Epidermal Growth Factor Receptor in Vulvar Malignancies and Its Relationship to Metastasis and Patient Survival

doi:10.1006/gyno.1997.4660

Gynecologic Oncology

Volume 65, Issue 3, June 1997, Pages 425-429

https://doi.org/10.1006/gyno.1997.4660 Get rights and content

Abstract

Objective.To evaluate the level of epidermal growth factor receptor (EGF-R) expression in vulvar malignancies and to determine if a correlation exists between EGF-R levels and metastasis or patient survival.

Methods.All patients with a diagnosis of invasive squamous cell carcinoma of the vulva who were treated at our institution with a primary radical vulvectomy and inguinal lymph node dissection from 1983 to 1993 were eligible for the study. Sixty-one patients with available tissue blocks of benign vulvar epithelium, the primary malignant vulvar lesion, and groin node metastasis (when positive) were included in the study. Semiquantitative EGF-R expression was determined in a blinded fashion utilizing immunohistochemical staining of appropriate tissue samples. Survival was calculated utilizing Kaplan–Meier life table analysis based upon disease-free survival.

Results.A significant increase (P< 0.001) in mean EGF-R levels was demonstrated in the primary tumor (67%) versus benign vulvar epithelium (31%). In the 14 patients with lymph node metastasis, the mean EGF-R level in the primary tumor was 65% versus 88% in the metastatic lesion (P< 0.001). The likelihood of lymph node metastasis was elevated in those patients with a benign tissue EGF-R level ≥40% (P< 0.03) and in those patients with a primary tumor EGF-R level ≥90% (P< 0.025). Life table analysis revealed a cumulative disease-free survival of 45% for all patients. Disease-free survival in those patients with EGF-R levels ≥90% in the primary tumor was 25%, contrasting with a disease-free survival of 54% in those patients with EGF-R levels <90% (P< 0.05).

Conclusions.There is a progressive increase in EGF-R expression from benign vulvar epithelium to primary malignant tissue to metastatic lesions within the same patient. Increased expression of EGF-R in the primary vulvar malignancy is significantly associated with lymph node metastasis and decreased patient survival. Increased expression of EGF-R in histologically benign vulvar epithelium has a significant association with lymph node metastasis and may predict decreased patient survival.

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Molecular events in the pathogenesis of vulvar squamous cell carcinoma
2021, Seminars in Diagnostic Pathology
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.
Potential targets for tumor-specific imaging of vulvar squamous cell carcinoma: A systematic review of candidate biomarkers
2020, Gynecologic Oncology
Citation Excerpt :
Scores were summarized in Table 2. With an expression average of 59% or higher (score > 0): EGFR [11–21], CD44v6 [22–25], GLUT1 [26–28], MRP1 [12,13], MUC1 [29] and CXCR-4 [30] were considered potential candidates for tumor-specific imaging of VSCC. Although VEGF-A [22,27,31] showed an average expression of 45% (score 0), it fulfilled both other criteria and therefore this marker was included as well.
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.
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.
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.
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.
STAT3 signaling mediates tumour resistance to EGFR targeted therapeutics
2017, Molecular and Cellular Endocrinology
Citation Excerpt :
Due to its critical regulatory role in many cellular processes, it is no surprise that alterations in EGFR activation including activating mutations and gene amplification (leading to over-expression) has been commonly observed in tumour biopsies compared to normal adjacent tissue. Furthermore, many reports have linked EGFR activation with increased tumour invasiveness and tumour metastatic potential (Neal et al., 1985; Sainsbury et al., 1987; Abbott and Pratt, 1991; Damstrup et al., 1998; Johnson et al., 1997; Khazaie et al., 1993; Parker et al., 1998; Radinsky et al., 1995; Toi et al., 1991). Indeed breast, bladder, ovarian, oesophageal, non-small cell and squamous cell lung carcinoma (NSCLC), colon, head and neck and brain cancers have all been shown to over-express the EGFR (Neal et al., 1985; Sainsbury et al., 1987; Bartlett et al., 1996; Ekstrand et al., 1991; Hendler and Ozanne, 1984; Hollstein et al., 1988; Ishitoya et al., 1989; Libermann et al., 1985; Veale et al., 1987), and this over-expression has often been correlated with poorer overall survival outcomes (Neal et al., 1985; Sainsbury et al., 1987; Bartlett et al., 1996; Veale et al., 1987; Jaros et al., 1992; Mayer et al., 1993).
Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC). In this mini-review, we specifically focus on the role of the STAT3 signaling axis in providing both intrinsic and acquired resistance to inhibitors of the EGFR. We also focus on STAT3 pathway targeting in an attempt to overcome resistance to anti-EGFR therapeutics.
Identification of molecular targets in vulvar cancers
2017, Gynecologic Oncology
To identify molecular alterations that contribute to vulvar cancer pathogenesis with the intent of identifying molecular targets for treatment.
After retrospective analysis of a database of molecularly-profiled gynecologic cancer patients, 149 vulvar cancer patients were included and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and gene amplification (C/FISH). A Fisher's exact test was used when indicated with a p-value ≤ 0.05 indicating significance.
Median age was 65. 85% had squamous cell carcinoma (SCC) and 15% adenocarcinoma (ADC) histologies. 46% had metastatic (Stage IV) disease. Targeted hot-spot sequencing identified variants in the following genes: TP53 (33%), PIK3CA/BRCA2 (8%, 10%, respectively), HRAS/FBXW7 (5%, 4%, respectively) and ERBB4/GNAS (3%, 3% respectively). Mutations in AKT1, ATM, FGFR2, KRAS, NRAS (n = 1, respectively) and BRAF (n = 2) also occurred. Specific protein changes for targetable genes included clinically pathogenic mutations commonly found in other cancers (e.g. PIK3CA: exon 9 [E545K], RAS: G13D, Q61L, BRCA2: S1667X, BRAF: R443T, FBXW7: E471fs, etc.). Drug targets identified by IHC and ISH methodologies include cMET (32% IHC, 2% ISH), PDL1 (18%), PTEN loss (56%), HER2 (4% IHC, 2% ISH) and hormone receptors (AR, 4%; ER, 11%; PR, 4%). Comparisons between SCC and ADC identified differential rates for AR, ER, HER2 and GNAS with an increased presence in ADC (p-values all < 0.05).
Molecularly-guided precision medicine could provide vulvar cancer patients alternative, targeted treatment options.
New Therapies in Vulvar Cancer
2017, Translational Advances in Gynecologic Cancers
Major advances have been made in vulvar cancer treatment during the last decades, exploring less morbid treatment options without compromising survival. The introduction of the sentinel lymph node procedure is one of the most important advances in surgical management of early-stage vulvar cancer patients, resulting in a significant decrease in treatment-related morbidity. Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V) II is currently investigating the safety of replacing inguinofemoral lymphadenectomy by radiotherapy in patients with a metastatic sentinel lymph node. Targeted therapy in vulvar cancer is still in its infancy; preliminary results from pilot studies are promising, however large studies are lacking. Since vulvar cancer originates by two different pathways, an human papillomavirus (HPV)-dependent and HPV-independent type, studies on targeted therapy should take this into account.
The forgotten woman's cancer: Vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy
2016, Annals of Oncology
Citation Excerpt :
As regulators of cellular activity, tyrosine kinase proteins have been investigated for their role in mediating vulvar tumorigenesis and progression. Among tyrosine kinases, C-Kit and epidermal growth factor receptor (EGFR) have been studied most extensively in VSCC [38–45]. The proto-oncogene C-Kit encodes a trans-membrane receptor-type tyrosine kinase that has been implicated in various solid tumors, including lung, breast and testicular cancers [46, 47].
The incidence of vulvar squamous cell carcinoma (VSCC) has been on the rise since the 1990s. There has been no new treatment for advanced and recurrent disease in decades, with most women succumbing to the disease. Despite two distinct etiologies of VSCC, human papillomavirus (HPV)-associated and HPV-independent disease, there is no difference in therapeutic options.
A literature review was carried out by searching EMBASE and Medline databases between January 1990 and March 2016 by pairing the keywords of vulvar carcinoma, vulva cancer, vulvar and vulva with molecular markers involved in the cell cycle, apoptosis and angiogenesis. Molecular targets of prognostic significance were identified and targeted agents of therapeutic relevance to both HPV-independent and HPV-associated VSCC were then reviewed.
Recent advances in our understanding of the molecular biology of VSCC provide insight into the future management of VSCC with molecular targeted therapies. Aberrant cell cycle activity is common in both HPV-associated and HPV-independent VSCC and is characterized by overexpression of p53, Rb and cyclin D1, supporting targeting of these protein products and their downstream pathways. Extracellular regulators of cellular activity, such as EGFR, as well as inhibitors of angiogenesis are being clinically evaluated in VSCC. HPV-independent VSCC is characterized by actionable mutations, including PI3K, CDKN2A and PTEN. In HPV-associated disease, therapeutic vaccines targeting the E6 and E7 HPV oncogenes and immune-based therapies are under investigation.
There has been a paucity of clinical trials in recent years in this neglected women's cancer. Directed therapy against cell cycle regulatory molecules and extracellular proteins and the inhibition of angiogenesis are of broad therapeutic relevance in VSCC. Therapeutic strategies that target actionable mutations should be explored. In HPV-associated VSCC, novel treatments that exploit the virology of HPV and/or enhance the host immune response merit further study.

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^☆: M, B. SpornA, B, RobertsD, S, Goodman, eds

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Regular ArticleEpidermal Growth Factor Receptor in Vulvar Malignancies and Its Relationship to Metastasis and Patient Survival☆

Abstract

J Urol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Am J Obstet Gynecol

Gynecol Oncol

Eur J Cancer

Am J Obstet Gynecol

Am J Obstet Gynecol

Eur J Cancer

Obstet Gynecol

Am J Obstet Gynecol

Prospective study of the prognostic significance of epidermal growth factor receptor in primary breast cancer

Int J Cancer

Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer

J Clin Oncol

The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival

Br J Cancer

Prognostic utility of epidermal growth factor receptor overexpression in endometrial adenocarcinoma

Cancer

Expression of epidermal growth factor receptor and HER-2/Neu and in normal and neoplastic cervix, vulva, and vagina

Obstet Gynecol

Prognostic value of epidermal growth factor receptor expression in cervical carcinoma

J Clin Pathol

Synergistic inhibitory effect of gamma-interferon and EGF on A431 cells

Anticancer Res

Tissue-specific transformation by oncogenic mutants of epidermal growth factor receptor

Crit Rev Oncogen

Epidermal growth factor receptor expression and the presence of human papillomavirus in cervical squamous intraepithelial lesions

Int J Gynecol Pathol

Epidermal growth factor-related peptides and the epidermal growth factor receptor in normal and malignant prostate

World J Urol

Immunohistochemical study of HER-2/new, epidermal growth factor receptor and steroid receptor expression in normal and malignant endometrium

Obstet Gynecol

Immunohistochemical expression of epidermal growth factor receptor in salivary gland tumours

Virchows Arch A Pathol Anat

Regular Article
Epidermal Growth Factor Receptor in Vulvar Malignancies and Its Relationship to Metastasis and Patient Survival☆