1
Department of Pathology, Umraniye Training
and Research Hospital, University of Health
Sciences, Istanbul, Turkey
2
Department of Neurosurgery, Health
Sciences University Umraniye Training and
Research Hospital, Istanbul, Turkey
3
Department of Radiation Oncology, Health
Sciences University Umraniye Training and
Research Hospital, Istanbul, Turkey
4
Department of Radiology, Health Sciences
University Umraniye Training and Research
Hospital, Istanbul, Turkey
5
Department of Radiology, Health Sciences
University Umraniye Training, and Research
Hospital, Istanbul, Turkey
Correspondence
Ali Koyuncuer, Department of Pathology,
Health Sciences University Umraniye Training
and Research Hospital, Istanbul, Turkey.
Email: alikoyuncuer@hotmail.com and
alikoyuncuer@gmail.com

Abstract

Metastases from ovarian cancer to the central nervous system (CNS) are rare, in par-
ticular, isolated leptomeningeal metastases (LM) are extremely rare. The gold stan-
dard in the diagnosis of leptomeningeal carcinomatosis (LC) is the detection of

malignant cells in cerebrospinal fluid (CSF) cytology. A 58-year-old woman diagnosed
with ovarian cancer 2 years ago underwent lumbar puncture and CSF cytology in
recent months due to new weakness, loss of strength in the lower extremities, and
speech disorders. Magnetic resonance imaging CNS was simultaneously visualized
and linear leptomeningeal enhancement was demonstrated. CSF cytology showed

tumor cells as isolated cells or small clusters of tumor cells with large, partially vacuo-
lated, and abundant cytoplasm, mostly with centrally located nuclei. Given her history

of high-grade clear cell ovarian cancer,CSF cytology was positive for malignant cells and

a diagnosis of leptomeningeal carcinomatosis was made by the neuro-oncology multidis-
ciplinary tumor board. Since LM also implies a systemic disease, the prognosis is very

poor, CSF cytology will play an important role in rapid diagnosis and will be useful both
in the right choice of treatment and in the early initiation of palliative care.
KEYWORDS
carcinoma, cytology, leptomeningeal carcinomatosis, metastasis, ovarian cancer

1 | INTRODUCTION
Metastases to the central nervous system are usually caused by lung
cancer, breast cancer, and malignant melanomas.1 Brain metastases from
ovarian cancers are very rare, accounting for about 1%–2% of all brain
metastases.1 In the literature, brain metastases have been reported in
521 patients in 38 clinical studies including ovarian carcinomas with brain
metastases, and 413 cases (1.19%) in 29 clinical series including 34.728
cases of ovarian carcinoma.2 Compared to epithelial carcinomas of the
ovary, ovarian clear cell carcinoma (OCCC) has a poorer prognosis and
the number of OCCC with brain metastasis is very few in the literature,
with 13 cases so far, with our case as the 14th case.3–5 Carcinomatous
meningitis (CM) or leptomeningeal carcinomatosis (LC) occurs when

tumor cells spread away from the primary tumor sites into the subarach-
noid, pia mater and cerebrospinal (CSF) fluid of the brain and spinal

cord.6 CM was first described by Beerman in 1912 for the metastasis of
cancer cells to the meninges without the presence of cancer cells in the
parenchyma of the central nervous system.7,8 The reported cases of

ovarian cancer with leptomeningeal metastasis without brain paren-
chyma in isolation are very limited.9

2 | CASE REPORT
A 58-year-old woman was operated on for a left ovarian mass about
twoyears ago. On histopathologic examination, ovarian clear cell

Received: 14 March 2023 Revised: 5 April 2023 Accepted: 10 April 2023
DOI: 10.1002/dc.25145

Diagnostic Cytopathology. 2023;1–4. wileyonlinelibrary.com/journal/dc © 2023 Wiley Periodicals LLC. 1

carcinoma was diagnosed and chemotherapy (Topotekan 4 mg/4 mL

infusion 2 day, Filgrastim 30 MIU/0.5 mL infusion 9 week, Grani-
setron 2 mg tablets 6 months) were administered regularly for

7 months. However, a cytologic examination of cerebrospinal fluid
performed at an outside hospital where she had been admitted for
the last forty-five days due to increasing weakness and weakness in

the lower extremities was found to be non-diagnostic/inadequate and

no diagnosis was made. Magnetic resonance imaging (MRI) was per-
formed and brain parenchyma and meninges were evaluated. No

gross tumor was observed in the parenchyma, but the thickening of
the dura, which showed faint appearances without increased
perfusion (Figure 1A,B), was found to be significant in terms of

FIGURE 1 (A, B) Brain
magnetic resonance imaging

(MRI): T1-weighted contrast-
enhanced cranial MRI shows dural

thickening with diffuse
enhancement, and linear and
nodular leptomeningeal
enhancement (black arrow).

FIGURE 2 (A–D) Leptomeningeal carcinomatosis (LC): Cerebrospinal fluid (CSF) cytology showed tumor cells as isolated cells or small clusters
(2A, D, Papanicolaou stain 400) of tumor cells with large, partially vacuolated (2B, black arrow Papanicolaou stain 400) and abundant
cytoplasm with centrally located nuclei. Numerous imbibed polys within the cytoplasm (2C, black arrow, Papanicolaou stain 400), and tumor
diathesis were observed among tumor cell groups (red arrow).
2 KOYUNCUER ET AL.
10970339, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dc.25145 by Turkey Cochrane Evidence Aid, Wiley Online Library on [29/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

leptomeningeal involvement, and CSF cytology was recommended for
early examination. Two preparations prepared with an automatic
Thin-Prep device from the material sent in 20 milliliters of Thin-Prep
solution were stained with a special Thin-PrepPAP staining set.
Scanned in “integrated imager” system. CSF cytology showed clusters
and dispersed single tumor cells. Some of these cells had abundant
clear pale vacuolated cytoplasm and centrally located moderately

pleomorphic nuclei. Nuclei showed binucleation and prominent nucle-
olus. Numerous imbibed polys within the cytoplasm and tumor diathe-
sis were observed among tumor cell groups. It was considered

positive for malignant cells (Figure 2A–D). In our case, adenocarci-
noma cells, reactive macrophages and infectious meningitis, intracra-
nial infarction, or hemorrhages were included in the differential

diagnosis of CSF cytology. Based on the clinical history, previous his-
tological diagnosis, and clinicopathological findings, the case was

accepted as leptomeningeal involvement of OCCC by the Neuro-
Oncology Multidisciplinary Tumor Board. Whole brain RT (WBRT)

with 30 Gy in 10 fractions was planned.

3 | DISCUSSION
The incidence of ovarian cancer ranks second among all gynecologic
malignancies and first in mortality.10 Mortality is high because the
overwhelming majority of ovarian cancers present with extensive

metastases to the abdominal cavity. Cancer can spread by direct inva-
sion of nearby organs and structures, or the shed cancer cells can

spread through the peritoneum with peritoneal fluid and ascitic fluid.
Unlike other cancers, metastasis via vascular channels is rare, but
spread to pelvic and para-aortic lymph nodes is common.11 The most
common distant metastases from epithelial ovarian cancer are pleural,
followed in descending order by liver, lung, pelvic/para-aortic lymph

node chains, skin, pericardial, brain, and bone metastases.2 Leptome-
ningeal metastases from gynecological cancers are extremely rare.

While disease-free life expectancy has been prolonged due to the
advances in chemotherapy, metastasis of these tumors to the central
nervous system has also increased. Yano et al. reported that of

24 gynecologic cancers with CNS metastases, five patients hadlepto-
meningeal metastasis (LM).12 The incidence of LC in ovarian cancer is

exceedingly rare, usually occurring in cases of disseminated disease or
advanced stages.2 Our patient was admitted to the intensive care unit
due to a deteriorating clinical condition and liver and lung metastases
were identified. In their retrospective study, Pectasides et al. found
CNS metastases in only 17 (1.17%) of 1450 patients with primary
malignant ovarian tumors and could not detect LC in any of these
patients.13,14 In a study by Cormio et al. leptomeningeal metastases
were found in only one case out of 23 patients with epithelial ovarian
carcinoma with CNS metastases. Only one case had histology of clear

cell carcinoma. Unlike in this study, the histology of the surgical re-
section specimen was confirmed in only 5 patients and a CSF diagno-
sis was made in only one patient. A clinical-radiological metastasis

was diagnosed in 17 patients.15 Sanderson et al. reported cerebral
metastases in 13 (1.1%) of 1222 cases of ovarian cancer based on

computed tomography (CT) and magnetic resonance imaging (MRI)
findings. The histopathologic diagnosis of two of these cases was

clear cell carcinoma, the remainder being serous carcinoma, endome-
trioid, and small cell carcinoma.16 Leptomeningial carcinomatosis can

cause symptoms by obstructing CSF flow, infiltrating nerves in the

subarachnoid space, occluding pial blood vessels, or invading or irritat-
ing the brain parenchyma. Clinical manifestations include increased

intracranial pressure, neurological deficits, radiculopathies, stroke-like

symptoms, encephalopathy, and epileptic seizures.17 Because follow-
up of epithelial ovarian cancer focuses primarily on intra-abdominal

recurrences, CT scans of the brain parenchyma and meninges are gen-
erally not recommended. However, a CT or MRI scan for LM is war-
ranted if neurological symptoms develop.14 Given the multifocal

spread to LC, leptomeninges, and CSF, the sensitivity of the MRI
imaging technique is high.18 Although CSF cytology is tumor negative

in some patients with LC (about 10%), it is still one of the most com-
mon diagnostic methods.17,19 Hyun et al. reported that 22% of

519 patients with LM were diagnosed by CSF cytology, 35% by MRI,
and 42% by both MRI and CSF cytology. CSF cytology is a very useful
diagnostic tool to establish the diagnosis of LM, particularly when
MRI is negative or has pitfalls and when LC is suspected, even when
the CSF cell count is biochemically normal.20 Both diagnostic methods
were synchronously positive in our case. Serum CA-125 levels have
been observed to increase (>35 U/mL) in a significant proportion, but
not all, of ovarian cancer with brain metastases.2,21,22 In our patient,
the last test showed a serum value of 492.There are currently several
treatment modalities for LM. Intrathecal chemotherapy, whole-brain
radiation therapy (WBRT), radiation therapy for spinal cord disease
(RT), and CNS-sensitive chemotherapy regimens can be selected.23
LM represents an advanced disease with a short survival time and an
aggressive clinical presentation. The median progression-free survival
after diagnosis of LM is 3.4 months and the median overall survival is
2.8 months.24

4 | CONCLUSION
Metastasis of ovarian cell carcinoma OCCC to the brain parenchyma
and leptomeninges is extremely rare. Since the prognosis of brain

metastases from ovarian cancer is very poor, CSF cytology examina-
tion is very important for rapid diagnosis and treatment and can have

a positive effect on the prognosis.
AUTHOR CONTRIBUTIONS

Ali Koyuncuer: writing and revision of manuscript, cytological evalua-
tion; Eyup Varol: detailed clinical history; Bengul Seraslan: conception

and design; Yas ̧ar Bükte: helped to collect clinical and follow-up data
of the case.
FUNDING INFORMATION
This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors (no specific funding
was disclosed).

KOYUNCUER ET AL. 3
10970339, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/dc.25145 by Turkey Cochrane Evidence Aid, Wiley Online Library on [29/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

CONFLICT OF INTEREST STATEMENT
It is declared that all authors have no conflicts of interest to disclose.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Ali Koyuncuer https://orcid.org/0000-0002-0994-1275
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How to cite this article: Koyuncuer A, Varol E, Serarslan
Yagcio

glu B, Bükte Y, Sakcı Z. Cerebrospinal fluid-
dissemination of a ovarian clear cell carcinoma: A

leptomeningial carcinomatosis with diagnostic challenges.
Diagnostic Cytopathology. 2023;1‐4. doi:10.1002/dc.25145