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Keywords:

  • clear cell carcinoma;
  • endometrioid carcinoma;
  • molecular pathology;
  • mucinous carcinoma;
  • ovarian carcinoma;
  • serous carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

The histopathological classification of ovarian surface epithelial carcinomas (referred to hereafter as ‘ovarian carcinoma’) has shifted over the past 10 years to reflect more clearly our understanding of molecular events during carcinogenesis. Ovarian carcinoma is no longer viewed as a single entity but as multiple disease processes, with each having different molecular pathways altered during oncogenesis, resulting in differences in clinical and pathological features, such as biomarker expression, pattern of spread and response to chemotherapy. There are five subtypes of ovarian carcinoma that are sufficiently distinct and well-characterized that they should be considered to be different diseases, i.e. high-grade serous, clear cell, endometrioid, mucinous and low-grade serous, from most to least common, respectively. This review summarizes the molecular abnormalities of these five ovarian carcinoma subtypes, relating them to clinical and pathological features.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

In the 2002 World Health Organization (WHO) Blue Book[1] a wide range of ovarian carcinoma subtypes are described, but the reality of the era when the book was written was that ovarian carcinoma was managed as if it were a single disease. Since then, there have been significant advances in our understanding of the molecular alterations in ovarian carcinoma, with refinement of the diagnostic criteria for ovarian carcinoma subtypes, which will be reflected in the forthcoming update to the WHO classification system. It is no longer appropriate to consider ovarian carcinoma to be a single disease. While a simplified classification of ovarian carcinoma into Type I and Type II tumours has been suggested,[2, 3] this system perpetuates the earlier error of lumping together unrelated tumour types (e.g. mucinous and clear cell); this has had the effect of holding back progress towards subtype specific therapy, and is to be avoided. Some valid points are made within this classification system, in that the Type I (low-grade) tumours (including low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas) generally harbour somatic mutations in genes encoding specific protein kinases and other signalling molecules, creating opportunities for targeted therapy, while the Type II (high-grade serous) tumours do not have frequent/recurrent mutations in specific oncogenes. None the less, there are consistent differences between the tumour subtypes lumped together as Type I and these subtypes are best considered as specific tumour types. It is worth noting that high-grade serous carcinomas account for 70% of all ovarian carcinomas and are responsible for 90% of ovarian cancer deaths[4, 5]; significantly lowering overall morbidity and mortality from ovarian carcinoma will therefore necessarily have to focus on this subtype.

This review will discuss recent advances in understanding the molecular pathology and pathogenesis of ovarian carcinoma, considering each of the five subtypes. Their respective responses to currently available treatments will be discussed briefly, along with emerging subtype-specific therapeutic agents.

High-grade serous carcinoma (HGSC)

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Clinical and Pathological Features

High-grade serous carcinoma (HGSC) are the most common and lethal of all ovarian carcinomas. HGSC account for 70% of all ovarian carcinomas and 90% of ovarian cancer deaths in North America.[4, 6] Fewer than 1% of HGSCs are confined to the ovary at the time of diagnosis.[7] The 5-year survival rate is 29% for patients with stage IIIc and 13% for patients with stage IV disease.[8] Platinum/taxane combination chemotherapy has been standard care for approximately 20 years. Until recently, many HGSC were diagnosed incorrectly as high-grade endometrioid carcinoma or mixed serous and clear cell carcinoma.[9-11] Molecular testing, including immunostaining, has indicated that the morphological spectrum of HGSC is broader than was previously appreciated and includes solid, glandular and transitional-like, as well as papillary architectural patterns (Figure 1). Although there is some evidence of molecular differences in HGSC with differing architectures,[12, 13] this has not been corroborated independently and at present there are no clinically relevant morphological subcategories of HGSC. Nuclear atypia is marked and the mitotic index is very high in HGSC.

image

Figure 1. Tumour with an endometrioid-like pattern is adjacent to papillary areas in this high-grade serous carcinoma (HGSC) (A). p53 immunohistochemistry shows complete loss of staining in the tumour; intratumoral lymphocytes are positive (B). Positive nuclear WT-1 staining is present, as is typical for HGSC (C).

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Molecular Characteristics

TP53 mutations are present in 97% of HGSC.[14] p53 plays a key role in cell cycle regulation and DNA repair. Acting at the G2 checkpoint, p53 can arrest cellular growth and repair DNA damage before cellular replication occurs. If the damage is beyond repair, p53 triggers apoptosis.[15] Therefore, p53 mutations lead to propagation of DNA damage and chromosomal instability. Immunostaining for p53 correlates, albeit imperfectly, with TP53 mutation status; with missense mutations (the most common TP53 abnormality) there is typically nuclear accumulation of mutant protein, and p53 IHC staining is strongly and diffusely positive, while nonsense mutations or deletions lead to complete absence of p53 protein; these staining patterns contrast with the p53 intact or normal pattern, where occasional tumour cells show nuclear staining (Figure 1B).[16, 17] Germline mutations in BRCA1 or BRCA2 are present in more than 15% of HGSC, while somatic BRCA1/2 mutations or BRCA1 promoter methylation are present in an additional 14%–22% of HGSCs.[18] Both genes encode DNA repair proteins, the loss of which results in defective repair of double-strand DNA breaks through homologous recombination (HR), leading to chromosomal instability.[19] The loss of BRCA1/2 function is normally lethal to cells; however, in the presence of p53 mutations these cells are able to survive.[5] As well as BRCA1/2 abnormalities, HR defects can also occur in HGSC as a result of EMSY amplification (8% of cases), PTEN deletion (7% of cases), RAD51C hypermethylation (2% of cases) or other rare mechanisms, such that HR is defective in 50% or more of HGSC.[20] The Cancer Genome Atlas (TCGA) in-depth molecular survey of more than 400 HGSC showed that single gene mutations are uncommon in HGSC, with the exception of TP53 and BRCA1/2, with only six additional genes having recurrent mutations at a statistically significant level, and all of these were low-frequency events (<10%).[20] The hallmark of HGSC was not recurrent mutations, but numerous somatic copy number alterations (SCNA), with more than 100 recurrent amplifications and deletions identified. These SCNA span multiple genes per event, making identification of the most important affected genes challenging. The TCGA study also identified signalling pathways that are commonly affected in HGSC (in addition to HR, mentioned previously); these include retinoblastoma (RB) protein, phosphatidylinositol-3 kinase/RAS, NOTCH and forkhead box protein M1 (FoxM1) pathways, making these candidates for targeted therapy.[20] Molecular abnormalities in HGSC are summarized in Table 1.

Table 1. High-grade serous carcinoma: molecular features
  1. a

    Somatic copy number alterations.

Chromosomal instability/aneuploidy (100%)
p53 mutations (>90%), BRCA loss (30%–45%)
Few mutations, numerous SCNAa
Homologous recombination defects
FoxM1 (84% of cases), RB (67%), PI3K/RAS (45%) and NOTCH (22%) signalling alterations

Pathogenesis

In 2001, serous tubal intra-epithelial carcinoma (STIC) was described in the fimbriae of fallopian tubes.[21] Intra-epithelial neoplasia/dysplasia of the fallopian tube, as a diagnostic category, has a long and undistinguished history; earlier literature (i.e. pre-2001) is based on variable case definitions and these studies are uninterpretable. The current criteria for STIC include high-grade nuclear atypia, of the sort seen in HGSC.[22] Since 2001, multiple studies have shown that, when carefully sought through thorough examination of the fallopian tubes, STIC is the most common precursor lesion identified in patients with BRCA1/2 germline mutations who are undergoing risk-reducing salpingo-oophorectomy, and that STIC are also present in 50%–60% of women with sporadic ovarian carcinoma.[23, 24] Molecular characterization of STIC showed the same genetic abnormalities as HGSC.[24-26] Malignant cells from STIC are theorized to exfoliate from the fimbriae and secondarily implant onto the ovarian surface.[27] In support of this theory, positive pelvic washings have been found in patients with only STIC lesions.[28] While the evidence is not yet conclusive, there is increasing acceptance that a majority of HGSC originate from the epithelium of the fimbriated end of the fallopian tube.

Treatment Considerations

High-grade serous carcinoma (HGSC) is treated with surgical debulking (either as primary surgical intervention or post-neoadjuvant chemotherapy) and platinum/taxane chemotherapy. Most (70%–80%) HGSC show an initial response to chemotherapy, but the majority of tumours recur as chemoresistant disease.[29] Poly (ADP-ribose) polymerase (PARP) inhibitors (e.g. olaparib) are a promising new therapy for HGSC. PARP inhibitors target the nucleotide–excision–repair pathway of DNA repair. While normal cells can cope with the loss of this pathway, cells which also lack a functional HR DNA repair pathway undergo crisis and die when exposed to PARP inhibitors.[30-32] Early results from clinical trials in HGSC are promising,[33, 34] and further trials are in progress. Angiogenesis is a required component of tumour growth and metastasis, and bevacizumab, an anti-vascular endothelial growth factor (VEGF)-A agent, has been used in patients with refractory ovarian carcinoma with response rates of 15.9%–21%[35, 36] and modest survival improvements in clinical trials.[37, 38] At present there are no predictive markers to identify the minority of patients with HGSC who stand to benefit from this treatment approach.

Clear cell carcinoma (CCC)

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Clinical and Pathological Features

Clear cell carcinoma (CCC) account for approximately 10% of cases of ovarian carcinoma in North America, but there is considerable variability worldwide.[5, 39-43] Compared to HGSC, CCC present with lower stage disease, and they are less responsive to platinum/taxane chemotherapy.[44-47] CCC commonly display admixtures of tubulocystic, papillary and solid architectural patterns; similarly, individual tumours often show an admixture of cell types (clear cells, hobnail cells and oxyphil cells) (Figure 2A). Clear cell carcinomas tend to show low mitotic and apoptotic activity, compared to HGSC.[10] As noted by DeLair et al., [48]clear cell-rich tumours which do not show classic morphological patterns of CCC should prompt consideration of alternate diagnoses; immunostaining may be helpful in arriving at a correct subtype diagnosis (e.g. HGSC or endometrioid carcinoma with clear cells) in such cases.

image

Figure 2. Clear cell carcinoma of the ovary (A), with nuclear positivity for hepatocyte nuclear factor-1beta (HNF-1β) in tumour cells (B).

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Molecular Characteristics

Common molecular abnormalities in CCC are summarized in Table 2. The AT-rich interactive domain 1A gene (ARID1A) encodes the BAF250a protein, which is one of the accessory subunits of the SWI–SNF chromatin remodelling complex involved in the regulation of a variety of cellular processes, including proliferation, differentiation, development and DNA repair,[49] and is mutated in approximately 50% of CCC, but not in HGSC.[50, 51] CCC show mutations in the gene encoding the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) in 43% of cases.[52] Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in cell growth and survival, as well as playing a role as a tumour suppressor.[53, 54] PPP2R1A, the gene encoding the alpha-isoform of the regulatory subunit A of PP2A, is mutated at a low frequency (4%–7%) in CCC.[55, 56] Up-regulation of hepatocyte nuclear factor-1beta (HNF-1β), at both mRNA and protein levels, is seen in almost all ovarian CCC[57] (Figure 2B) and can be used as a diagnostic marker for this tumour.[58] By gene expression profiling, pathways involved in allowing successful adaption to hypoxia/oxidative stress are commonly up-regulated.[59, 60] CCC is associated with loss of expression of mismatch repair proteins (MLS1, MSH2, MSH6 or PMS2) in approximately 10% of cases.[61]

Table 2. Clear cell carcinoma: molecular features
  1. a

    Microsatellite instability (MSI)/loss of mismatch repair protein expression.

Most are diploid or tetraploid
ARID1A, PIK3CA, PPP2R1A mutations
MSIa
HNF-1β expression
Hypoxic growth, angiogenesis and glucose metabolism pathways altered

Pathogenesis

The frequent association between CCC and coexisting endometriosis has been recognized for many years.[62, 63] The observation that a significant minority of CCC arise within endometriotic cysts adds further circumstantial evidence in support of an aetiological link between endometriosis and CCC. Atypical endometriosis, characterized by areas of pronounced cytological atypia, with cytological features characteristic of clear cell carcinoma within endometriosis, has been proposed as a specific CCC precursor. ARID1A mutations with loss of BAF250a protein expression were demonstrated in CCC and contiguous atypical endometriosis.[50] PIK3CA mutations are seen frequently in CCC, and Yamamoto et al. [52]found identical mutations in 90% of adjacent foci of endometriosis, including in 60% of cases where there was no cytological atypia in the adjacent endometriosis. While there is compelling evidence that some CCC arise from endometriosis, some may not; there is a subset of CCC with an adenofibromatous background, and these may not be related to endometriosis (although we have certainly seen CCC, clear cell adenofibroma and endometriosis coexisting in the same ovary, and the adenofibromatous tumours may also arise from endometriosis).

Treatment Implications

The observation of altered expression of angiogenesis/hypoxia-related pathways in CCC led to preclinical investigations of sunitinib, which targets angiogenesis signalling (and is used in the treatment of clear cell carcinoma of the kidney), with demonstration of a response to sunitinib in CCC but not HGSC xenografts.[59] A small series of patients with CCC have also shown a response to sunitinib therapy.[64] In retrospective studies, CCC have shown a better outcome when treated with radiotherapy, which may also reflect vulnerability through targeting of angiogenesis.[65] There is potential to move away from the relatively ineffective current chemotherapy to more effective targeted therapy in CCC, but prospective clinical trials are needed to support such a dramatic change in treatment. The recently closed Japanese Gynecologic Oncology Group (JGOG) 3017 trial compared carboplatin/paxlitaxel to cisplatin/irinotecan in CCC and results are awaited, but testing a relatively small change from conventional chemotherapy (addition of irinotecan to platinum) is unlikely to yield a dramatic result; none the less, the precedent for large subtype-specific clinical trials in ovarian carcinoma is now established.

Endometrioid carcinoma (EC)

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Clinical and Pathological Features

Endometrioid carcinoma (EC) account for approximately 10% of ovarian carcinomas, and are usually both low-stage and low-grade at presentation (although progression to high-grade carcinoma can occur). EC are associated with a favourable prognosis, and perhaps because of that they are relatively poorly characterized at present. EC of the ovary show an identical spectrum of morphological features to that observed in EC of the endometrium. Glandular architecture with squamous differentiation is the most common pattern encountered (Figure 3A).

image

Figure 3. Endometrioid adenocarcinoma showing focal squamous differentiation (A). Tumours with somatic mutations in the beta-catenin gene show nuclear localization of beta-catenin (B).

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Molecular Features

Common molecular abnormalities in EC are summarized in Table 3. ARID1A and PPP2R1A mutations are seen in both CCC and EC, with 30% of EC having ARID1A mutations and 12% having PPP2R1A mutations.[50, 55] Somatic mutations in exon 3 of the beta-catenin gene (CTNNB1) occur in 38%–50% of EC, with nuclear beta-catenin protein being detected in greater than 80% of cases (Figure 3B). PTEN mutations, which occur between exons 3 and 8, occur in 20% of cases of EC.[1] PIK3CA mutations occur in EC, but are less common than in CCC.[66] EC is associated with loss of expression of mismatch repair proteins (MLS1, MSH2, MSH6 or PMS2) in approximately 10% of cases.[61]

Table 3. Endometrioid carcinoma: molecular features
  1. a

    Microsatellite instability (MSI)/loss of mismatch repair protein expression.

PTEN, CTNNB1, ARID1A, PPP2R1A mutations
MSIa

Pathogenesis

Regarding CCC, the association between EC and endometriosis is well established. The putative precursor lesion, so-called ‘borderline’ change, is morphologically equivalent to complex atypical hyperplasia of the endometrium. It has been suggested that a subset of endometrioid carcinomas unrelated to endometriosis exist, and differ from those related to endometriosis (e.g. in showing expression of WT1)[67]; in our opinion, these non-endometriosis-related ‘endometrioid’ carcinomas of the ovary are most probably high-grade serous carcinomas with prominent glandular differentiation, in which case the lack of association with endometriosis is to be expected.

Treatment Implications

Because of the favourable prognosis of EC, subtype-specific trials of therapy have not been pursued for this subtype. For stage 1A low-grade EC, treatment beyond surgical removal is not needed.[68] In higher-stage disease, where adjuvant treatment is indicated, conventional platinum/taxane chemotherapy remains the only option. Should targeted therapies be developed for the more common endometrial carcinoma of endometrioid type, they would be obvious choices for testing in ovarian EC, given the similar mutational profiles.

Mucinous carcinoma (MC)

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Clinical and Pathological Features

Mucinous carcinomas (MC) are the least studied of all ovarian epithelial carcinomas because of their rarity; MC make up 2%–4% of ovarian epithelial carcinomas, once metastatic carcinomas have been carefully excluded.[69-71] The majority of ovarian mucinous tumours are borderline tumours or stage 1 MC.[72, 73] Being low-stage at presentation, MC generally have a good prognosis and stage Ia, grades 1 or 2 tumours can be treated with complete surgical excision without adjuvant chemotherapy.[68] Preservation of fertility is an option, as MC is rarely bilateral. Recurrent or metastatic MC, however, is associated with a poor prognosis, and recurrences may be in unusual locations (for ovarian carcinoma) such as lung or bone.[74] Mucinous carcinomas, by definition, are characterized by the presence of mucin within tumour cells (Figure 4A). Mucin production is most prominent in the borderline components that are present in most MC; with progression to carcinoma, mucin within tumour cells becomes less conspicuous, and in recurrent MC mucin production, based on light microscopic examination, may be absent.

image

Figure 4. Mucinous ovarian adenocarcinoma (A), 15% of which show HER2 overamplification with membranous staining on immunohistochemistry (B). Chromogenic in-situ hybridization showing amplification of HER2 (C).

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Molecular Characteristics

The most common molecular abnormalities in MC are summarized in Table 4. KRAS mutations occur in more than 75% of primary MC.[70, 75-77] Recent studies indicate that HER2 gene amplification and overexpression is present in approximately 15% of MC (Figure 4B,C).[72-78] KRAS mutation and HER2 amplification are almost mutually exclusive, with those cases of MC lacking either KRAS mutation or HER2 amplification having a worse prognosis.[72]

Table 4. Mucinous carcinoma: molecular features
  1. a

    HER2 amplification and KRAS mutation are near mutually exclusive.

KRAS mutations
HER2 amplification and overexpressiona

Pathogenesis

The pathogenesis of MC is not well understood. Most MC are associated with areas showing either benign mucinous epithelium, mucinous borderline tumour of intestinal type or both components.[29, 76, 79, 80] Identical KRAS mutations have been found in the histologically benign and borderline components and adjacent carcinoma, supporting a stepwise progression of tumorigenesis from mucinous cystadenoma to mucinous borderline tumour (intestinal-type) to MC.[29, 76, 79, 80] Mucinous metaplasia is rarely observed in cortical inclusion cysts, making these structures an unlikely site of origin for MC. Brenner tumours and Walthard cell nests, however, commonly show mucinous metaplasia and are often associated with mucinous tumours (18% of mucinous cystadenomas contain foci of Brenner tumour).[70, 81] Although there is no supporting molecular evidence, the observations suggest a possible origin from transitional epithelial nests at the para-ovarian tuboperitoneal junction.[70, 81] MC can also, rarely, be of germ cell origin, arising from a teratoma.[82]

Treatment Considerations

Mucinous carcinomas (MC) are usually localized to the ovary at the time of diagnosis and can be cured by surgery alone. Metastatic disease at the time of presentation or recurrences presents a challenge, as MC are typically not sensitive to platinum-based chemotherapy.[83-85] The discovery of HER2 amplification and overexpression in 15% of MC opens the possibility of trastuzumab therapy in this subset of cases.[78] From treatment experience with KRAS-mutated colorectal carcinomas, MC with KRAS mutations would be expected to fail anti-epidermal growth factor receptor (EGFR) therapy,[86, 87] and anti-EGFR inhibitors could be offered to the minority of patients with KRAS wild-type MC.[78] In cases with KRAS mutation and no HER2 amplification, which constitute a majority of cases of MC, no novel treatment options are available at this time.

Low-grade serous carcinoma (LGSC)

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Clinical and Pathological Features

It has only recently been accepted that LGSC and HGSC are two completely separate tumours with different precursors and molecular pathways of carcinogenesis. Unlike HGSC, LGSC are uncommon tumours and account for approximately 2% of all cases of ovarian carcinomas.[5] LGSC are typically slow-growing tumours that present with high-stage disease.[88, 89] LGSC is distinguished from HGSC based on a less than threefold variation in nuclear size, with a secondary criterion of mitotic rate less than 13 mitotic figures/10 high-power fields (Figure 5A).[90, 91] While these criteria accurately identify the subset of serous carcinomas referred to collectively as LGSC in a large majority of cases, we have encountered a serous carcinoma with a somatic TP53 mutation, arising in a patient with a BRCA germline mutation, that showed minimal nuclear variability (i.e. the morphological criteria would have resulted in a diagnosis of LGSC in a tumour that, based on molecular features, was HGSC), and further refinements may be needed in the future.

image

Figure 5. Low-grade serous carcinoma (LGSC) infiltrating surrounding fat (A). Diffuse p53 nuclear staining would be seen in high-grade serous carcinoma, while patchy staining, as shown here, supports a diagnosis of LGSC (B).

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Molecular Characteristics

The molecular abnormalities of LGSC are summarized in Table 5. LGSC are diploid or near-diploid tumours with very few point mutations.[92] LGSC contain KRAS or BRAF mutations in 60%–70% of cases.[79, 93, 94] Mutations in KRAS and BRAF lead to constitutive activation of the mitogen activated protein kinase (MAPK) pathway. MAPKs are serine–threonine kinases that respond to extracellular signals (mitogens) to regulate a multitude of cellular activities, including gene expression, mitosis, cellular differentiation and cell survival.[2] Mutations in KRAS and BRAF are mutually exclusive. Interestingly, advanced-stage LGSC are less likely to have mutations in BRAF, suggesting that LGSC lacking this mutation have a more aggressive behaviour and worse prognosis.[95] This is similar to the situation with MC, where the tumours lacking either KRAS mutation or HER2 amplification have a worse prognosis. HER2 mutation is present in 9% of LGSC, and is not usually seen in combination with KRAS and BRAF mutations.[96] Unlike HGSC, TP53 mutations are rare in LGSC (Figure 5B).[95] Oestrogen receptor (ER) and/or progesterone receptor (PR) are expressed in most LGSC.

Table 5. Low-grade serous carcinoma: molecular features
Genomically stable/diploid or near diploid
BRAF or KRAS mutations
Expression of ER/PR

Pathogenesis

Low-grade serous carcinoma (LGSC) usually coexist with a borderline component, and these components have identical molecular alterations, indicating a clonal relationship.[97, 98] Serous cystadenomas containing less than 10% epithelial atypia were also found to harbour KRAS and BRAF mutations, suggesting that this lesion is the very first step in the carcinogenesis pathway.[97, 99, 100] A recently described lesion, papillary tubal hyperplasia of the fimbria, has been proposed as the earliest precursor of LGSC.[70] In this theory, tubal epithelial cells exfoliate from the fimbriae and implant onto the ovarian surface. These cells produce simple cysts that then give rise to cystadenomas, borderline tumours and LGSC in a stepwise fashion.[70] Further studies are needed to test this hypothesis; as LGSC is a rare tumour investigations are, practically, more difficult.

Treatment Considerations

Low-grade serous carcinoma (LGSC) do not respond well to chemotherapy regimens used for HGSC.[101] Due to its relative rarity and recent recognition as an entity, no widely accepted alternative treatment approach for this group of tumours has emerged. Hormonal therapy has been evaluated, given the consistent expression of hormone receptors in these tumours, and was found to show moderate anti-tumour activity against recurrent LGSC.[102] Targeting molecules downstream of RAS in those tumours with activating RAS mutations, e.g. MEK inhibitors,[103] has been proposed, and data are awaited on such trials. Because of the relatively indolent but progressive nature of LGSC, multiple courses of therapy may be used in an individual patient over the course of recurrent disease, allowing informal evaluation of different treatment regimens in these patients.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References

Major advances in our understanding of the molecular pathology of all ovarian carcinoma subtypes have occurred in the past several years; simultaneously, there has been significant progress towards subtype-specific treatment of ovarian carcinoma. Histopathological examination and accurate subtype diagnosis has become increasingly important in guiding patient management and, as such, is the most important currently available ovarian carcinoma ‘biomarker’. Work undertaken in the years to come will attempt to exploit the specific molecular abnormalities of the ovarian carcinoma subtypes in the development of effective targeted therapies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. High-grade serous carcinoma (HGSC)
  5. Clear cell carcinoma (CCC)
  6. Endometrioid carcinoma (EC)
  7. Mucinous carcinoma (MC)
  8. Low-grade serous carcinoma (LGSC)
  9. Conclusions
  10. References
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