany
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Mitra S, Lami MS, Ghosh A, Das R, Tallei TE, Fatimawali, Islam F, Dhama K, Begum MY, Aldahish A, Chidambaram K, Emran TB. Hormonal Therapy for Gynecological Cancers: How Far Has Science Progressed toward Clinical Applications? Cancers (Basel) 2022; 14:759. [PMID: 35159024 PMCID: PMC8833573 DOI: 10.3390/cancers14030759] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/27/2022] [Accepted: 01/30/2022] [Indexed: 02/01/2023] Open
Abstract
In recent years, hormone therapy has been shown to be a remarkable treatment option for cancer. Hormone treatment for gynecological cancers involves the use of medications that reduce the level of hormones or inhibit their biological activity, thereby stopping or slowing cancer growth. Hormone treatment works by preventing hormones from causing cancer cells to multiply. Aromatase inhibitors, anti-estrogens, progestin, estrogen receptor (ER) antagonists, GnRH agonists, and progestogen are effectively used as therapeutics for vulvar cancer, cervical cancer, vaginal cancer, uterine cancer, and ovarian cancer. Hormone replacement therapy has a high success rate. In particular, progestogen and estrogen replacement are associated with a decreased incidence of gynecological cancers in women infected with human papillomavirus (HPV). The activation of estrogen via the transcriptional functionality of ERα may either be promoted or decreased by gene products of HPV. Hormonal treatment is frequently administered to patients with hormone-sensitive recurring or metastatic gynecologic malignancies, although response rates and therapeutic outcomes are inconsistent. Therefore, this review outlines the use of hormonal therapy for gynecological cancers and identifies the current knowledge gaps.
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Affiliation(s)
- Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh; (S.M.); (M.S.L.); (A.G.); (R.D.)
| | - Mashia Subha Lami
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh; (S.M.); (M.S.L.); (A.G.); (R.D.)
| | - Avoy Ghosh
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh; (S.M.); (M.S.L.); (A.G.); (R.D.)
| | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh; (S.M.); (M.S.L.); (A.G.); (R.D.)
| | - Trina Ekawati Tallei
- Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado 95115, Indonesia;
- The University Center of Excellence for Biotechnology and Conservation of Wallacea, Institute for Research and Community Services, Sam Ratulangi University, Manado 95115, Indonesia;
| | - Fatimawali
- The University Center of Excellence for Biotechnology and Conservation of Wallacea, Institute for Research and Community Services, Sam Ratulangi University, Manado 95115, Indonesia;
- Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado 95115, Indonesia
| | - Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health of Sciences, Daffodil International University, Dhaka 1207, Bangladesh;
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India;
| | - M. Yasmin Begum
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61441, Saudi Arabia;
| | - Afaf Aldahish
- Department of Pharmacology and Toxicology, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia; (A.A.); (K.C.)
| | - Kumarappan Chidambaram
- Department of Pharmacology and Toxicology, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia; (A.A.); (K.C.)
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
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Valle‑Mendiola A, Bustos‑Rodríguez R, Domínguez‑Melendez V, Zerecero‑Carreón O, Gutiérrez‑Hoya A, Weiss‑Steider B, Soto‑cruz I. Mutations in the helix αC of the catalytic domain from the EGFR affect its activity in cervical cancer cell lines. Oncol Lett 2022; 23:71. [PMID: 35069880 PMCID: PMC8756430 DOI: 10.3892/ol.2022.13191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/26/2021] [Indexed: 11/06/2022] Open
Abstract
The EGFR is a protein that belongs to the ErbB family of tyrosine kinase receptors. The EGFR is often overexpressed in human carcinomas. Amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain occur in patients with cancer. In cervical cancer, the expression level of the EGFR protein appears to directly associate with human papillomavirus infection. Our previous research demonstrated that in the cervical cancer cell lines, CALO and INBL, the EGFR is non-phosphorylated. The aim of the current study was to analyze the catalytic activity of the isolated EGFR and the presence of mutations in the control region αC. Catalytic activity was assessed by a universal in vitro kinase assay using polyGluTyr as a substrate, and the proteins were visualized by western blotting. For mutation analysis, DNA from CALO and INBL cell lines was isolated, and PCR was used to amplify the exons corresponding to the helix αC in the EGFR. The PCR products were visualized by agarose gel electrophoresis. The bands were isolated using a Zymoclean Gel DNA Recovery kit and directly sequenced. The EGFR, which was isolated and analyzed using the in vitro kinase assay, had catalytic activity. The receptor contained some mutations in the helix αC of the catalytic domain in both cell lines. The observed changes in the amino acid sequence may induce a different spatial arrangement and, therefore, a different conformation, which may confer different activities to this receptor. Thus, it was concluded that non-phosphorylated EGFR has catalytic activity, and it bears some amino acid changes in the helix αC of the catalytic domain in the CALO and INBL cells. These results suggest that the EGFR may function as an activator of other ErbB family receptors in these cervical cancer cells.
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Affiliation(s)
- Arturo Valle‑Mendiola
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Ricardo Bustos‑Rodríguez
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | | | - Octavio Zerecero‑Carreón
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Adriana Gutiérrez‑Hoya
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Benny Weiss‑Steider
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Isabel Soto‑cruz
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
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Baiocchi G, de Freitas RR, Bovolim G, Badiglian-Filho L, da Costa AABA, De Brot L. Immunohistochemical expression of ErbB/HER family proteins in patients with vulvar cancer. Int J Gynaecol Obstet 2021; 157:102-109. [PMID: 34270807 DOI: 10.1002/ijgo.13829] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/14/2021] [Accepted: 07/12/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate the immunohistochemical (IHC) expression of the ErbB/HER family in primary vulvar squamous cell carcinoma (VSCC). METHODS We analyzed a series of 125 patients who were surgically treated for VSCC from January 1980 to June 2016. All cases had lymph node (LN) staging and 80 had LN metastasis. A tissue microarray was built for epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 IHC staining. RESULTS In the primary tumor we found positive expressions for EGFR, HER2, HER3, and HER4 in 5%, 0.9%, 0.9%, and 22.8%, respectively. For the LN metastasis, expressions of EGFR and HER4 were positive in 22.2% and 39.1%, respectively. No cases had positive staining for HER2 and HER3 in the LN metastasis. For HER4, positive expression correlated with smaller tumor sizes (P = 0.02). However, positive HER4 was related to adverse prognostic factors such as: histological grade (P = 0.012), presence of lymphovascular space invasion (40.9% vs 16.2%; P = 0.035), and perineural invasion (57.1% vs 16.7%; P = 0.006). Notably, all cases with LN metastasis had positive HER4 in the primary tumor (P < 0.001). ErbB/HER family expression was not related to worse survival. CONCLUSION EGFR, HER2, and HER3 were infrequently expressed in VSCC by IHC. HER4 IHC expression was found in 22.8% of cases and was related to adverse prognostic factors.
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Affiliation(s)
- Glauco Baiocchi
- Department of Gynecologic Oncology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | | | - Graziele Bovolim
- Department of Anatomic Pathology, AC Camargo Cancer Center, Sao Paulo, Brazil
| | | | | | - Louise De Brot
- Department of Anatomic Pathology, AC Camargo Cancer Center, Sao Paulo, Brazil
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Wölber L, Jaeger A. Vulvadysplasie und Vulvakarzinom. COLOPROCTOLOGY 2021. [DOI: 10.1007/s00053-021-00543-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Xing D, Fadare O. Molecular events in the pathogenesis of vulvar squamous cell carcinoma. Semin Diagn Pathol 2021; 38:50-61. [PMID: 33032902 PMCID: PMC7749059 DOI: 10.1053/j.semdp.2020.09.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022]
Abstract
Vulvar squamous cell carcinomas (VSCC), which constitute over 90% of vulvar malignancies in adults, are classifiable into 2 subgroups that are mostly clinicopathologically distinct, a classification that is fundamentally based whether or not the tumors are HPV-mediated. In this review, we aim to summarize the recent advances in the understanding of molecular events in the pathogenesis of VSCC, including common and targetable mutations, copy number alterations, epigenetics, noncoding RNAs, and tumor immune microenvironment, which may provide insight into the future management of the disease. These events show substantial differences between the 2 subgroups, although significant areas of overlap exist. Recurrent, driver mutations appear to be substantially more prevalent in HPV(-) VSCC. TP53 mutations are the most common somatic mutations in VSCC overall, and are notably predominant in the HPV(-) VSCC, where 30-88% show a mutation. TP53 mutations are associated with worse patient outcomes, and co-mutations between TP53 and either HRAS, PIK3CA or CDKN2A appear to define subsets with even worse outcomes. A wide variety of other somatic mutations have been identified, including a subset with different mutational frequencies between HPV(+) and HPV(-) VSCC. CDKN2A mutations are common, and have been identified in 21 to 55% of HPV(-) VSCC, and in 2 to 25% of HPV(+) VSCC. Hypermethylation of CDKN2A is the most frequently reported epigenetic alteration in VSCC and the expression of some microRNAs may be associated with patient outcomes. The PTEN/PI3K/AKT/mTOR pathway is commonly altered in HPV(+) VSCC, and is accordingly potentially targetable. HPV-positivity/p16 block expression by immunohistochemistry has been found to be an independent prognostic marker for improved survival in VSCC, and may have some predictive value in VSCC patients treated with definitive radiotherapy. 22-39.3% and 68% of VSCC show EGFR amplification and protein overexpression respectively, although the prognostic and predictive value of an EGFR alteration requires additional study. Recurrent chromosomal gains in VSCCs have been found at 1q, 2q, 3q, 4p, 5p, 7p, 8p, 8q, and 12q, and there may be differential patterns of alterations depending on HPV-status. At least one-third of VSCC patients may potentially benefit from immune checkpoint inhibition therapy, based on a high frequency of PD-L1 expression or amplification, or a high tumor mutational burden. Additional studies are ultimately required to better understand the global landscape of genetic and epigenetic alterations in VSCC, and to identify and test potential targets for clinical application.
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Affiliation(s)
- Deyin Xing
- Departments of Pathology, Oncology, Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Oluwole Fadare
- Department of Pathology, University of California San Diego Health, La Jolla, CA, United States
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Woelber L, Mathey S, Prieske K, Kuerti S, Hillen C, Burandt E, Coym A, Mueller V, Schmalfeldt B, Jaeger A. Targeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature. Oncol Res 2020; 28:645-659. [PMID: 33308371 PMCID: PMC7962928 DOI: 10.3727/096504020x16076861118243] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Therapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 2013–2019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: “vulvar cancer” AND “targeted therapy,” “erlotinib,” “EGFR,” “bevacizumab,” “VEGF,” “pembrolizumab,” or “immunotherapy.” Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 2–5)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 2–6 months). Bevacizumab (n = 9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n = 2/9 22.2%). Median duration of treatment was 7 months (range 4–13 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n = 3) subset was SD (n = 1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 3–4 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.
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Affiliation(s)
- Linn Woelber
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Sabrina Mathey
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Katharina Prieske
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Sascha Kuerti
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Christoph Hillen
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Eike Burandt
- Department of Pathology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Anja Coym
- Center for Oncology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Volkmar Mueller
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Barbara Schmalfeldt
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
| | - Anna Jaeger
- Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany
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Giulia Mantovani, Fragomeni SM, Inzani F, Fagotti A, Della Corte L, Gentileschi S, Tagliaferri L, Zannoni GF, Scambia G, Garganese G. Molecular pathways in vulvar squamous cell carcinoma: implications for target therapeutic strategies. J Cancer Res Clin Oncol 2020; 146:1647-1658. [PMID: 32335720 DOI: 10.1007/s00432-020-03226-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.
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Affiliation(s)
- Giulia Mantovani
- Dipartimento di Ginecologia e Ostetricia, Ginecologia Oncologica e Chirurgia Pelvica Mini-Invasiva, International School of Surgical Anatomy, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy
| | - Simona Maria Fragomeni
- Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
| | - Frediano Inzani
- Unità di Gineco-Patologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Anna Fagotti
- Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luigi Della Corte
- Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Scuola di Medicina e Chirurgia, Università degli studi di Napoli Federico II, Naples, Italy
| | - Stefano Gentileschi
- Unità di Chirurgia Plastica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Istituto di Clinica Chirurgica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luca Tagliaferri
- Unità Operativa Complessa di Radioterapia, Dipartimento di Scienze Radiologiche, Radioterapiche ed Ematologiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
| | - Gian Franco Zannoni
- Unità di Gineco-Patologia e Patologia Mammaria, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Scambia
- Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giorgia Garganese
- Unità di Ginecologia Oncologica, Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Gynecology and Breast Care Center, Mater Olbia Hospital, Olbia, Italy
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Huisman BW, Burggraaf J, Vahrmeijer AL, Schoones JW, Rissmann RA, Sier CFM, van Poelgeest MIE. Potential targets for tumor-specific imaging of vulvar squamous cell carcinoma: A systematic review of candidate biomarkers. Gynecol Oncol 2020; 156:734-743. [PMID: 31928804 DOI: 10.1016/j.ygyno.2019.12.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC. METHODS Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and III) in vivo application. RESULTS In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A. DISCUSSION This overview identified 7 potential biomarkers that can be used in the development of VSCC-specific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions.
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Affiliation(s)
- B W Huisman
- Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands; Department of Gynecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
| | - J Burggraaf
- Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands; Leiden Academic Center for Drug Research, Leiden University, Einstein weg 55, 2333 CC Leiden, the Netherlands; Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
| | - A L Vahrmeijer
- Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
| | - J W Schoones
- Walaeus Library, Leiden University Medical Center, Leiden, PO Box 9600, 2300 RC, the Netherlands.
| | - R A Rissmann
- Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands; Leiden Academic Center for Drug Research, Leiden University, Einstein weg 55, 2333 CC Leiden, the Netherlands.
| | - C F M Sier
- Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
| | - M I E van Poelgeest
- Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, the Netherlands; Department of Gynecology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.
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Cerebral metastasis in recurrent squamous cell carcinoma of the vulva: case report and review of the literature. Arch Gynecol Obstet 2019; 301:327-332. [PMID: 31823036 DOI: 10.1007/s00404-019-05403-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/02/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Distant metastases from squamous cell cancer of the vulva (VSCC) are encountered rarely and are associated with a poor prognosis. Cerebral metastases have only been described anecdotally. CASE HISTORY A 51-year old woman was diagnosed with hepatic metastases due to VSCC. Initial therapy comprised wide local excision of the primary tumor with inguino-femoral lymphadenectomy (LAE) followed by stereotactic radiation of the singular hepatic metastasis while adjuvant chemoradiation of the vulva and lymphatics was declined. 3 years later, she subsequently developed lung and cerebral metastases. CONCLUSION The course of metastatic disease in VSCC is poorly understood. Further knowledge of the metastatic patterns in vulvar cancer is required for guidance of future therapeutic interventions.
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Abstract
Human papillomavirus (HPV) is involved in one of the at least 2 pathways leading to vulvar squamous cell carcinoma (VSCC). Inactivation of p53 and retinoblastoma by the viral products E6 and E7 is involved in malignant transformation. The percentage of HPV-positive VSCCs ranges from 18% to 75%, depending on the geographical area. HPV-associated tumors affect relatively young women and arise from high-grade intraepithelial lesions, identical to other HPV-associated premalignant lesions of the anogenital tract. HPV-independent tumors tend to affect older women and usually arise in a background of inflammatory skin disorders and a subtle variant of in situ lesion called differentiated vulvar intraepithelial neoplasia. HPV-positive tumors tend to be of basaloid or warty types, whereas HPV-independent tumors tend to be of keratinizing type, but there is frequent overlap between histologic types. There is no conclusive evidence yet on the best strategy in terms of determining HPV attribution. HPV DNA detection is generally considered the gold standard although there is some concern about misclassification when using this technique alone. p16 immunostaining has shown to be an excellent surrogate marker of HPV infection. Positive results for both techniques are considered the best evidence for HPV-association. The prognostic role of HPV in VSCC is still contradictory, but increasing evidence suggests that HPV-associated tumors are less aggressive. Currently, there are no differences in treatment between HPV-associated and HPV-independent VSCC, but novel immunological strategies based on anti-HPV antigens are being evaluated in clinical trials.
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Prieske K, Haeringer N, Grimm D, Trillsch F, Eulenburg C, Burandt E, Schmalfeldt B, Mahner S, Mueller V, Woelber L. Patterns of distant metastases in vulvar cancer. Gynecol Oncol 2016; 142:427-34. [DOI: 10.1016/j.ygyno.2016.07.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 07/04/2016] [Accepted: 07/05/2016] [Indexed: 01/11/2023]
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Clancy A, Spaans J, Weberpals J. The forgotten woman's cancer: vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy. Ann Oncol 2016; 27:1696-705. [DOI: 10.1093/annonc/mdw242] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 06/08/2016] [Indexed: 01/22/2023] Open
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Adjacent Lichen Sclerosis predicts local recurrence and second field tumour in women with vulvar squamous cell carcinoma. Gynecol Oncol 2016; 142:420-6. [PMID: 27396942 DOI: 10.1016/j.ygyno.2016.06.019] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 06/23/2016] [Accepted: 06/26/2016] [Indexed: 11/22/2022]
Abstract
OBJECTIVE In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC). METHODS The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred <2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence. RESULTS The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR. CONCLUSIONS Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.
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McDaniel AS, Hovelson DH, Cani AK, Liu CJ, Zhai Y, Zhang Y, Weizer AZ, Mehra R, Feng FY, Alva AS, Morgan TM, Montgomery JS, Siddiqui J, Sadis S, Bandla S, Williams PD, Cho KR, Rhodes DR, Tomlins SA. Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy. Cancer Res 2016; 75:5219-27. [PMID: 26670561 DOI: 10.1158/0008-5472.can-15-1004] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0-5 and 0-6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR.
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Affiliation(s)
- Andrew S McDaniel
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Daniel H Hovelson
- Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Andi K Cani
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Chia-Jen Liu
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Yali Zhai
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Yajia Zhang
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Alon Z Weizer
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | - Rohit Mehra
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Felix Y Feng
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Ajjai S Alva
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Todd M Morgan
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | | | - Javed Siddiqui
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan
| | - Seth Sadis
- Thermo Fisher Scientific, Ann Arbor, Michigan
| | | | | | - Kathleen R Cho
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Daniel R Rhodes
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Thermo Fisher Scientific, Ann Arbor, Michigan
| | - Scott A Tomlins
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Urology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
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Holst F. Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate. World J Clin Oncol 2016; 7:160-173. [PMID: 27081639 PMCID: PMC4826962 DOI: 10.5306/wjco.v7.i2.160] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 01/05/2016] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Twenty-five years ago, Nembrot and colleagues reported amplification of the estrogen receptor alpha gene (ESR1) in breast cancer, initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration, which affects one of the most important genes in breast cancer. Since then, a multitude of studies on this topic has been published, covering a wide range of divergent results and arguments. The reported prevalence of this alteration in breast cancer ranges from 0% to 75%, suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues. To date, two major issues related to ESR1 amplification remain to be conclusively addressed: (1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1, and (2) the clinical relevance of ESR1 amplification: Such relevance is strongly disputed, with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies, or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1. This review provides a comprehensive summary of the various views on ESR1 amplification, and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.
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Mahner S, Prieske K, Grimm D, Trillsch F, Prieske S, von Amsberg G, Petersen C, Mueller V, Jaenicke F, Woelber L. Systemic treatment of vulvar cancer. Expert Rev Anticancer Ther 2015; 15:629-37. [DOI: 10.1586/14737140.2015.1037837] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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McWhirter RE, Marthick JR, Boyle JA, Dickinson JL. Genetic and epigenetic variation in vulvar cancer: Current research and future clinical practice. Aust N Z J Obstet Gynaecol 2014; 54:406-11. [DOI: 10.1111/ajo.12241] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 06/22/2014] [Indexed: 12/25/2022]
Affiliation(s)
- Rebekah E. McWhirter
- Menzies Research Institute Tasmania; University of Tasmania; Hobart Tasmania Australia
- Menzies School of Health Research; Charles Darwin University; Darwin Northern Territory Australia
| | - James R. Marthick
- Menzies Research Institute Tasmania; University of Tasmania; Hobart Tasmania Australia
| | - Jacqueline A. Boyle
- Monash Centre for Health Research and Implementation; School of Public Health and Preventive Medicine; Monash University; Clayton Victoria Australia
| | - Joanne L. Dickinson
- Menzies Research Institute Tasmania; University of Tasmania; Hobart Tasmania Australia
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EGFR expression in vulvar cancer: clinical implications and tumor heterogeneity. Hum Pathol 2014; 45:917-25. [PMID: 24746196 DOI: 10.1016/j.humpath.2014.01.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/10/2014] [Accepted: 01/15/2014] [Indexed: 11/23/2022]
Abstract
Epidermal growth factor receptor (EGFR) protein expression was assessed by immunohistochemistry (IHC) in 150 cases of invasive vulvar squamous cell carcinoma. In addition, gene copy number status by fluorescence in situ hybridization was performed in a smaller set of samples. Results were correlated with patient's clinical data and prognostic factors. EGFR overexpression (2+ and 3+) was observed on the membrane in 24.66% and 21.33% of all cases, respectively. Higher EGFR expression was associated with depth of invasion (P = .0409) and disease recurrence (P = .0401). Cytoplasm staining was found in 21.33% of the cases and was associated with absence of nodal metastasis (P = .0061) and better survival (P = .0199). Intratumor heterogeneity of EGFR IHC staining was frequently observed (55.33%) and was associated with the presence of nodal metastasis (P = .0207) and tumor invasion (P = .0161). Worse survival outcomes have been demonstrated in tumors with EGFR heterogeneity (P = .0434). EGFR gene status evaluated by fluorescence in situ hybridization did not correlate with protein expression evaluated by IHC. In conclusion, EGFR cytoplasm staining has no link with poorer outcome; still, this pattern of staining is even more related to better prognosis. EGFR heterogeneity of staining correlated with more aggressive tumors, and presented to be an important marker of poor prognosis in vulvar squamous cell carcinoma. The usage of small biopsies or even tissue microarrays for vulvar cancer evaluation should be carefully reconsidered for the assessment of EGFR as the results may be misleading. Protein overexpression may be independent on gene amplification, showing that other molecular mechanisms than copy number variation may regulate protein expression of EGFR in vulvar cancer.
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EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder. Mod Pathol 2014; 27:107-12. [PMID: 23887300 DOI: 10.1038/modpathol.2013.132] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 01/08/2023]
Abstract
The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.
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Moelans CB, Holst F, Hellwinkel O, Simon R, van Diest PJ. ESR1 amplification in breast cancer by optimized RNase FISH: frequent but low-level and heterogeneous. PLoS One 2013; 8:e84189. [PMID: 24367641 PMCID: PMC3867473 DOI: 10.1371/journal.pone.0084189] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 11/13/2013] [Indexed: 01/09/2023] Open
Abstract
Prevalence of ESR1 amplification in breast cancer is highly disputed and discrepancies have been related to different technical protocols and different scoring approaches. In addition, pre-mRNA artifacts have been proposed to influence outcome of ESR1 FISH analysis. We analyzed ESR1 gene copy number status combining an improved RNase FISH protocol with multiplex ligation-dependent probe amplification (MLPA) after laser microdissection. FISH showed a high prevalence of ESR1 gains and amplifications despite RNase treatment but MLPA did not confirm ESR1 copy number increases detected by FISH in more than half of cases. We suggest that the combination of the ESR1-specific intra-tumor heterogeneity and low-level copy number increase accounts for these discrepancies.
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Affiliation(s)
- Cathy B. Moelans
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Frederik Holst
- Section of Gynecology and Obstetrics, Department of Clinical Science, Haukeland University Hospital, Bergen, Norway
- Department of Pathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Olaf Hellwinkel
- Department of Legal Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Paul J. van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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Zhou Q, Gong Y, Huang F, Lin Q, Zeng B, Li Z, Chen R. Expression levels and significance of nuclear factor-κB and epidermal growth factor receptor in hepatolithiasis associated with intrahepatic cholangiocarcinoma. Dig Surg 2013; 30:309-16. [PMID: 24008372 DOI: 10.1159/000354341] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Accepted: 07/14/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND An increasing incidence of cholangiocarcinoma (CCA) and CCA mortality rates has been observed around the world. Patients with intrahepatic biliary stones have a 10% risk of developing CCA, and up to 70% of patients with histologically confirmed CCA have hepatolithiasis. Few previous studies have addressed the associations between the expression of nuclear factor (NF)-κB and epidermal growth factor receptor (EGFR) and clinicopathological prognosis in patients with hepatolithiasis-associated intrahepatic CCA. AIMS This study was designed to investigate the clinicopathological and prognostic significance of NF-κB and EGFR expression in hepatolithiasis-associated intrahepatic CCA and hepatolithiasis. METHODS A total of 90 liver specimens were immunohistochemically stained for NF-κB and EGFR expression, and the characteristics of 90 individual patients were retrospectively reviewed. RESULTS Differences in the positive rates of NF-κB and EGFR expression between the hepatolithiasis-associated intrahepatic CCA group, intrahepatic lithiasis group, and control group were found to be statistically significant. EGFR expression was closely associated with the degree of differentiation and depth of invasion (p < 0.05). The 1-, 3-, and 5-year overall survival rates were respectively 42.8, 21.0, and 10.3% in intrahepatic CCA groups. The survival rate of the EGFR-negative group was higher than in the EGFR-positive group (p < 0.01). Lymph node metastasis (HR 1.24, 95% CI 1.02-1.51) and EGFR positivity (HR 1.74, 95% CI 1.30-2.23) were associated with decreases in the survival rate. CONCLUSION The expression of NF-κB may be an early step in intrahepatic cholangiocarcinogenesis. Overexpression of EGFR is associated with the degree of malignancy and with poor prognosis. NF-κB and EGFR may cooperate during intrahepatic cholangiocarcinogenesis and progression. Lymph node metastasis and EGFR positivity were associated with decreases in the survival rate.
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Affiliation(s)
- Quanbo Zhou
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Choschzick M, Hess S, Grob T, Burandt E, Wölber L, Simon R, Sauter G. HER2 amplification in squamous cell carcinomas of the vulva. Histopathology 2013; 62:965-7. [PMID: 23444903 DOI: 10.1111/his.12090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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