Genetics and Biology of Gynecologic Cancers

Douglas A. Levine

All cancer is genetic, meaning that all cancers have a genetic basis and result from an accumulation of mutations or other genetic defects. Cancer can be caused by many different factors, but all cancers function through genetic mutation or other alterations. Most cancers occur when the normal functioning of a single cell in a tissue of origin goes awry. The old tenet of cancer being an imbalance of growth and death still holds true, but over the years, we have learned much about the causes and details of how this growth/death dichotomy becomes muddled. For some, cancer will have an inherited origin passed down through generations; for others it will be a newly developed, or de novo, mutation obtained by the tissue of origin to turn normal tissue into cancer. Many of the cancer-causing genes can be grouped into categories of tumor suppressors and oncogenes. There are a number of cancer syndromes that predispose to the development of gynecologic malignancies. In some cases, environmental factors may increase the risk of certain cancer types.

PRINCIPLES OF CANCER MOLECULAR GENETICS

Oncogenes

Oncogenes are cancer drivers that have the ability to initiate tumor formation when turned on, most commonly by mutations. Before a gene becomes an oncogene or develops the ability to transform normal cells to malignant cells, it is referred to as a proto-oncogene, or a gene with oncogenic potential. In addition to mutation, proto-oncogenes can transform into oncogenes through structural rearrangements such as translocations, duplications, or splice variants, as well as overexpression of the gene product. Genes can function as oncogenes through increasing protein activity or by losing the ability to suppress negative regulators of growth. The first oncogene, src, was discovered in chickens. RAS and MYC were other early oncogenes found to regulate transcription and affect cell proliferation. Since then, many other oncogenes, which are often activated by somatic mutations, have been discovered. An example of a more recently discovered oncogene is PIK3CA, which is activated by cell surface receptor tyrosine kinases and regulates AKT activation, cell growth, and survival (Figure 2-1). Through sequence analysis of various human tumors, PIK3CA mutations in multiple human tumors were identified.¹ Remarkably, most of these mutations were clustered at a limited number of nucleotide positions, termed hotspots, making them useful for cancer diagnostics and therapeutics. Mutations in related genes such as PIK3R1 and PIK3R2, which encode the regulatory and structural subunits of the PI3K protein, have also been identified. Currently, there are many drugs designed to target various subunits of PI3K that have the potential for effectiveness in tumors with activating PI3K mutations and others. Other regulatory genes, such as microRNAs, can function as oncogenes by promoting cancer development and growth. MicroRNAs usually negatively regulate gene expression, but if they release their normal negative inhibition, unsuppressed growth can result in oncogenic activity. Thus a gene can have direct or indirect oncogenic potential (Figure 2-2).

FIGURE 2-1. Schematic diagram of PI3K signaling. PTEN is a tumor suppressor gene inhibiting the pathway. Classically, both copies of PTEN need to be lost to release this inhibition and allow for uncontrolled AKT activity, as is seen in many solid tumors. PTEN can be lost through a combination of mutation, methylation, and deletion. PIK3CA encodes a catalytic subunit of PI3K. A single activating mutation in 1 copy of PIK3CA is necessary to activate AKT and result in uncontrolled growth, as it is an oncogene. (Reprinted [modified] by permission from Macmillan Publishers Ltd: Oncogene [Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497-5510], copyright 2008.)

FIGURE 2-2. MicroRNAs can function as oncogenes or tumor suppressor genes. Let-7 inhibits the RAS oncogene and therefore is functioning as a TSG. When lost, it would release its inhibition, and the RAS oncogene would be active, as happens in many malignancies. The miR17-92 cluster of microRNAs functions as an oncogene in that it inhibits the TSGs PTEN. PTEN normally inhibits AKT activity, but when inhibited itself, the PI3K/AKT pathway is activated/no longer inhibited, and cancer can develop or progress. (Reprinted from Hammond SM. MicroRNAs as oncogenes. Curr Opin Genet Dev. 2006;16:4-9, with permission from Elsevier.)

Tumor Suppressor Genes

Tumor suppressor genes (TSGs) are genes that have normal inhibitory function that, when lost, permit cell transformation or tumor growth. Unlike oncogenes, which promote growth when activated, TSGs require complete inactivation in order to fully release inhibitory activity. Classically, this has been referred to as the “two-hit hypothesis,” in which both copies of a TSG need to be lost in order to release inhibitory function sufficiently to promote cancer development and growth. The loss of both copies, or alleles, of a TSG can occur by 2 mutations developing over time, such that the first mutation increases the likelihood of developing a second mutation.

Alternatively, first copy of a TSG can be inactivated by mutation, and the second copy can be inactivated by a separate mechanism such as methylation, structural rearrangement, or loss of heterozygosity. BRCA1 is a good example of a TSG in that both alleles are lost in ovarian tumors. Interestingly, this has not been uniformly shown to be the case for breast cancer.² Commonly mutated TSGs include PTEN, which suppresses activation of the PI3K/AKT pathway; RB1, the retinoblastoma gene; APC in colon cancer; and the most commonly mutated TSG, TP53, which is mutated in nearly all serous ovarian cancers and approximately half of most other epithelial malignancies. When 1 copy of a TSG is lost, such as when a BRCA1 mutation is inherited from a parent, this is termed haploinsufficiency. The functional impact of haploinsufficiency is unclear and likely varies between tissue types and biologic circumstances, but in some cases it may predispose to loss of the second allele.

Mismatch Repair Proteins

Mismatch repair (MMR) proteins help to correct normal errors in DNA replication. Every time a cell divides, its DNA undergoes replication, which is not a perfect process. In fact, when DNA is replicating, errors occur 1 in every 10⁶ to 10⁸ nucleotides. Considering the size of the human genome, many errors occur. Thus mechanisms to repair DNA replication errors must be robust. Most errors in replication are repaired during the replication process itself through a mechanism called proofreading. However, some errors persist after replication and are fixed through MMR. MMR is one of several DNA repair mechanisms. In general, DNA repair mechanisms can be grouped into 2 classes: those that repair single-strand DNA breaks and those that repair double-strand DNA breaks.

Mechanisms that repair single-strand DNA damage include base excision repair, nucleotide excision repair, and MMR. MMR is the only mechanism of single-strand repair that repairs undamaged, misaligned DNA primarily due to errors of replication. The MMR proteins that are most commonly mutated in gynecologic cancer syndromes are MLH1 and MSH2. MMR mutation leads to greater errors of DNA replication in repetitive regions of the genome within tumors. This phenomenon is referred to as microsatellite instability (MI), in which short repeat regions undergo expansion or contraction in the number of repetitive elements. It is particularly common in endometrial and colorectal cancers. MI can be detected by sequencing DNA from normal tissues (such as blood) and comparing it with malignant tissues. When the malignant tissue has greater or fewer repetitive elements than the normal tissue, this is referred to as MI. In addition to MI developing as a consequence of MMR mutations, which can often be inherited, MI can also develop from somatic changes, such as methylation of the MLH1 promoter.

Inheritance Patterns

Inheritance refers to traits or genes obtained from parents and can be referred to as hereditary or inherited. Traditional inheritance patterns are autosomal dominant, autosomal recessive, and sex- (or X-) linked. Dominant inheritance occurs when the trait or gene is functional or active by inheriting a single copy from either parent. Dominantly inherited traits have a 50% chance of being passed down to each offspring. BRCA1/2 mutations are a good example of a dominantly inherited trait in that each offspring has a 50% chance of inheriting the mutation from a single parent who carries the mutation. Recessive patterns of inheritance are less common and require inheritance of a trait or gene from each parent, as 2 affected alleles are required for disease manifestation. X-linked traits can be inherited from either parent, but recessive traits are manifest in males, who only carry one X chromosome, whereas dominant traits would be manifest equally in males and females. Recessive X-linked traits require inheritance from each parent for manifestation. All inherited traits or mutations do not manifest themselves. The genetic composition of mutations or other variations are referred to as genotypes, and the manifestation of these mutations or traits are referred to as phenotypes. All mutations (or mutated genotypes) do not result in a disease phenotype; this phenomenon is referred to as incomplete penetrance, in which the diseased gene is only manifest in a subset of people. For most biologic situations, we do not understand the factors (or modifiers) that affect penetrance. Consider a BRCA1 mutation that confers a lifetime risk of 40% for ovarian cancer, meaning that not everyone with a BRCA1 inherited mutation develops ovarian cancer. The penetrance of a BRCA1 mutation for ovarian cancer is approximately 40%. The patterns of inheritance refer to the germline, or every cell in your body. When you inherit a mutation from a parent, it is present in every cell of your body. A disease-causing mutation may not cause disease in every cell of your body, but it is present in every cell of your body. This is in contrast to somatic mutations, which are not inherited but develop within the host and are commonly found in cancer. Many germline mutations will predispose to somatic mutations, which can function as the “second hit” to inactivate a TSG and initiate tumor formation. This distinction between germline events or mutations and somatic mutations is key to understanding what tumor-causing mechanisms are inherited and which develop de novo.

BIOLOGY OF GYNECOLOGIC CANCER

Endometrial Cancer

Endometrial cancers are broadly classified into 2 groups. Type 1 tumors are of endometrioid histology and are directly related to estrogen excess. Most commonly, the excess estrogen is derived from adipocytes and thus is more frequent in obese women. Many years ago, the most common source of exogenous estrogen was unopposed ingested estrogen, before combination hormone replacement therapy was prescribed. The initial report from the New England Journal of Medicine in 1975 identified a 4.5-fold increased risk of endometrial cancer in users of unopposed estrogens.³ Once the link between unopposed estrogen and endometrial cancer was established, hormone replacement therapy began including progestins for women who had their uterus in place. Other causes of unopposed estrogen include polycystic ovarian syndrome, in which anovulation leads to metabolic and hormonal derangements, which increase the risk of endometrial cancer in premenopausal women.⁴

Type 2 tumors are of more aggressive histologic subtypes, with the prototypic tumor being of serous histology. The etiology of type 2 tumors is less understood, but they have a higher propensity for recurrence and likely benefit from adjuvant treatment after surgical resection. These tumors are not associated with obesity and have no specific epidemiologic predilection, although they appear more common in nonobese women. Other aggressive type 2 histology subtypes include carcinosarcoma and clear cell (Table 2-1).

Table 2-1 Comparison Between Type 1 and Type 2 Endometrial Cancers

Pathology of Type 1 and Type 2 Endometrial Carcinoma

Type 1 endometrioid tumors follow a natural progression from normal endometrium to endometrial hyper-plasia (with or without atypia) followed by invasive cancer. A premalignant lesion within regions of endometrial hyperplasia has been recently identified and termed endometrial intraepithelial neoplasia (EIN). EIN is associated with a far greater increase in endometrial cancer risk than simple endometrial hyperplasia. The risk of progression from a precursor lesion to endometrial carcinoma increases with greater complexity and nuclear atypia. From the most recent comprehensive review, the risk of progression to invasive endometrial cancer was < 1% for simple hyperplasia without atypia, 7% to 9% for either simple hyperplasia with atypia or complex hyperplasia without atypia, and 20% for complex hyperplasia with atypia. These risks are all approximately doubled in the presence of EIN.⁵

Type 2 serous tumors do not have a logical and stepwise progression from a well-defined precursor lesion to invasive carcinoma. Often, uterine serous carcinoma can be confined to a small endometrial polyp, yet present with metastatic disease, at the time of comprehensive surgical staging. A precursor lesion has been identified and termed endometrial intraepithelial carcinoma (EIC). EIC has been specifically associated with uterine serous tumors and uterine carcinosarcomas that contain a serous epithelial component and can be found adjacent to most established uterine serous carcinomas.⁶ Epidemiologic studies suggest that nearly 50% of apparently uterine-confined disease have spread beyond the uterus at the time of diagnosis.⁷ Unlike type 1 tumors, which typically develop in a background of hyperplasia, type 2 tumors, particularly serous tumors, develop in a background of relative endometrial atrophy, with uterine polyps or other focal changes occurring at the site of tumorigenesis. These tumors also lack the presence of hormone receptors commonly seen in type 1 tumors.

Endometrial carcinosarcoma is an aggressive type 2 tumor that was initially thought to be 2 tumor types that collided at a well-defined interface. Subsequent molecular studies clearly proved that these tumors arise through clonal evolution where a given malignant epithelial cell undergoes differentiation into 2 histologically distinct lineages. Thus these tumors have traditionally been considered as a subset of uterine sarcomas, but in fact, they represent poorly differentiated and divergent epithelial tumors with sarcomatous differentiation.⁸ If any part of the sarcomatous component contains cell types that are not native to the uterine corpus, this is referred to as a heterologous differentiation. If all cell types are commonly seen within the uterus, this is referred to as a homologous differentiation. In several well-designed studies, it has been reported that patients with endometrial carcinosarcomas having heterologous differentiation have a worse outcome as compared with patients having homologous differentiation for both early- and late-stage disease.⁹

Genetics of Type 1 and Type 2 Endometrial Carcinoma

In addition to the well-defined histologic progression of type 1 endometrioid tumors, the genetics of type 1 tumors are also fairly well understood. It is thought that PTEN, a tumor suppressor gene that negatively regulates the PI3K/AKT pathway, is lost early in the neoplastic process. In fact, PTEN mutations have been found in the preneoplastic EIN lesions. PTEN loss can occur through a number of mechanisms, including somatic mutation, promoter methylation, or deletion. In the uncommon Cowden syndrome, which includes development of hamartomas and increased risks of endometrial, breast, renal, thyroid, and possibly colorectal malignancies, PTEN mutation is present in the germline (and thus is inherited). Subsequent to PTEN loss, additional mutations are accumulated that also frequently occur in the PI3K/AKT pathway. PIK3CA encodes the catalytic subunit of the PI3K enzyme and contains activating mutations in approximately 25% of endometrioid and serous tumors. Interestingly, mutations in this gene are often identified at the same genetic position, or at the same nucleotide, and are therefore termed hotspot mutations. These types of hotspot mutations in PIK3CA and other genes can be easily detected through modern laboratory assays such as mass spectrometry and are therefore good targets for both diagnostics and therapeutics. In fact, there are many PIK3CA inhibitors being developed and in early-phase clinical trials. The regulatory and structural units of the PI3K enzyme are encoded by the genes PIK3R1 and PIK3R2, both of which are also frequently mutated in type 1 cancers.

Mutations in FGFR2 were first reported in 2007 and are present in 10% to 15% of type 1 tumors.¹⁰ This finding has clinical relevance, as there are small-molecule inhibitors of FGFR2 in addition to other targets. High-grade type 1 endometrial tumors, like other high-grade solid tumors, have fairly frequent mutations in TP53, in the order of 50%. Other commonly mutated genes include CTNNB1, KRAS, and occasionally AKT1. Type 1 tumors also have a 20% to 25% frequency of MI, which can be easily detected through a consensus panel of 5 microsatellite markers and has been adopted as a reference set by the National Cancer Institute.¹¹ The clinical significance of MI in endometrial cancer is unclear, with studies demonstrating both improved and worse outcomes in the setting of MI. For colorectal cancer, it is well established that MI tumors have an improved clinical course.¹²

The lack of well-defined progression from normal histology to cancer for type 2 tumors is also reflected in the genetics of these lesions. EIC is thought to be the precursor lesion, which overexpresses and contains mutations in TP53. TP53 mutation is also found in 80% to 90% of uterine serous carcinomas, in contrast to the low frequency in low-grade endometrioid type 1 tumors and modestly higher frequency in high-grade type 1 tumors. Type 2 tumors are also characterized by the lack of MI and a very low frequency of KRAS, PTEN, and CTNNB1 mutations. There is a similar frequency of mutations in PIK3CA, offering the possibility that PI3K-targeted therapy may be equally successful in type I and type 2 tumors. TP53 mutations are also commonly seen in uterine carcinosarcomas but occur at low frequency in clear cell tumors.¹³

Lynch Syndrome

First described by Henry T. Lynch, this syndrome commonly includes malignancies of the uterus, colon, stomach, and ovary.¹⁴ Less frequent malignancies that are part of this syndrome include small bowel, upper urinary tract, brain, and biliary tract. Lynch syndrome is primarily caused by an inherited germline mutation in one of several MMR genes: MLH1, MSH2, and less often MSH6, PMS1, and PMS2. The syndrome was initially divided into 2 subtypes—Lynch I and Lynch II—based on whether or not extracolonic tumors were included in a given pedigree. It was quickly realized that the genetic basis of these 2 subtypes was similar, and the syndrome was commonly referred to as hereditary nonpolyposis colorectal cancer syndrome (HNPCC). This was due mostly to the fact that the predominant malignancy was colon cancer. However, this name soon became a misnomer when the high frequency of endometrial cancer was identified in women. Furthermore, the colons within which the colorectal tumors developed as part of HNPCC did in fact contain multiple colonic polyps in many cases; however, the extent of the polyposis was far less than that seen in the related familial adenomatous polyposis (FAP) syndrome, in which a great many polyps are found throughout the colon due to a germline mutation in APC. One main difference in the risk of colorectal cancer between these 2 syndromes is that the risk of colorectal cancer with FAP is nearly 100%, but the risk of colorectal cancer in HNPCC is approximately 80% and occurs at a later onset than with FAP. For these reasons, HNPCC is no longer an accurate description of the clinical and genetic syndrome, and Lynch syndrome (without any further distinction between type I and type II) is now the preferred terminology.

Pathogenesis and Pathology

Lynch syndrome is due to inherited mutations in 1 of 5 MMR genes. MLH1 and MSH2 are the most commonly mutated genes in this syndrome. These defects lead to faulty DNA repair and increased risk of malignancy. In women, endometrial cancer and colon cancer have an equal likelihood of being the sentinel malignancy in this syndrome. In women with Lynch syndrome, the lifetime risk of colon cancer and endometrial cancer are both approximately 50%, in contrast to the risk of colon cancer in men, which is 50% greater.^15,16 The mean age of endometrial cancer diagnosis in Lynch syndrome patients is approximately 45 years, as compared with a mean age of 62 years for endometrial cancer in general. In women under 50 years of age with endometrial cancer, the likelihood of having Lynch syndrome as determined by a germline mutation in one of the MMR genes is 9%.¹⁷ Young patients with Lynch syndrome tend to have a lower body mass index than young patients with sporadic endometrial cancer. Immunohistochemical markers are now robustly available for testing for the absence (abnormal) of expression in MLH1, MSH2, MSH6, and PMS2.

The absence of MMR protein expression is indicative of MI, but a fair portion of these cases may be due to promoter methylation of MLH1 and not an inherited germline mutation, which is the only circumstance diagnostic of Lynch syndrome. If immunohisto-chemistry (IHC) only is applied to endometrial cancer patients younger than 50 years of age, 25% to 35% of tumors have been found to lack normal IHC staining, which increases when considering only nonobese women. Nonetheless, approximately one-third to one-half of these cases may be due to MI without a true germline mutation secondary to epigenetic/methylation silencing.^18,19 The lifetime risk of Lynch syndrome–associated ovarian cancer ranges from 8% to 12%. Ovarian cancers appear to be moderate to high grade, mostly epithelial in nature, and, unlike sporadic ovarian cancer, predominately stage I or II. Endometrial cancer is diagnosed synchronously in approximately 20% of Lynch syndrome patients with ovarian cancer. The mean age of ovarian cancer diagnosis in Lynch syndrome patients is approximately 43 years, as compared with a mean age of 63 years for ovarian cancer in general.²⁰ Women with synchronous ovarian and endometrial cancer have a 7% risk of having Lynch syndrome²¹ (Figure 2-3).

FIGURE 2-3. Lifetime risk for colon, endometrial, and ovarian cancer in individuals with Lynch syndrome compared with the general population. (Reproduced, with permission, from Schmeler KM, Lu KH. Gynecologic cancers associated with Lynch syndrome/HNPCC. Clin Transl Oncol. 2008;10:313-317.)

Endometrial tumors associated with Lynch syndrome are more commonly found in the lower uterine segment and are more often poorly differentiated and deeply invasive, with a higher mitotic rate and more tumor-infiltrating lymphocytes (TILs).²² However, a comprehensive review comparing Lynch-associated endometrial cancer with sporadic endometrial cancer and MLH1 promoter methylated tumors found a similar frequency of non-endometrioid histologies between groups, but the MLH1 methylated tumors were more likely to be undifferentiated.²³ This review also found similar frequencies of myometrial invasion, high stage, and TILs. Many centers have adopted pathologic screening approaches to identify patients who may have Lynch syndrome and should be referred for genetic counseling. These varied algorithms typically start with standard IHC directed toward the 4 common MMR proteins: MLH1, MSH2, MSH6, and PMS2 in women under the age of 50 years with endometrial cancer, those with a family history suggestive of Lynch syndrome, or in patients with characteristic tumor morphology such as lower uterine segment involvement and prominent TILs. If MLH1 immuno-staining is absent/lost, a follow-up assay is performed for MLH1 methylation, as this is a common cause of both MLH1 loss and MI, but is not inherited or associated with Lynch syndrome. If there is IHC loss in any of the tested proteins and no evidence of MLH1 promoter methylation, patients should then be referred for genetic counseling and consideration of germline testing for inherited mutations in these 4 genes. At any time, if there is high clinical suspicion, patients should be referred for genetic counseling, regardless of screening test results.

Screening and Prevention

Ovarian and endometrial screening is recommended for women with Lynch syndrome in addition to all screening recommended for both sexes. Physical examination, CA-125 measurements, and transvaginal sonography should be performed twice yearly and begin at age 30 to 35 years. This screening approach is the standard for women at high risk for ovarian cancer and will also identify gross abnormalities within the uterine cavity based on sonography. However, this screening approach has never been proven to reduce the risk of death from these diseases; nonetheless, it appears reasonable and awaits full validation and, in the absence of better screening approaches, is currently the best management scheme. Because this approach will not fully evaluate the uterine cavity for early lesions, annual endometrial sampling/biopsy is also recommended. For women who have completed childbearing, risk-reducing total hysterectomy with bilateral salpingo-oophorectomy is recommended. This approach reduces the risk of ovarian and endometrial cancer to approximately zero. In one study, the incidence of endometrial cancer in a control group was 33% compared with none in the risk-reducing hysterectomy group. The incidence of ovarian cancer in a control group was 5% compared with none in the risk-reducing salpingo-oophorectomy group.²⁴ Colonoscopy should be performed every 1 to 2 years for at-risk patients.

Endometrial Cancer in Young Women

Endometrial cancer diagnosed in young women presents a difficult clinical dilemma. Because the mean age of endometrial cancer diagnosis is 63 years, “young women” can be characterized as those under the age of 50 or even 40 years. For early noninvasive endometrial cancer, conservative therapy may be appropriate for women who have not yet completed childbearing. The specific algorithms and outcomes are beyond the scope of this section; however, a portion of these patients will present with synchronous ovarian cancer or develop metachronous ovarian cancer. Clearly, young women with endometrial cancer are candidates for genetic counseling and Lynch syndrome testing. Recent data suggest that fewer than 10% of women with synchronous endometrial and ovarian cancer have Lynch syndrome, suggesting other pathobiology for women with these synchronous tumors, of which only half are under the age of 50 years at diagnosis.²¹ Young, normalweight women with endometrial cancer appear to have a relatively high incidence of infertility and/or irregular menstrual cycles, likely due to anovulation, which may also contribute to the increased risk of endometrial cancer.²⁵

Approximately one-quarter of the normal weight, young women with endometrial cancer also had a synchronous ovarian cancer. Most of the synchronous ovarian tumors are of endometrioid histology, suggesting a possible field effect or link through endometriosis, as most sporadic ovarian cancer is of serous histology. Approximately 15% of the obese young women with endometrial cancer also had a synchronous ovarian cancer, suggesting greater frequency and possible different pathoetiology of synchronous ovarian cancer in young women with endometrial cancer based on body mass index and associated hormonal dysfunction. Additional studies have confirmed the approximate 25% incidence of synchronous ovarian cancer in young women with endometrial cancer.²⁶

Synchronous endometrioid histologies have been associated with more favorable outcomes. These findings suggest that synchronous ovarian cancers develop in young women with endometrial cancer at a high rate for reasons that are not entirely clear, but this should be discussed with patients considering conservative management of early endometrial cancer. Risk-reducing salpingo-oophorectomy and hysterectomy should be considered for these patients once childbearing is complete.

Ovarian Cancer

The majority of ovarian cancers are epithelial in nature; a small percentage of them are sarcomas, and even fewer are germ cell or sex–cord stromal tumors. These uncommon tumors will be discussed elsewhere in the text. The most common histologic subtypes of epithelial ovarian cancer are serous, endometrioid, clear cell, and mucinous. Transitional cell tumors were described as an epithelial subtype, but more recently, they have been considered a simple epithelial variant and not a separate histologic subtype as originally thought.

Epithelial tumors of serous histology were thought to arise from the ovarian surface epithelium. Two common hypotheses of their origin are based on incessant or repeated ovulation and excessive hormonal stimulation. The first hypothesis implicates the ovarian surface epithelium and repeated cycles of ovulatory damage and repair. This hypothesis is supported by data that late menarche, early menopause, multiparity, and oral contraceptive use all decrease the risk of ovarian cancer. However, the reduction in the number of ovulatory cycles does not account for the associated magnitude of risk reduction. The evidence to support a hormonal basis of ovarian cancer arises from several areas. Lower gonadotropin levels, present during pregnancy and oral contraceptive use, reduce the risk of ovarian cancer. Women with polycystic ovarian disease, who have increased circulating androgens, are at an increased risk of developing ovarian cancer. Inclusions cysts, which have also been proposed to be the precursor cell to ovarian cancer, are found within the cortex of the ovary in close proximity to the vasculature, circulating hormones, and follicular cysts, which have high levels of androgen.²⁷ Therefore, although ovulation and hormones have been directly linked to ovarian tumorigenesis, there are insufficiencies that fail to fully explain epidemiologic findings, suggesting a different set of biochemical, anatomic, and hormonal interactions, which will be discussed later.

Ovarian cancers have been broadly classified into 2 groups. Type 1 tumors are of endometrioid, mucinous, clear cell, and low-grade serous histology and thought to arise from ovarian cysts and secondary mullerian sites, such as endometriosis. These tumors appear to progress in a stepwise fashion from benign to borderline or atypical to malignant and invasive tumors. In this regard, various precursor lesions can be potentially identified and used for screening or prevention as appropriate. Type 2 tumors are more aggressive and contain high-grade serous tumors. These tumors most likely have a precursor lesion within the fallopian tube (discussed later) and metastasize early, present at an advanced stage, and account for most deaths from this disease. High-grade endometrioid tumors were thought to be a small subset of the more aggressive, advanced-stage ovarian epithelial tumors, but recent work has suggested that when IHC is incorporated into the diagnostic algorithm, many high-grade endometrioid tumors are morphologic variants of high-grade serous carcinoma, and only a few high-grade endometrioid tumors truly represent progression from a low-grade endometrioid tumor.^28,29 Carcinosarcoma is another aggressive type 2 histology subtype, but is relatively uncommon (Table 2-2).

Table 2-2 Comparison Between Type 1 and Type 2 Ovarian Cancers

Stay updated, free articles. Join our Telegram channel

Join