Central Nervous System Metastases in Epithelial Ovarian Carcinoma: Presentation of Four Cases and Review of the Literature

Abstract

Background: The purpose of this report is to summarize the incidence, clinical features, treatment, and prognosis of central nervous system (CNS) metastases following ovarian carcinoma. CNS involvement by epithelial ovarian carcinoma is rare, but the incidence may be increasing. The prognosis is poor and a standard treatment is not well defined. Cases: Four patients with a past medical history of ovarian carcinoma presented with neurologic symptoms. Investigations revealed CNS metastases consistent with ovarian origin. The clinicopathologic presentation and the different treatments are reported here. The associated literature is also reviewed. Results: In this series, 3 patients died within a year of being diagnosed with CNS metastases, and 1 was lost to follow-up. Conclusions: Ovarian carcinoma is common, but rarely metastasizes to the CNS. Such metastases indicate poor prognosis. An aggressive multidisciplinary therapeutic approach including surgery, radiotherapy, and chemotherapy is reasonable to improve the outcome of patients, whenever is feasible. (J GYNECOL SURG 28:223)

Introduction

Ovarian cancer is the seventh most common cancer and the fifth leading cause of cancer death in the world. Central nervous system (CNS) involvement by ovarian cancer is extremely rare; <1% of brain metastases are of ovarian origin,¹ but recent studies have suggested an increased incidence of these metastases. Brain involvement is usually associated with widespread disseminated disease. The symptoms are nonspecific, and even small metastases may cause incapacitating neurologic symptoms. Surgery, radiotherapy, and chemotherapy comprise the treatment regimen for prolonging survival, but the prognosis remains poor regardless of the treatment modalities.

The aim of this article is to report the features of clinical presentation, diagnosis difficulties, and treatment modalities of four cases of CNS metastases from ovarian cancer.

Cases

Case 1

In December 2000, a 62-year-old woman underwent explorative laparotomy for a 3 month-history of pelvic pain. A stage IIC clear cell carcinoma of the ovary was diagnosed, and debulking surgery was performed, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, para-aortic lymphadenectomy, and appendectomy. A macroscopic tumor was left behind (radical surgery [R2] resection) and six courses of systemic chemotherapy including cyclophosphamide and Cisplatin were conducted until September 2001. This regimen was complicated with neuropathy and ototoxicity. In November 2001, a second-look laparotomy did not reveal any macroscopic lesion, and multiple biopsies were negative for disease. In March 2004, digital pelvic examination revealed a laterovesical mass that measured 5 cm on echography. CA-125 serum level was a normal 18 international units [UI]/L, and a complete resection of this mass was performed. Histopathologic examination yielded a moderately differentiated serous adenocarcinoma consistent with an ovarian origin, and consequently, the patient received four cycles of chemotherapy based on cyclophosphamide and carboplatin. In January 2009, 4 years after the pelvic relapse, the patient experienced generalized tonic–clonic seizures with loss of consciousness. A cerebral computed tomography (CT) scan revealed multiple intraaxial, infra- and supratentorial lesions consistent with metastases. CA-125 serum level increased to 622 UI/L. Palliative treatment based on phenobarbital, corticosteroid, and whole brain radiotherapy 18 Gy in three fractions was given. The patient's general condition improved temporarily. In November 2009, she was admitted to the Department of Medical Oncology at Salah Azaiez Institute with lethargy, disorientation, and deep deterioration of her general condition, and she died the same week, that is, 9 years after the initial diagnosis of ovarian cancer and 11 months after brain metastases.

Case 2

A 33-year old woman with past medical history of infertility presented with an abdominopelvic mass and poor appetite in February 2005. Investigations revealed bilateral ovarian masses and an increased serum level of CA-125 (600 U/mL). She underwent laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, para-aortic lymphadenectomy, and appendectomy. Histopathologic examination demonstrated stage IV poorly differentiated epithelial ovarian carcinoma. Postoperative surgery was completely uneventful and the patient subsequently received six courses of combination chemotherapy using paclitaxel (175 mg/m²) and carboplatin (area under the curve [AUC]=5) at 3-week intervals, starting on March 2005. Her CA-125 level fell to 0.52 U/mL in July 2005 and findings from a clinical examination were unremarkable. She remained well with no clinical or radiologic evidence of recurrence until September 2005 (date of her last follow-up). After 4 years of absence, she presented in January 2010 with increased abdominal girth and dyspnea. A CT scan showed hepatic and pulmonary metastases. CA-125 level was 26 U/mL. She received nine courses of chemotherapy (paclitaxel and carboplatin) with complete response in both the liver and the lung. After 3 months of follow-up, she presented with visual blur. Ophthalmologic examination disclosed a deep decline of visual acuity and chorioretinal mass. A cerebral magnetic resonance imaging (MRI) revealed cerebral and right ocular expansive lesions consistent with metastases. She received corticosteroids and whole brain radiation therapy (WBRT) 18 Gy in three fractions was conducted. Her general condition was improved, but she refused any further treatment, especially second-line chemotherapy based on gemcitabine and Adriamycin. She has been lost to follow-up since February 2011.

Case 3

A 65-year-old woman presented with abdominal swelling, weight loss, and a pelvic mass in July 2007. CA-125 serum level was 1201 U/mL. She underwent explorative laparotomy and a stage IIIC poorly differentiated serous carcinoma of the ovary was diagnosed. No resection was performed, because of the bulky tumor mass and adherences. She received six cycles of systemic chemotherapy including paclitaxel 175mg/m² and carboplatin AUC 5 at 3-week intervals. In December 2007, ascites had disappeared, CA-125 serum level fell to 14 U/mL, and CT scan control revealed a good response in both the primary tumor site and the peritoneal carcinomatosis. Consequently, the patient underwent second-look laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, para-aortic lymphadenectomy, and appendisectomy. All the lymph nodes were negative and microscopic examination of the margins did not show any tumor cells (curative resection [R0 resection]). Three courses of the same chemotherapy were added until April 2008. The patient did well until February 2010, when she complained of headache and disorders of consciousness. A cerebral MRI revealed multiple cerebral lesions. Biopsy of the lesions was not attempted, but CA-125 serum level increased to 480 U/mL, and abdominopelvic CT scan revealed recurrent disease in the pelvis and the presence of ascites with multiple peritoneal nodules. In spite of receiving whole brain radiation therapy 18 Gy in three fractions associated with corticosteroids, the general condition of the patient deteriorated quickly and she died with recurrent widespread abdominopelvic disease and brain metastases in May 2010, 34 months after initial diagnosis, and only 4 months after diagnosis of cerebral metastases. Autopsy was not performed.

Case 4

In July 2008, a 57-year-old woman, gravida 3 para 3, underwent optimal surgery for ovarian cancer stage IC. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, para-aortic lymphadenectomy, and appendectomy, were performed, leaving no residual disease. Histopathologic examination demonstrated an endometrioid carcinoma of the ovary. Afterwards, six courses of systemic chemotherapy based on cyclophosphamide and Cisplatin were performed at 3-week intervals, with no side effects. In February 2009, 8 months after initial diagnosis, the patient developed CNS symptoms including headaches and a falling level of consciousness. Clinical examination did not reveal fever or meningeal syndrome, and her Glasgow coma score was 9/15. A lumbar puncture was hemorrhagic and revealed malignant cells. Cerebral MRI objectified thickness and enhancement of the leptomeninges in the left temporoparietal region related to leptomeningeal carcinomatosis. In addition, abdominopelvic CT scan revealed a 5 cm ill-defined pelvic mass, and CA-125 serum level was 320 U/mL, confirming the diagnosis of pelvic relapse with central nervous metastasis. Because of the rapid deterioration of her general condition, the patient received only corticosteroid, and she died after 1 week. Autopsy was not performed.

Results

To summarize, in this series, 3 patients died within a year of being diagnosed with CNS metastases, and 1 was lost to follow-up.

Discussion

Brain metastases following ovarian malignancies are uncommon. The incidence of these metastases ranges between 1 and 3.3%^2,3 and they usually occur late and as part of multiorgan involvement. Recent studies have reported an apparent increase in the occurrence of CNS metastases.⁴ This rising of incidence can be explained in many ways. The efficiency of chemotherapy for ovarian carcinoma has prolonged survival, allowing metastases in distant sites to implant and grow and become clinically evident disease.^4,5 Related are their features: having high-molecular weight, being large and non-lipid soluble, and the fact that chemotherapeutic agents (Cisplatin, paclitaxel) do not sufficiently cross the blood–brain barrier (BBB), which means that their concentrations are too low in the CNS to sterilize the brain from metastatic disease. On the other hand, some authors attributed this increasing of incidence to the disruption of the BBB caused by chemotherapeutics agents making the brain a target for tumor emboli. Finally, advances in imaging technology and the application of CT scan, MRI, and positron emission tomography (PET) scan may reveal some small lesions that had been undetected.²

Usually, patients with CNS metastasis from ovarian cancer had had the primary tumor diagnosed years before, but some cases of synchronous metastases are reported.⁶ Such metastases have a preference for the parenchyma rather than the leptomeninges. The mean age of patients with CNS metastases is 54 years for ovarian cancer (range 31–79 years).² More of the patients are in an advanced stage (III or IV). Serous adenocarcinoma is the most common pathologic type to metastasize to the brain.⁶ The most common histologic grade is III. Advanced disease and poorly differentiated disease, at the time of diagnosis, place a patient at increased risk for CNS metastases.

The clinical manifestations mainly include headache and vomiting caused by intracranial hypertension. Nonspecific nervous symptoms such language disorders, visual acuity decrease, visual disturbance, focal weakness, hemiparesis, cognitive dysfunction, seizures, gait ataxia, dysarthria, or personality changes have also been reported. Clinical manifestations of CNS metastases are highly variable depending upon the location of the lesions.

Presently, no known biologic marker is able to detect CNS metastases from ovarian carcinoma. The blood level of CA-125 is not reliable for surveillance of such metastases for many reasons: these metastases do not always produce CA-125 increase, the BBB is relatively impervious to the large CA-125 molecule in the early stages of metastases, and, finally, elevation of CA-125 may be caused by other distant metastases.⁷ In patients with elevated CA-125 without any evidence of local or other distant recurrence and those who have any change in neurologic function even without elevation of CA-125, evaluation of the CNS should be strongly considered.

A negative second-look surgery does not rule out the later development of CNS metastases. The diagnosis mainly relies on imaging examination including CT, MRI, or PET scan. Cerebrospinal fluid examination for malignant cells may confirm the presence of meningeal spread. However pathologic examination remains the gold standard. The subclinical cases or microfoci can be undetectable by imaging investigation, and some differential diagnoses should be made to exclude primary intracranial tumors, especially for massive focus, and cerebral vascular disease for small focus.

Because of the rarity and resulting small number of this entity, the optimal treatment for CNS metastases from ovarian carcinoma is currently ill defined. It is based on corticosteroids, surgical resection, WBRT, radiosurgery (gamma-knife surgery [GKS]), or chemotherapy. These modalities can be used alone or in combination. However, aggressive treatment is not always indicated. The Radiation Therapy Oncology Group has developed three prognostic classes using recursive partitioning analysis (RPA) to determine the appropriate treatment for patients with brain metastases (Table 1). In addition, treatment of CNS metastases does not result in cure; its main goal is to alleviate the neurologic symptoms and improve quality of life.² WBRT is considered the treatment of choice for patients with multiple brain metastases with or without extracranial disease. The preferred dose of WBRT is 30 Gy in 10 fractions over 2 weeks, and recently, a large study showed no difference in survival using hyperfractionated treatments compared with the standard schema.⁸ However, WBRT is associated with a number of late complications including brain atrophy, necrosis, endocrine dysfunction, and dementia.⁹

Table 1.

Definition of RPA Class According to the Original Analysis by the Radiation Therapy Oncology Group

Class	Definition
RPA class I	KPS ≥70% and controlled primary tumor and no extracerebral metastases and age ≤65 years.
RPA class II	KPS ≥70% or uncontrolled primary tumor or extracerebral metastases or age >65 years
RPA class III	KPS <70%.

RPA, recursive partitioning analysis; KPS, Karnofsky performance status.

In patients with solitary brain metastasis, surgical resection, followed or not by WBRT, is feasible and effective even in the presence of other resectable metastases.² But the role of surgery in multiple lesions remains controversial.⁹ Concerning the radiosurgery, gamma-knife stereotactic radiosurgery is being considered as an alternative to surgical resection for small metastases (<3cm) with minimal mass effect, lesions in or near the eloquent cortex, deep lesions, or high anesthetic risk.¹⁰ The role of chemotherapy is not well defined, but the addition of systemic chemotherapy, especially a platin-based regimen, improves local control of brain metastases,¹¹ because of the well diffusion of drugs caused by the alteration of the BBB. Complete response of brain metastases after carboplatin has been reported in the literature.¹² Also, chemotherapy is effective against occult recurrent disease at other sites, and does not cause side effects such as dementia, as radiotherapy can do. And finally, corticosteroids and anticonvulsant agents are indicated for patients with poor performance status.²

Once CNS metastases occur, prognosis is generally poor, regardless of treatment. The median survival rate after the diagnosis of CNS metastases ranges between 3 and 16.3 months.^2,3,13 The survival rates of patients at 1 and 5 years of follow-up are 31% and 5%, respectively.³According to the modality of treatment, the median survival may vary. It ranged between 3 and 6 months for patients treated exclusively with WBRT,² 8 months for patients treated with radiosurgery,² between 10 and 12 months with combined radiotherapy and chemotherapy,^2,4,11 between 9.4 and 16 months when surgery was performed,² and ≥16 months, when there was a combination of surgery, radiotherapy, and chemotherapy.^5,11 There are some factors that affect survival after diagnosis of CNS metastases: the RPA class, solitary brain lesions, absence of metastases to other distant sites, and treatment modality including GKS.¹⁴ Multivariate analysis showed that treatment modality including GKS was a more important prognostic factor than RPA class (p ¼ 0.04).¹⁵

These data highlight the importance of multimodality treatment and an aggressive treatment whenever is possible.

Conclusions

It is important to remember that CNS metastases from ovarian carcinoma are more frequent than described in the literature. This rare event may occur early or late in the course of disease. Any new or changing neurologic problem should alert the clinician to the possibility of CNS metastasis, especially in patients with past history of ovarian carcinoma, even if the CA-125 serum level was normal, there are no other metastases in distant sites, and the second look surgery is negative. An aggressive treatment is recommended whenever it is possible. Since the era of radiosurgery, we can expect an improvement in the outcome of these patients.

Footnotes

Disclosure Statement

No competing financial conflicts exist.

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