Low stage, low grade, synchronous endometrioid adenocarcinomas of the endometrium and right ovary. Background of complex atypical hyperplasia in the endometrium. Numerous foci of atypical endometriosis in the bilateral adnexa. Omentum and appendix involved by endosalpingiosis and benign endometriosis. The patient was screened for mismatch repair defects, but had preserved staining for MLH1, PMS2, MSH2, and MSH6.
The presence of coexistent ovarian and endometrial carcinomas has been identified in 3 to 30% of patients with endometrial carcinoma and 3 to 10% of patients with ovarian carcinoma.[1-5] This condition may arise from ovarian metastasis of endometrial carcinoma, endometrial metastasis of ovarian carcinoma, or synchronous development of independent primary lesions. Various histologic and immunohistochemical criteria have been proposed to differentiate the site or sites of origin. Factors which favor separate primary tumors include histologic dissimilarity, no or superficial myometrial invasion of the endometrial tumor, the presence of atypical endometrial hyperplasia, unilateral ovarian tumor which is located in the parenchyma, lack of vascular invasion, surface implants, or other evidence of endometrial or ovarian tumor spread, and dissimilar findings of molecular genetic, karyotype, or loss of heterozygosity studies.[6-9]
The most common presenting symptom of coexistent tumors, whether metastatic or synchronous primaries, is abnormal uterine bleeding. Abdominal distension, abdominal or pelvic masses, and abdominal or pelvic pain have also been described.[3, 4] Women with coexistent tumors tend to be premenopausal and diagnosed at a younger age (median 41 to 53) than women with either ovarian or endometrial tumors alone.[2-4, 8] This finding is further supported by evidence that young women (age 45 or below) who are diagnosed with endometrial carcinoma are more likely to have synchronous ovarian carcinoma.[10, 11] Other factors which have been associated with coexistent endometrial and ovarian tumors include nulliparity, tobacco use, and increased BMI.[8, 10] These factors were not found to vary significantly between patients with metastatic or synchronous primary lesions. Additionally, endometriosis has been shown to be present in 31% of patients with coexisting ovarian and endometrial carcinomas.
Ovarian tumors which are present concurrently with endometrial tumors have been shown to have multiple histologic types including endometrioid, clear cell, serous, mucinous, and mixed. Interestingly, although the majority of ovarian tumors occurring singly are serous type, up to 90% of patients with coexistent endometrial and ovarian tumors have endometrioid type ovarian carcinoma.[1, 3, 11, 12] In contrast, the frequency of endometrioid carcinoma in endometrial tumors is similar for singly detected and coexistent lesions. Endometrial lesions with clear cell, mucinous, serous, and mixed cell types have also been described in patients with concurrent ovarian tumors.[8, 12] In a series of 74 cases Zaino, et al found the same ovarian and endometrial histologic cell type in 93% of cases despite the fact that only 1-19% had features consistent with metastatic lesions rather than independent primaries.
Patients with carcinomas involving both the ovary and endometrium are more likely to be diagnosed with early stage lesions (FIGO Stage I or II) of low histologic grade (Grade I).[3, 4, 12] They were also shown to have high rates of disease-free and overall survival. In the study by Zaino, et al, recurrence at 5 years was 15% and was dependent on presence of metastases at diagnosis and on histologic grade. In this study, 5 year survival was 85.9% and 10 year survival was 80.3% [2, 4, 12] Further, patients with endometrioid ovarian carcinoma and endometrioid endometrial carcinoma had lower rates of recurrence and higher rates of overall survival than patients with tumors of other histologic cell type.[3, 8, 12]
Given the characteristics of the patient population, as well as the increased presence of concurrent endometriosis, many have suggested that the pathogenesis of synchronous carcinomas could involve a "field effect" whereby hormonal or other stimuli lead to the malignant transformation of multiple similar epithelia.[1, 8, 13] This theory is supported by increasing evidence that endometrioid ovarian carcinomas, the most common form in synchronous lesions, arise from endometriosis.[14, 15] Both endometrioid ovarian and endometrioid endometrial carcinomas have been shown to have mutations in PTEN, PIK3CA, ARID1A, PP2R1A, and CTNNB1, although the frequency of these mutations varies widely based on the organ site. The presence of a mutation in PTEN or CTNNB1 has been proposed as a marker to differentiate metastatic from synchronous primary carcinomas.[17, 18] Other potential genetic markers for differentiation include DNA flow cytometry, loss of heterozygosity, and X-chromosome inactivation.[19-23]
Despite the link between familial ovarian and endometrial cancers with an endometrioid phenotype and diagnosis at a young age, there does not appear to be a strong prevalence of familial cancers in patients who present with synchronous primary malignancies.[24, 25] In a study of 84 cases by Soliman, et al only two patients were identified with familial breast cancer syndromes (one with HPNCC and one with hereditary breast and ovarian cancer syndrome). Another study demonstrated that the prevalence of familial cancers was significantly higher in patients with metastatic lesions than in those with synchronous primary tumors. A third case series found a high likelihood of Lynch syndrome in 7% of patients, all of whom had a personal history of or first degree relative with a Lynch syndrome associated cancer.
In summary, the patient described presented with coexistent lesions of the right ovary and uterus. Although these lesions shared similar histology and immunohistochemical staining patterns multiple features led to the determination that they were independent, synchronous primary tumors. These included the lack of evidence for direct or lymphovascular spread of either the ovarian or the endometrial carcinoma, the presence of a single and unifocal ovarian mass, the presence of extensive endometriosis including some atypical endometriosis, the presence of complex atypical hyperplasia in the endometrium, and the lack of extensive myometrial invasion. The patient also shares many of the clinical findings which were described in the various case reports.
Contributed by Michelle Heayn, MD, PhD and Jeffery Fine, MD