Uncommon Gynecologic Cancers (eBook)

Marcela del Carmen, John O. Schorge, Robert H. Young (Herausgeber)

eBook Download: EPUB

2014 | 1. Auflage
280 Seiten
Wiley-Blackwell (Verlag)
978-1-118-65531-3 (ISBN)

Infos

Rare gynecological cancers kill all too commonly

Gynecological cancer is a frightening prospect for women. It is terrifying also for physicians who need, but often can’t find, guidance on how to investigate and appropriately treat the tumors. Rare cancers provide greater challenges as information can be harder to find and more difficult to verify.

Rare Gynecologic Cancers: Diagnosis and Management brings together all you need to know on these life-threatening diseases. Straightforward summaries of pathophysiologic processes lead to the investigations that will improve your diagnostic accuracy. This provides the basis for you to identify effective treatment strategies for your patients. Written by a world-leading team of Editors and Authors and covering cancers of the

•             Ovaries

•             Uterus

•             Vulva

•             Vagina

•             Cervix

Rare Gynecologic Cancers: Diagnosis and Management will guide you to the best life-saving treatment for your patients.

Autor

John O. Schorge, MD, Associate Professor of Obstetrics and Gynecology, Harvard Medical School, Boston and Chief, Gynecologic Oncology, OB/GYN, Massachusetts General Hospital. Robert H Young, MD, Robert E. Scully Professor of Pathology, Harvard Medical School, Boston. Michael J Birrer, MD, PhD, Professor, Department of Medicine, Harvard Medical School. Marcela del Carmen, MD, Associate Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School and Associate Professor, Gynecologic Oncology, Massachusetts General Hospital.

Inhalt

List of Contributors vi

Preface viii

Part 1 General Principles 1

1 Molecular Targets in Gynecologic Cancers 3
Whitfield Growdon, Rosemary Foster, and Bo Rueda

2 Imaging of Rare Gynecologic Tumors 18
Hima B. Prabhakar and Dinushi S. Perera

3 Pathology Overview of Rare Gynecologic Tumors 35
Robert H. Young

Part 2 Rare Ovarian Cancers 51

4 Ovarian Clear Cell Carcinoma 53
Rachel M. Clark and John O. Schorge

5 Mucinous Epithelial Ovarian Cancer 64
Marcela G. del Carmen

6 Pseudomyxoma Peritonei 70
Leslie S. Bradford and Annekathryn Goodman

7 Squamous Cell Carcinoma of the Ovary 81
Ryan J. Spencer and Laurel W. Rice

8 Endometriosis-Associated Ovarian Cancer 94
Leslie A. Garrett and Marcela G. del Carmen

9 Carcinosarcoma of the Ovary 109
J. Alejandro Rauh-Hain and Marcela G. del Carmen

10 Malignant Germ Cell Tumors of the Ovary 120
Marcela G. del Carmen

11 Malignant Sex Cord-Stromal Tumors of the Ovary 132
Marcela G. del Carmen and Richard T. Penson

12 Small Cell and Neuroendocrine Cancers of the Ovary 139
Ariel A. Kaphan and Cesar M. Castro

13 Carcinoid Tumors of the Ovary 148
Michael J. Worley Jr., and Michael G. Muto

Part 3 Rare Uterine Cancers 157

14 Uterine Carcinosarcoma 159
Premal H. Thaker and Don S. Dizon

15 Uterine Leiomyosarcoma 167
Marcela G. del Carmen

16 Mucinous Tumors of the Uterine Corpus 178
Rachel M. Clark and Marcela G. del Carmen

17 Uterine Clear Cell Carcinoma 186
J. Alejandro Rauh-Hain, Alexander B. Olawaiye, and David M. Boruta

18 Updates on the Management of Uterine Serous Carcinoma 195
Amanda Ramos and Amanda Nickles Fader

19 Endometrial Stromal Sarcomas 205
Kathleen M. Schmeler, J. Alejandro Rauh-Hain, and Marcela G. del Carmen

Part 4 Rare Cancers of the Cervix, Vulva and Vagina 217

20 Small Cell Neuroendocrine Carcinoma of the Cervix 219
Olivia W. Foley, Leslie S. Bradford, and Marcela G. del Carmen

21 Primary Malignant Melanoma of the Vagina and Vulva 228
Alexander B. Olawaiye

22 Sarcomas of the Vulva and Vagina 236
Rachel M. Clark, J. Alejandro Rauh-Hain, and Marcela G. del Carmen

23 Gestational Trophoblastic Disease 245
Whitfield Growdon

Index 260

Textauszug

Chapter 1
Molecular Targets in Gynecologic Cancers

Whitfield Growdon, Rosemary Foster, and Bo Rueda

Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA

Introduction

The past two decades have brought an exponential increase in our understanding of the molecular drivers of cancer. These insights have led to the concept of personalized cancer care where an individual tumor can be interrogated for specific molecular alterations that may render the cancer susceptible to novel therapeutics that target that particular alteration. The advent of HER2 (ERBB2) targeted therapies for HER2 overexpressing breast cancer and EGFR inhibitors for EGFR (ERBB1) gene-mutated lung cancers are notable successes that support the concept that targeting specific molecular profiles can lead to clinical benefit.

Regarding gynecologic cancers, investigators now understand that the underlying drivers of any individual tumor may exhibit marked diversity even if both tumors have identical histology. Identifying key molecular pathways that drive subsets of tumors within ovarian, endometrial, and cervical cancer is crucial to the development of clinical trials utilizing the next generation of targeted therapeutics. This chapter seeks to explore several molecular pathways and proteins that have been shown to contribute to the pathology of significant subsets of ovarian, endometrial, cervical, and vulvar cancers. While the promise of personalized cancer medicine has yet to be fulfilled in gynecologic cancers, therapies targeting the PI3K, MAPK signaling pathways, as well as HER2 and VEGF receptors and PARP protein have been shown to have the potential to improve the therapeutic options for patients.

Phosphoinositol 3-kinase (PI3K) pathway

Oncogenic alterations in the phosphoinositol 3-kinase (PI3K) pathway (Figure 1.1) are frequent in endometrial and ovarian carcinomas [1–3]. PI3K is the upstream activator of Akt, and ultimately mTOR and it contributes to regulation of cell growth, angiogenesis, migration, and survival [2,4]. While three classes of PI3K enzymes have been described, class IA PI3Ks have been most associated with promoting carcinogenesis [5]. PI3K enzymes are activated by receptor tyrosine kinases and G-protein-coupled receptors and transfer phosphate groups to the inositol ring of phosphatidylinositol 4,5 bi-phosphate (PIP2) to produce the signaling molecule phosphatidylinositol 3,4,5 tri-phosphate (PIP3) [1]. This process is negatively regulated by the phosphatase and tensin homologue (PTEN) [5]. Direct downstream mediators AKT and mTOR become activated via phosphorylation leading to transcription events that promote growth, invasion, metastases, and cell survival.

Figure 1.1 PI3K signaling cascade. Schematic showing the PI3K/AKT/mTOR and MAPK pathways and the current agents in development for targeting this cascade.

There are many underlying mechanisms for PI3K pathway activation in cancer, including receptor tyrosine kinase activation or amplification, mutation, deletion, silencing of negative regulators of the PI3K pathway, and activation or amplification of downstream kinase mediators [4]. Correlative investigations have demonstrated a significant prevalence of gain of function mutations in the PIK3CA gene in breast, colon, pancreatic, brain, ovary, and, recently, high-risk endometrial cancers [2,6–12]. Recent reports have suggested that gene amplification affects approximately 20–40% of ovarian, endometrial, and cervical carcinomas across all subtypes, while gain of function mutations occur more commonly in endometrioid endometrial cancer and in clear-cell and endometrioid ovarian tumors at approximately a 20% rate [13–18]. Additionally, PI3K activation via these mechanisms was associated with chemoresistance and worsened survival, suggesting targeted inhibition could potentiate conventional platinum-based chemotherapy [19–24].

Given the high prevalence of PI3K pathway activation in gynecologic cancer, targeted strategies inhibiting this cascade could hold tremendous potential to benefit patients with ovarian, endometrial, and cervical cancer [11,25]. Multiple phase I and II clinical trials in endometrial and ovarian cancer have tested agents that target the PI3K pathway [26–28]. Reports from phase II trials of rapalogs inhibiting the mammalian target of rapamycin (mTOR), a downstream mediator of the PI3K pathway, have revealed both objective responses as well as clinically significant disease stabilization [27,29,30]. In addition to the rapalogs, several other classes of PI3K pathway inhibitors including direct PI3K inhibitors, PI3K/mTOR dual inhibitors, and AKT inhibitors are in development for treating ovarian and endometrial cancer [5,28,31]. Early reports from clinical trials suggest that responses to single-agent blockade have an approximately 30% prevalence, occur with or without gain of function mutations in PIK3CA, and manifest limited response durability resulting in treatment resistance [26, 32–35]. This observation has resulted in the hypothesis that targeted blockade of one overactive protein in a fundamental pathway, such as PI3K, AKT, or mTOR, may not result in significant clinical response. Understanding resistance mechanisms will be critical in the clinical implementation of targeted therapies.

The identification of a biomarker associated with response will be crucial to the success of targeted therapy in general. For the PI3K pathway, PIK3CA gene amplification and gain-of-function mutation in both the catalytic subunit (PIK3CA) and the regulatory subunit (PIK3R1) have been described in ovarian, endometrial, and cervical cancer. Some preclinical and clinical data have suggested that those tumors harboring a mutation have increased sensitivity to PI3K pathway inhibition [24,32,36]. Of the gynecologic malignancies, endometrial cancer has the highest prevalence of these molecular alterations. These data have clear implications for selecting candidates for clinical trials so that accrual can enrich for those patients most likely to respond; however, responses to PI3K pathway have been observed in patients that harbor no mutation or amplification, suggesting that additional criteria need to be utilized to identify those women most likely to respond [37–40]. These observations have been confirmed in phase I trials of PI3K inhibitors, although the most robust responses were witnessed in those patients that carry a tumor with specific gain-of-function mutations [41–55]. Selection of endometrial cancer patients by loss of PTEN or gain-of-function mutation in PIK3CA for clinical trials of agents targeting PI3K or AKT is ongoing and it has yet to be determined whether or not these signatures confer sensitivity to directed therapy.

Mitogen-activated protein kinase (MAPK) pathway

The mitogen-activated protein kinase (MAPK) signaling pathway is another growth-signaling cascade associated with multiple cancers that is an attractive target for the development of targeted therapeutics [56–58]. The receptor tyrosine kinases (RTK) family is one of the more recognized kinase families. The MAPK kinase kinase (MAPKKK) phosphorylates and activates MAPK kinase (MAPKK) that in turn can phosphorylate and activate MAPK by phosphorylation on the Thr and Tyr resides [59]. Members of the GTPase families, Ras and Rho, relay signals from the receptor complex to the MAPKKK. There are four major MAPK signaling pathways in mammals. These include extracellular signal-related kinase (ERK), ERK5, p38-MAPK 1 and 2, and c-jun N-terminal kinase (JNK)1, 2, and 3. Typically, the ERK pathways respond to growth factor stimuli and p38 MAPK and c-jun are activated in response to stress stimuli such as UV irradiation and inflammatory cytokine [60,61]. There are, however, examples of growth factors activating the p38-MAPK and c-JNK via cross talk.

Ras proteins are integral intermediate modulators connecting the membrane receptors on the cell surface with their downstream effector MAPK signaling pathways. It has been reported that between 11.6% and 83% of endometrioid endometrial cancers harbor k-ras mutations [62–67]. Investigations utilizing endometrial cancer cell line models have suggested that MAPK/ERK1-2 is involved in promoting endometrial cancer cell proliferation in a number of in vitro studies utilizing KRAS mutant cell lines and MEK inhibitor [68–73].

A recent study further highlights the complexity of the interaction among the signaling pathways. Metformin, an oral biguanide commonly used for the treatment of type II diabetes, is thought to inhibit cell proliferation locally via activation of the AMPK signaling pathway, counteracting the growth-promoting effects of the PI3K/AKT/mTOR pathway. Recently, it was shown to be effective in down-regulating of ERK and AKT signaling and increasing cell death in endometrial cancer cells that constitutively expressed k-ras in endometrial cancer. Metformin resulted in concentration-dependent activation of AMPK in endometrial cancer cell lines [74,75]. The MAPK inhibitor, Selumetinib® (AZD-6244) is being tested in the recurrent endometrial cancer (NCT01011933) [75].

MAPK appears to play a significant role in the...

Produkt-Details

• Erscheint lt. Verlag: 11.11.2014
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Gynäkologie / Geburtshilfe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Schlagworte: appropriately • Cancer • cancers • Cant • challenges • commonly • difficult • Diseases • frightening • greater • Gynäkologie • Gynäkologie • Gynecologic • Gynecological • gynecology • Information • lifethreatening • Medical Science • Medizin • Oncology & Radiotherapy • Onkologie u. Strahlentherapie • Pathologie • Pathology • Physicians • prospect • provide • straightforward • terrifying • Tumors • Women
• ISBN-10: 1-118-65531-1 / 1118655311
• ISBN-13: 978-1-118-65531-3 / 9781118655313