Review
Leptomeningeal carcinomatosis in patients with breast cancer

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Abstract

Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma, a relatively uncommon but devastating complication of many malignancies. Although only 5% of patients with breast cancer develop leptomeningeal involvement, it remains the most common etiology of LC. It can occur as a late-stage complication of systemic progression or present as the first sign of metastatic disease, with or without parenchymal brain metastases. Lobular carcinomas have a higher propensity to metastasize into the meninges when compared to ductal carcinoma, especially the triple-negative subtype, which usually is associated with a shorter interval between metastatic breast cancer diagnosis and the development of LC. Prognosis remains poor, with median survival of 4 months for patients receiving state-of-the-art treatment. The main factors associated with survival are performance status at diagnosis, CSF protein level and triple-negative subtype. Headache is commonly the first clinical presentation of LC, and the diagnostic workup usually requires CSF-cytological analysis and or/MRI. The current management of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiotherapy and/or best-supportive care. The standard intra-CSF chemotherapy regimen is methotrexate. Radiotherapy is used for relieving obstruction points on CSF-outflow channels due to ependymal nodules, tumor deposits or bulky disease. Objective responses have been reported with intrathecal administration of trastuzumab for HER2-positive disease, yet this strategy is still under investigation. Further prospective trials are needed to better address the impact of these treatment modalities on overall survival and quality of life.

Introduction

Metastases to the central nervous system in patients with breast cancer can cause substantial morbidity and mortality (Huang et al., 2018). They may occur either within the brain parenchyma, along the leptomeninges, or both (Sekhar et al., 2017).

Leptomeningeal carcinomatosis (LC) is defined as leptomeningeal infiltration, including the pia mater, arachnoid and subarachnoid space from a solid primary tumor. It is a rare complication of breast cancer, with an incidence rate of approximately 5% (Corbin and Nagpal, 2016, Gauthier et al., 2010, Kokkoris, 1983). Considering the high incidence of breast cancer worldwide, in absolute numbers it constitutes the most common etiology of LC. It presents concurrently with brain metastasis in breast cancer in 14% of the cases (de Azevedo et al., 2011).

Section snippets

Methodology

We performed a comprehensive systematic literature search in PubMed (Cochrane, Scopus, Embase and Medline) with key-words such as “leptomeningeal carcinomatosis AND breast cancer” = total of 265 citations or “leptomeningeal metastasis AND breast cancer = 182 citations”, or “neoplastic meningitis AND breast cancer = 272 citations”. The final search was performed in May 2018. Articles in languages other than English, duplicated articles, articles referring to etiologies of leptomeningeal disease

Breast cancer subtype and leptomeningeal carcinomatosis

A predisposition to LC of lobular histological type is well established and described by many authors, accounting for approximately 35% of the LC associated with breast cancer. However, our literature review demonstrated that the rate of parenchymal brain metastasis in lobular carcinoma is only about 7%. This suggests a propensity for leptomeningeal dissemination of this subtype even in the absence of cerebral metastasis (Abouharb et al., 2014, Niwińska et al., 2013). A possible explanation for

Pathogenesis: how does breast cancer reach the leptomeninges?

The possible pathways by which cancer cells reach the leptomeninges have been extensively discussed in the literature. Such dissemination may occur by hematogenous spread through the arterial or venous circulation, or endoneural, perineural, perivascular of lymphatic spread. In large cohorts, brain metastases were associated with LC in 33–54% of the cases (de Azevedo et al., 2011, Gauthier et al., 2010, Lara-Medina et al., 2012, Le Rhun et al., 2013, Lee et al., 2011, Niwińska et al., 2013,

Prognosis

Although LC from breast cancer has the best prognosis when compared to LC secondary to other malignancies, it still carries a poor prognosis, with a median overall survival (OS) of approximately 4 weeks, that can be prolonged to 4 months in some patients with aggressive multimodal treatment (Chen et al., 2015, Huang et al., 2018, Meattini et al., 2012). Several factors have been identified as possible predictors of survival: the most commonly described in the literature include performance

Clinical features

Leptomeningeal carcinomatosis can present a large variety of clinical features turning the diagnosis oftentimes tricky. The symptoms arise according to the area of the CNS involved by the malignant cells (Hyun et al., 2016, Le Rhun et al., 2017a). Some of the often seen signs and symptoms include: headache, radicular pain, cranial nerve deficits, visual disturbances, hearing loss, seizures and causa equine syndrome. Another possible clinical presentation is a new onset of a psychiatric disorder

Diagnostic workup

The diagnosis of LC remains difficult and is established by the presence of malignant cells in the CSF or, in the absence of malignant cells in the CSF, by concomitant characteristic clinical symptoms or signs and typical MRI findings (Altundag et al., 2007, Le Rhun et al., 2017b, Nayar et al., 2017, Yu et al., 2001).

The gold standard for the diagnosis of LC remains the demonstration of tumor cells on CSF which is positive in up to 60% of the patients (Lee et al., 2015). However; the

Treatment

There is currently no generally accepted standard of care in the treatment of breast cancer LC. The current management of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiotherapy or best-supportive care and should be individualized on a case by case (Dawood and Gonzalez-Angulo, 2013, Dudani et al., 2016, Kim et al., 2012, Le Rhun et al., 2017b, Lin et al., 2017, Niwińska et al., 2018, Singh et al., 2013).

Treatment decisions are influenced by the individual's

Treatment implications of the blood-brain barrier (BBB) and the Blood-CSF barrier

One important point about the treatment of LC is that the traditional chemotherapy and targeted therapies utilized to treat systemic disease are limited by the blood-brain barrier (BBB). The tight junctions between the astrocytes of the BBB protect the brain from accidental toxins, but in doing so also shield the brain from intentional toxins, like chemotherapy (Bartsch et al., 2013). Most chemotherapy drugs are too large to pass from the blood into the cerebrospinal fluid and access the CNS.

Intrathecal chemotherapy

For all the reasons mentioned above, the idea of administering treatment directly into the subarachnoid space is the theoretical purpose behind intrathecal (IT) chemotherapy (Tetef et al., 2000).

IT and/or intraventricular chemotherapy has become a standard approach for patients with LC in many institutions. It has been studied prospectively and retrospectively. Most data come from observational studies, primarily retrospective. Until now, no prospective trial has demonstrated that IT prolongs

Final considerations

LC from breast cancer causes serious morbidity and carries a poor prognosis. Without treatment this condition leads do death within 4–6 weeks. It presents differences in time to presentation and prognosis in each molecular breast cancer subtype. Investigation with imaging studies (cerebrospinal MRI) and CSF analyses should start as soon as the patient presents suggestive clinical signs. The choice of treatment should consider prognostic evaluation and multidisciplinary discussion. Radiotherapy

Funding

None.

Conflicts of interest

The authors of this manuscript declare no conflict of interests.

Acknowledgements

We are thankful to ASCO's Virtual Mentor program for pairing a young oncologist in training in Brazil with a senior oncologist from an American Center to work together on this manuscript

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