A Case of Synchronous Primary Tumors of the Left Ovary and Uterus

Background

Multiple primary cancers are defined by the existence of more than one primary malignancy in different organs, or two or more primary malignancies developed from different cell types within the same organ [1]. Cancers are said to be synchronous when a second primary cancer is diagnosed within 6 months of the diagnosis the initial primary cancer. They are considered metachronous if they are diagnosed beyond 6 months of one another [1,2]. Synchronous cancers have been described in the literature as having a frequency ranging from 2% to 17% [3]. The incidence of synchronous gynecological cancers is estimated to be 1% to 6% [4]. The most common types of synchronous tumors of the female genital tract are primary endometrial and ovarian cancers [4].

Determining whether there are multiple primary tumors or a single tumor with metastasis presents a diagnostic challenge in which correct diagnosis and classification are critical in guiding management. We present the case of a 45-year-old female patient exhibiting brain metastasis in the setting of synchronous endometrial and ovarian cancer (SEOC).

Case Report

A 45-year-old nulliparous female with a medical history significant for obesity (body mass index of 42.6) presented to our facility with worsening generalized weakness and intermittent episodes of confusion for the past 3 weeks. Her partner confirmed that the patient had forgetful episodes of staring into space. The patient reported a history of recurrent tension headaches; however, unlike her prior headache episodes, she had noticed that within the past 3 weeks she was unable to perform her daily routine tasks. The patient denied tobacco use and consumed alcohol sparingly. She denied any history of malignancy; however, her mother died of complications from metastatic melanoma.

The patient was pre-menopausal and was having regular menstruation cycles, except within the past 2 months in which she had noticed slight menorrhagia. Her menstruations had increased in quantity and duration 2 months prior to the generalized weakness and confusion. She denied ever having any gynecologic examinations or Papanicolaou smears performed in her lifetime and had no documented history of iron deficiency anemia or menorrhagia.

The patient was afebrile and hemodynamically stable upon admission. She was alert and oriented, but showed a delayed response to questions, with slight confusion. Her respiratory and cardiovascular examinations were unremarkable. She was aerating well, without any respiratory distress.

Abdominal examination was significant for a nontender but distended abdomen. A neurological examination did not reveal any lateralizing weakness or sensory deficits. The cranial nerves were grossly intact. Deep tendon bicep and patellar reflexes were elicited equally and bilaterally. Upper and lower extremity strength were equally diminished bilaterally and ranked 2 out of 5 in severity. She struggled to overcome the force of gravity and required assistance from staff to ambulate. She also had a weakened grip and dropped a urine cup. Gynecological examination was limited by the presence of a virginal hymenal ring and an inability to palpate the cervix.

A comprehensive laboratory workup illustrated reactive leukocytosis. There was no evidence of electrolyte disturbance or anemia, with the exception of a hemoglobin A1c level of 11.2%. A brain computerized tomography (CT) scan without contrast was obtained to further evaluate for possible causes of her neurologic symptoms. The results showed bilateral frontal intraparenchymal masses with extensive surrounding cerebral edema; these findings were suggestive of metastatic disease (Figure 1). Subsequent magnetic resonance imaging of the brain with and without contrast revealed 2 enhancing lesions in the bifrontal high convexities suggestive of metastatic disease (Figure 2).

The patient’s menorrhagia was associated with mild abdominal distention. Her initial cancer antigen-125 (CA-125) level was elevated at 468 U/mL (reference range 0–35 U/mL). A CT scan of the abdomen and pelvis without contrast indicated the presence of a midline complex cystic lesion, seemingly originating from the left ovary, and a distorted uterus (Figure 3).

Following the review of laboratory and imaging data, the patient underwent a frontal brain needle biopsy to identify a primary tumor site. Many small tissue fragments were obtained from different positions and were sent for frozen pathologic analysis. Biopsy results indicated a metastatic tumor, but the origin of the metastasis could not be determined. A metastatic poorly differentiated carcinoma was confirmed on permanent sections by permanent paraffin section immunohistochemistry evaluation. However, the morphology and immunoprofile, with incorporating multiple organ/tissue specific markers for immunohistochemistry, was nonspecific (ie, no primary tumor site was suggested through this study). A decision was made to perform a bilateral frontal craniotomy for resection of the tumors to send the specimens to the Pathology Department for further evaluation and further pathologic characterization, from which a similar diagnosis and comment as described earlier were rendered.

The CT imaging of her abdomen and pelvis revealed left-sided hydronephrosis and a 25-cm complex cystic mass with septations and soft tissue components (Figure 3). The mass was suspected to be arising from the left ovary. The imaging was correlated to her symptoms of abdominal distention and bloating as well as an elevated CA-125 of 468 U/mL measurement. The Gynecological Oncology team and the patient made the decision to perform an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. The patient also underwent a left ureterolysis with complete gross cytoreduction to further relieve her left-sided hydronephrosis. Following these surgical procedures, a repeat follow-up CA-125 was obtained weeks later and revealed a significantly decreased level of 44.9 U/mL.

Based on the pathology report, 2 synchronous tumors of the left ovary and uterus were identified. The first was an International Federation of Gynecology and Obstetrics (FIGO) endometrioid carcinoma of the endometrium with 99% myometrial invasion and positive paracervical margins. The second tumor was a mixed clear cell (20%) and FIGO 1–3 endometrioid carcinoma (80%) of the ovary. Of note, clear cell carcinoma of the ovary is considered a high-grade tumor. These are in line with a stage IV disease with synchronous carcinomas of ovary and uterus, both displaying brain metastases.

Additionally, in the pathology reports, the immunoprofile (loss of PAX8 and estrogen receptor expression) and morphology of the metastatic poorly differentiated brain carcinoma within brain and morphology of FIGO 1–3 endometrioid carcinoma raised the possibility of dedifferentiation from the endometrioid carcinoma. Furthermore, the left ovary was considered as 1 primary tumor site because of the presence of endometriosis, serous cystadenoma, and spectrum (FIGO 1–3) of endometrioid adenocarcinoma. The FIGO 3 endometrioid carcinoma of the uterus contained no low-grade component or clear cell carcinoma and therefore supported a characterization of synchronous tumor. However, the morphologic evaluation and immunostaining were unable to determine whether or not these 2 malignancies were clonally related.

After a diagnosis of SEOC was made by using the pathology results, the patient was started on adjuvant cranial radiation and was administered systemic chemotherapy consisting of carboplatin and paclitaxel chemotherapy. This treatment was to be scheduled every 3 weeks for 6 cycles. The patient was stable throughout her hospitalization despite some generalized physical weakness from being hospitalized and mild dysarthria. She verbalized an understanding of her condition and was prepared to go home with her partner. She was discharged from the hospital with recommendations to schedule a follow-up with the Oncology Department. She was lost to follow-up upon discharge from the hospital.

Discussion

The present case aims to add to the current existing literature on the diagnosis of SEOC. A literature search indicates that this appears to represent the first reported case report in which a patient was discovered to have 2 primary gynecological cancers following the initial findings of cranial metastasis.

Although the metastatic cranial tumor was the first to be discovered, it was not until extensive workup allowed for the discovery of 2 primary tumors: one ovarian and the other urine in nature. The patient’s unusual initial chief complaint and presentation of neurological symptoms (headache and confusion) could have completely obscured and easily missed her diagnosis of 2 simultaneous primary female genital tract tumors. It was extensive clinical workup, diagnostic imaging, and histopathological analysis that ultimately led to discovery of malignancy and diagnosis of SEOC.

The probability of discovering 2 separate primary gynecological cancers at different sites within the female genital tract within a 6-month time frame is uncommon [5,6]. The rare occurrence of concomitant primary ovarian and endometrial cancers can produce a complex diagnostic picture and potentially increase the risk of misdiagnosis and unnecessary aggressive treatments [5]. The treatment and management of gynecological malignancy, including SEOC, is difficult and relies heavily on whether there are 2 separate primary tumor sites or a single site with distant metastasis [7]. Histopathological studies including molecular markers are helpful tools in guiding treatment and prognosis of SEOC.

In patients with recently diagnosed endometrial carcinoma, clinicians should also have a clinical index of suspicion and assess for the presence of a concomitant and separate ovarian tumor. Our patient was discovered to have endometrioid carcinoma of the endometrium. Typically, 5% of patients with this type of cancer also have concomitant ovarian cancer as well [5]. Synchronous primary tumors of the uterus and ovary require less aggressive treatment than endometrial cancer with metastasis to the ovary. Not only is treatment different, but also SEOC appears to have a more positive prognosis in comparison [5,7]. The presence of a separate ovarian mass is not always readily apparent upon radiological imaging as it was in the patient in this case. In this event, to ensure adequate and proper treatment, upon surgical treatment, resection and pathological characterization may be imperative to assess for the presence of ovarian cancer that may have been missed during radiological imaging.

In the United States, the most common malignancy of the female genital tract is endometrial cancer; additionally, 20% of endometrial cancers have been associated with another type of malignancy [8]. Of the 20% of patients with endometrial cancer and another malignancy, 4% had ovarian cancer [8]. Our patient fell within this 4% statistic.

Conclusions

This case report highlights the indolent growth and high risk of metastasis of an uncommon disease entity, SEOC, and demonstrates the importance of regular gynecologic examinations and cancer screening for women. This patient had 2 distinct cancers growing and metastasizing but she did not present with typical signs of endometrial or ovarian cancer. Her neurologic symptoms were found to be due to metastatic tumors, yet her limited gynecologic symptoms were not suggestive of such a case. Regular cancer screenings, possibly through bi-manual palpitation of the ovaries, may have found this earlier and improved this patient’s prognosis.