Unusual cerebrospinal fluid finding of intracytoplasmic granules in metaplastic carcinoma of the breast with acinar differentiation.

Cerebrospinal fluid (CSF) evaluation for total and differential cell count is a common practice in pathology for evaluation of various disease conditions. Although rare, these CSF samples yield interesting and unusual morphological findings, which are not only of academic interest, but also may play key roles in diagnosis. For diagnosing metastatic carcinoma in brain and meninges, CSF examination is one of the important tools along with imaging studies. Metaplastic breast carcinoma (MBC) encompasses a rare (<1% of all breast cancers), aggressive and highly heterogeneous group of tumors. MBC is almost always estrogen receptor, progesterone receptor and Her2 negative (triple negative) and shows frequent early distant metastases as well as sub-optimal response to systemic therapies. The involvement of leptomeninges is most commonly associated with these triple- negative subtypes. In this report, we present an unusual case of malignant cells with prominent intracytoplasmic granules in CSF smears of a 46-year-old female with metastatic MBC with acinar differentiation. An extensive review of literature in English language did not return any other reports of a similar finding.

Circulating epithelial tumor cell analysis in CSF in patients with leptomeningeal metastases.

OBJECTIVE: The primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC). METHODS: We tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR). RESULTS: The sensitivity of the CTC assay was 94% (95% confidence interval [CI] 80-99) and the specificity was 100% (95% CI 91-100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58-89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (EGFR). All 5 tested patients with LM demonstrated the primary EGFR driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF. CONCLUSION: CTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine EGFR mutations in both cfCSF and isolated CTC from CSF of patients with EGFR-mutated NSCLC and LM. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.

Aquaporin-4 antibody positive short transverse myelitis associated with breast cancer.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS). A typical finding on spinal magnetic resonance imaging (MRI) of NMOSD is longitudinally extensive transverse myelitis (LETM). However, patients with NMOSD presenting with short-segment transverse myelitis (STM) during myelitis attacks associated with breast cancer are uncommon. We report a case of a 35-year-old woman with STM and left eye optic neuritis. The patient was positive for serum aquaporin-4 antibodies (AQP4-IgG), and a biopsy of the left breast showed invasive ductal carcinoma. The patient was diagnosed with NMOSD and breast malignancy. This is the first report of a patient with NMOSD whose spinal MRI showed STM and serum test showed that the patient's AQP4-IgG was positive and complicated by breast cancer. This case improves our understanding of the association between NMOSD and cancer and raises the question of whether it was a coincidental occurrence. It is important to search for extensive malignancies in patients presenting with atypical MRI or no reaction to traditional therapies.

Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis.

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS-)], 21 with carcinomas (10 CNS+; 11 CNS-), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS- lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS- carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS- lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS- carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS- diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.

Proteomic Biomarker Identification in Cerebrospinal Fluid for Leptomeningeal Metastases with Neurological Complications.

Leptomeningeal metastases (LM) from solid tumours, lymphoma and leukaemia are characterized by multifocal neurological deficits with a high mortality rate. Early diagnosis and initiation of treatment are essential to kerb neurological deterioration. However, this is not always possible as 25% of cerebrospinal fluid samples produce false-negative results at first cytological examination. The identification of biomarkers that allow stratification of individuals according to risk for developing LM would be a major benefit. Proteomic-based approaches are now in increasing use for this purpose, and these are reviewed in this chapter with a focus on cerebrospinal fluid (CSF) analyses. The construction of a CSF proteome disease database would also facilitate analysis of other neurological disorders.

The cytologic findings in choroid plexus carcinoma: report of a case with differential diagnosis.

Choroid plexus carcinoma is a rare tumor of the choroid plexus that shows frank cytologic features of malignancy including frequent mitoses, increased cellularity, nuclear pleomorphism, loss of papillary architecture, and necrosis. It occurs predominantly in the pediatric population and is associated with a poor prognosis. We report the cerebrospinal fluid and intraoperative squash preparation cytologic findings of a case of choroid plexus carcinoma arising in the lateral ventricle of a 16-year-old girl who developed tumor recurrence in cerebrospinal fluid 6 years after initial resection. To the best of our knowledge, there are only a few reports in the English literature describing the cytologic features of choroid plexus carcinoma. Relevant differentials and the usefulness of ancillary studies in diagnosis are also discussed.

[Low-molecular DNA in blood plasma and spinal fluid of cancer patients].

Enhanced preoperative levels of low-molecular DNA in blood plasma and in cerebrospinal fluid were established in cancer patients. They rose even higher after surgery due to stress. Possible mechanisms are discussed.

Diagnosis and individualized therapy of neoplastic meningitis.

Neoplastic meningitis is a diffuse dissemination of tumor cells into the cerebrospinal fluid (CSF) and/or leptomeninges. It occurs in approximately 5-10% of malignant diseases, most often in breast cancer, lung cancer, melanoma or B-cell lymphoma. Symptoms of neoplastic meningitis are head or back pain, cranial nerve palsies, diffuse radicular symptoms or psychiatric disturbances. MRI shows nodular contrast enhancement lining CSF spaces. Positive CSF cytology requires optimal sampling and processing. Treatment must be individually shaped: the CSF dissemination may be treated with intrathecal chemotherapy with methotrexate or cytarabinoside (Ara-C). Liposomal Ara-C is distributed over the entire CSF space even after lumbar application and maintains cytotoxic levels for at least 2 weeks. Radiotherapy should be applied only to symptomatic solid spinal manifestations or fast progressing cranial nerve palsies. Systemic chemotherapy is needed to control solid manifestations or, in the case of substances entering the CSF, to support intrathecal chemotherapy.

Gastric cancer with isolated leptomeningeal metastases: a case report.

Leptomeningeal carcinomatosis due to gastric cancer is rare. Gadolinium enhanced MRI and CSF analysis for malignant cells are necessary to confirm the diagnosis.

Isolated oculomotor nerve palsy as the presenting clinical manifestation of a meningeal carcinomatosis: a case report.

We present a previously unreported case of isolated oculomotor nerve palsy as the inaugural clinical sign of meningeal carcinomatosis (MC). Gadolinium-enhanced magnetic resonance images (MRI) were unremarkable. Cerebrospinal fluid (CSF) analysis showed malignant cells consistent with a pulmonary adenocarcinoma; the chest CT revealed a small pulmonary mass in the upper right lobe. This case highlights the importance of considering MC in all patients who develop sudden oculomotor palsy; lumbar punctures should always be performed on patients with normal MRI when other possible causes of oculomotor palsy have been ruled out.

A case of anaplastic pleomorphic xanthoastrocytoma presenting with tumor bleeding and cerebrospinal fluid dissemination.

Pleomorphic xanthoastrocytoma (PXA) has been considered an astrocytic tumor with a relatively favorable prognosis. However, PXA cases having several recurrent patterns with poor prognosis have been reported in recent years, and a new concept of anaplastic PXA has been proposed. The present case was a 59-year-old woman who presented with tumor bleeding onset and cerebrospinal fluid dissemination. The patient had sudden-onset right hemiparesis, aphasia, and consciousness disturbance and was admitted to a local area hospital. After emergency surgery had removed the hematoma, postoperative contrast-enhanced CT scan revealed a left temporal tumor. A second surgery was therefore performed for initial tumor removal 2 months later. Histopathological findings showed that the tumor was typical PXA with strong pleomorphism and xanthomatous changes and contained an ependymoma-like component in the center area. However, endothelial proliferation and mitosis were more remarkable compared to ordinary PXA. The MIB-1 labeling index was 9.8% high. From these findings, the histopathological diagnosis was anaplastic PXA. The patient underwent surgery to remove recurrent tumors 5 and 16 months later. The patient died 36 months after the first onset, and CT revealed glioblastoma-like findings and cerebrospinal fluid dissemination. This case report is the first case in which PXA presented with tumor bleeding onset. Histopathological findings suggested anaplastic PXA from the first surgical specimens, and PXA recurred many times. We thus believe that the patient displayed primary anaplastic PXA rather than secondary anaplastic PXA that results in malignant transformation.

Isolated hypoglycorrachia: leptomeningeal carcinomatosis causing subacute confusion.

We report a 76-year-old caucasian man who presented with a 3-week history of progressive confusion. His past medical history included a left nephro-uretectomy for poorly differentiated transitional cell carcinoma 9 years previously. Besides his confusion, his clinical and neurological examination was unremarkable. Extensive investigation revealed only isolated hypoglycorrachia and mildly elevated CSF protein. Cerebral CT and MRI scans without contrast did not reveal any abnormalities. As his condition continued to decline, an MRI scan of the brain with gadolinium was performed which revealed extensive nodular enhancement of the surface of the cerebellum and brainstem and both temporal lobe convexities. Repeat lumbar puncture showed malignant cells in the CSF and confirmed the diagnosis of leptomeningeal carcinomatosis. This case illustrates that leptomeningeal carcinomatosis should be considered in the differential diagnosis of cognitive decline in the elderly, after other common aetiologies have been excluded. The index of suspicion should be increased in patients with a prior history of cancer.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis.

BACKGROUND: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. OBJECTIVE: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. MATERIALS AND METHODS: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. RESULTS AND DISCUSSION: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF. CONCLUSION: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

Intrathecal chemotherapy for patients with meningeal carcinomatosis.

BACKGROUND: Meningeal carcinomatosis (MC) is increasing, and these patients have a poor prognosis. We analyzed the effects of intrathecal (IT) chemotherapy for these patients. METHODS: Patients received both methotrexate (MTX) (15 mg/m(2)) and prednisolone (10 mg/m(2)) 6 times in 2 weeks by Ommaya reservoir, along with cytosine arabinoside (10 mg/m(2)) for 4 doses of MTX. A cycle consisted of a 2-week period during which patients received these drugs and then 2 weeks off. Treatments were repeated 3 to 6 cycles depending on the clinical status. Cerebrospinal fluid (CSF) samples were also analyzed for cytology and a few markers. RESULTS: Of the 58 patients treated the most common tumor was lymphoma (30 patients), followed by lung and breast. Elevated soluble IL-2 receptor levels were observed in 23 of 30 patients with lymphomatous meningitis. Median survival of MC patients with malignant lymphoma, lung cancer, and breast cancer was 32.8 +/- 9.8, 13.0 +/- 4.1, and 18.4 +/- 7.4 months, respectively. Thus, the patients with lymphoma responded best, both by clearing the CSF and clinically. CONCLUSIONS: Our treatment regimen can improve the neurologic status of patients with MC. In particular, early IT chemotherapy can be effective for patients with lymphoma.

[Brain metastasis and the carcinoembryonic antigen]. / Metástasis cerebrales y antígeno carcinoembrionario.

INTRODUCTION: Neurological complications have a notable repercussion on the quality of life of patients with systemic cancer, and can even become the direct cause of death. The complication that causes most concern is undoubtedly brain metastasis, because of its difficult management and because there has been an upward tendency in its incidence in the last few years. AIMS: The aim of this study is to provide a review of the literature about brain metastases and, more particularly, about the carcinoembryonic antigen (CEA) as a marker of these pathologies. DEVELOPMENT: In general it is reckoned that 60% of all brain metastases start from the lung and most of them are multiple when they are diagnosed, which suggests a possibly mistaken staging of these patients. The carcinoembryonic antigen is the prototypical tumour marker, and it is usually found in higher concentrations in the cerebrospinal fluid of patients with metastatic tumours in the central nervous system. As the CEA goes through the blood brain barrier, it behaves in a similar way to IgA due to their having homologous molecular weights. This allows us to employ the same hyperbolic distribution curve that is used as a reference for lgA to distinguish between intrathecally synthesized CEA and that which diffuses from the systemic circulation. CONCLUSIONS: In spite of the progress that has been obtained with the new therapies, brain metastases continue to have a poor prognosis. Hence, there is a need to identify new tumour markers that allow a diagnosis to be established before the clinical methods and presentations.

Unusual presentation of carcinomatous meningitis: case report and review of typical CSF findings.

This paper describes a previously unreported clinical onset of carcinomatous meningitis with bilateral deafness. Typical changes in the cerebrospinal fluid aside from positive cytology findings are reviewed. In cases of suspected carcinomatous meningitis the clustering of increased CSF protein, lactate, decreased glucose, and a high opening pressure is suggestive of the diagnosis.

[Carcinomatous meningitis revealing a cancer: study of two cases]. / Meningite carcinomateuse révélatrice de cancer: étude de deux cas.

Meningeal Carcinomatosis (MC) is rare (4 to 5% of patients with solid tumors). We report two cases. The first case is a 53 year-old man presenting flaccid paraplegia and the second is a 76 year-old man presenting a clinical picture suggestive of normal pressure hydrocephalus. In the two cases, the diagnosis of MC was achieved by the demonstration of malignant cells in the CSF. Prognosis was poor in the two cases. The clinical presentation of MC is non specific and the diagnosis is only confirmed by demonstrating carcinomatous cells in CSF.