Tumor heterogeneity is one of the characteristics of malignant tumors, which refers to the molecular biology or genetic changes in the daughter cells of tumors after multiple divisions and proliferation during the growth process, resulting in differences in tumor growth rate, invasion ability, drug sensitivity, prognosis and other aspects. Ovarian cancer is the leading cause of death from gynecologic malignancies, and its treatment approach has evolved into a complex framework designed to reflect the spatial and temporal heterogeneity of ovarian cancer, a disease that encompasses several subtypes. Molecular heterogeneity in these subtypes results in varying degrees of inherent resistance to conventional platinum-based chemotherapy. A recent review published in the journal Nat Rev Clin Oncol summarized the clinical and biological heterogeneity of ovarian cancer and how it forms and continues to form therapeutic algorithms, and defines the current therapeutic landscape [1]. This article focuses on the "clinical, histological and pathological heterogeneity of ovarian cancer".
Ovarian cancer is a highly heterogeneous solid tumor that includes various subtypes with different histopathological features and clinical behaviors (Figure 1). Tumor evolutionary analysis revealed that the plasticity of cancer cells led to a diverse phenotypic profile. In ovarian cancer, this heterogeneity limits the ability to establish tumor stratification and prognostic classification between different subtypes. Data on cell origins, prodromal lesions, and alterations in cancer-related pathways can provide prognostic information and reveal potential targets for therapeutic strategies (Figure 2). Detailed cellular and immunoomic analyses also show changes in immune tolerance from serous tubal intraepithelial precancerous lesions to early stages of cancer, as well as decreased immune cells as tumors progress and metastasize. DNA methylation-based stratification of ovarian cancer has demonstrated the potential of applying cell-origin-specific cancer methylation to distinguish tumor subtypes. This hierarchical approach combines multiple dimensions such as histological subtype, transcriptional signature, genomic instability index, and overall survival (OS). Continuous advancements in technology and algorithms, as well as the implementation of new protocols, are playing an important role in improving ovarian cancer management and detection, further advancing the field.
Figure 1a: This figure depicts the most important somatic changes in the different ovarian cancer subtypes, and Figure 1b: The relationship between ovarian cancer subtypes and their different molecular changes, clinical features, and outcomes
Figure 2: Development of ovarian cancer prodromal lesions
The World Health Organization (WHO) 2020 classification defines at least five major types of ovarian cancer based on histology, immunohistochemistry and molecular analysis: high-grade serous ovarian cancer (HGSOC), endometrioid ovarian cancer (EOVC), clear cell carcinoma of the ovary (OCCC), low-grade serous ovarian cancer (LGSOC), and mucinous ovarian cancer (MOC). Other rarer types include nephroid carcinoma, mixed carcinoma, and hypercalcemia of the ovarian small cell carcinoma (SCCOHT). Notably, serous mucinous carcinoma has been classified as a subtype of endometrioid carcinoma. The International Federation of Obstetrics and Gynecology (FIGO) grading system is the most commonly used standard for grading and staging ovarian cancer. The FIGO stage assesses the degree of differentiation of tumor cells, while the FIGO stage describes the extent to which the tumour has spread in the body. By applying this system, ovarian cancer can be divided into prognostic groups and guide the selection of appropriate treatments.
HGSOC is the most common subtype of ovarian cancer (70 percent), and most patients are diagnosed at an advanced stage and generally have a poor prognosis [2]. It is hypothesized that HGSOC may develop from serous intraepithelial cancer precursor cells and tubal epithelial cells that carry TP53-associated mutational signatures[3]. An extensive single-cell RNA sequencing study involving thousands of non-malignant tubal epithelial cells and HGSOC cells revealed a robust correlation between various secretory cell types and phenotypic diversity in HGSOC, which can be traced back to the genetic characteristics of the origin cells [3]. Therefore, identifying prodromal lesions in the tubal surface epithelium is important for developing prevention strategies (eg, prophylactic salpingectomy).
EOVC is the second most common subtype of ovarian cancer (10%) and typically presents as a unilateral solid mass. Endometriosis may be a prodrome of EOVC, and this subtype usually occurs in tandem with endometrial cancer. In the last decade, dysbiosis of carcinogenic microorganisms in the female reproductive tract has been thought to play an important role in the pathogenesis of EOVC [4].
OCCC accounts for 6%~10% of ovarian cancers in North America and is more prevalent in East Asia, accounting for 25%~30% in Japan[5]. Compared with HGSOC, OCCC typically emerges at a younger age and tends to be resistant to platinum-based agents, with a higher frequency of lymph node metastases [6]. The researchers identified two subgroups of OCCC by performing genomic and transcriptomic characterization of a large number of patients (n = 421) [7]. The classic subtype is the most common (83% of the total population), tends to emerge at an earlier stage, and is often associated with endometriosis. 'HGSOC-like' OCCC, which is not usually associated with endometriosis, is often diagnosed at an advanced stage, and has a worse prognosis than classical OCCC. This subtype classification requires prospective validation to clarify OCCC subtypes and their relevance in clinical practice [8].
LGSOC is a rare subtype (5%) that originates from adenofibromas or borderline tumors. The onset of LGSOC has a bimodal age distribution, mainly in people aged 20-30 years and 50-60 years. LGSOC responds poorly to chemotherapy in patients, including platinum-based regimens, compared with HGSOC. Although its biology allows for overall slow disease progression, there are some cases that can be aggressive. In addition, estrogen and progesterone receptor expression levels are higher in LGSOC than in HGSOC [9,10].
MOC (3%~4%) is a heterogeneous tumor type derived from mucin-secreting cells. Since these cells are absent in non-malignant ovarian tissue, scholars have proposed multiple theories to explain their histogenesis, and it is necessary to distinguish MOC from metastatic mucinous carcinoma (Krukenberg tumor). Most MOCs are diagnosed in women of childbearing age and are usually in an early stage, making fertility-sparing surgery a common treatment in this setting. However, due to the insufficient sensitivity of MOCs to chemotherapy, patients with MOCs diagnosed at an advanced stage have a poor prognosis [11,12].
SCCOHT is a rare subtype, accounting for less than 0.01% of all ovarian tumors. This subtype is highly aggressive and typically occurs in women younger than 40 years of age [13]. The histogenesis is not well understood, but oocytes are thought to be the origin cells [14]. Many patients develop hypercalcemia, which may be related to parathyroid hormone-related proteins. At the molecular level, SCCOHT is characterized by simultaneous loss of SMARCA2 and SMARCA4 subunits of the SWI/SNF chromatin remodeling complex. Diagnosis of SCCOHT can be challenging, so consultation with a gynecologic pathologist is encouraged. Given that almost all SCCOHTs carry loss-of-function mutations in SMARCA4, immunohistochemistry can assist in establishing the diagnosis of the transcriptional activator BRG1, the protein it encodes [13].
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