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Leptomeningeal Metastasis

Leptomeningeal Metastases

The spread of malignancies to the central nervous system may either result in a single leptomeningeal metastasis, multiple secondary tumors or parenchymal brain lesions. The former are located in the subarachnoid space and primarily affect pia mater and arachnoid mater, but may exert local mass effects and provoke severe neurological deficits and death.

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Presentation

The most common symptom of LM is headaches. The majority of affected individuals also claims nausea and vomiting. Furthermore, patients may experience neurological symptoms consistent with cranial nerve palsies, cerebellar dysfunction, and spinal neuropathies. In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. Because most affected individuals suffer from multiple LM, they may show neurological symptoms seemingly unrelated to each other. For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status. Additionally, focal or generalized seizures, as well as meningism, may be reported. Neither of the aforementioned symptoms is specific for LM [11].

Abdominal Lymphadenopathy
  • Computed tomography (CT) of the chest, abdomen and pelvis demonstrated widespread thoracic and abdominal lymphadenopathy and a lesion within the splenic flexure. This was confirmed as an adenocarcinoma after a colonoscopic biopsy.[ncbi.nlm.nih.gov]
Weakness
  • Abstract A patient with uvular cancer presented with lower limb weakness and paresthesiae, headache, neck stiffness and multiple cranial palsies. No malignant cells were found on lumbar puncture. CT, and MRI were normal.[ncbi.nlm.nih.gov]
  • Irradiation can be an important part of treatment if the pressure is very high or if signs or symptoms of pain, numbness, or weakness are significant.[jamanetwork.com]
  • After approximately 36 months, he presented with gradually progressive weakness of the left lower limb since 6 months, followed by weakness of the right lower limb along with numbness in both the lower limbs and bowel and bladder involvement for 10 days[jcvjs.com]
  • Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.[symptoma.com]
  • LM can cause many different symptoms, such as: Difficulty thinking Double vision Headaches Difficulty speaking or swallowing Pain Weakness or lack of coordination in your arms and legs Loss of bladder or bowel control Seizures You may have 1 or more of[mskcc.org]
Nausea
  • Abstract The authors report on a 15-year-old girl presenting with headache and nausea.[ncbi.nlm.nih.gov]
  • Abstract A 60-year-old woman with a history of ovarian carcinoma and complaining of gait instability, dizziness, nausea, and a right temporal headache visited a neurologist.[ncbi.nlm.nih.gov]
  • When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures.[ncbi.nlm.nih.gov]
  • METHODS: A 70-year-old man was referred to our group for cognitive mental disorder, left-sided frontal headache and nausea; the patient had a previous history of metastatic prostate cancer.[ncbi.nlm.nih.gov]
  • CASES: All patients suffered from severe headache and nausea. The primary lesion was histologically diagnosed as lung adenocarcinoma in each case. The duration from diagnosis to onset of hydrocephalus symptoms ranged from 0 to 52 (mean 26) months.[ncbi.nlm.nih.gov]
Vomiting
  • When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures.[ncbi.nlm.nih.gov]
  • Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction.[ncbi.nlm.nih.gov]
  • The majority of affected individuals also claims nausea and vomiting. Furthermore, patients may experience neurological symptoms consistent with cranial nerve palsies, cerebellar dysfunction, and spinal neuropathies.[symptoma.com]
  • Clinical presentation is varied, but most commonly includes a headache, spine or radicular limb pain or sensory abnormalities, nausea and vomiting, and focal neurological deficits 3 . Meningism is only present in a minority of patients (13% 3 ).[radiopaedia.org]
Constipation
  • Symptoms of leptomeningeal metastases may include: Headache Backache Loss of sensation in the face Mental confusion Dizziness Weakness or loss of sensation in the legs and inner thighs Loss of control of the bladder or bowel Constipation Vision and hearing[brainmetsbc.org]
  • In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed.[symptoma.com]
  • The patient eventually developed significant difficulty walking, lower extremity neuropathic pain and numbness, constipation, and urinary retention. In the emergency department, he was nonambulatory and was diagnosed with cauda equina syndrome.[appliedradiationoncology.com]
Fecal Incontinence
  • Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.[symptoma.com]
Muscle Weakness
  • weakness Glossopharyngeal: Hearing loss and vertigo Vagus: Difficulty swallowing and/or speaking Spinal accessory: Shoulder weakness Hypoglossal: Difficulty speaking (due to problems moving the tongue) Encephalopathy Encephalopathy is a general term[verywellhealth.com]
Diplopia
  • Nine months after the allogeneic SCT, she presented with oculomotor and trochlear nerve palsy (diplopia, ptosis of the right upper eye lid, and dilated right pupil).[bloodjournal.org]
  • For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status.[symptoma.com]
  • Diplopia is the most common symptom, but an extraocular muscle palsy may be present without symptomatic diplopia. Other cranial nerve symptoms include hearing loss, facial numbness, facial weakness, visual loss, dysphagia and hoarse voice.[cancerforum.org.au]
  • Patient B suffered from radicular pain in both legs and diplopia. The clinically suspected LMM initially could not be confirmed by cytological examination of the CSF.[clinchem.aaccjnls.org]
  • Cranial-nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common.[emedicine.medscape.com]
Visual Impairment
  • Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.[symptoma.com]
Behavior Disorder
  • RESULTS: With this case report, we highlight the importance of referring the patient to a psychiatrist or a member of the psychooncology unit when new behavioral disorders present.[ncbi.nlm.nih.gov]
Psychiatric Manifestation
  • Psychiatric manifestations can blur the neurological frame and confound management of this complication.[ncbi.nlm.nih.gov]
Urinary Retention
  • About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise.[mdedge.com]
  • The patient eventually developed significant difficulty walking, lower extremity neuropathic pain and numbness, constipation, and urinary retention. In the emergency department, he was nonambulatory and was diagnosed with cauda equina syndrome.[appliedradiationoncology.com]
Urinary Incontinence
  • A case of leptomeningeal metastasis from an unknown primary source presenting with urinary incontinence as the sole complaint is reported.[ncbi.nlm.nih.gov]
  • For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status.[symptoma.com]
Meningism
  • Carcinomatosis/metabolism Meningeal Carcinomatosis/mortality Meningeal Carcinomatosis/secondary* Middle Aged Neoplasm Staging Proportional Hazards Models Receptor, ErbB-2/biosynthesis Receptors, Estrogen/biosynthesis Receptors, Progesterone/biosynthesis[ncbi.nlm.nih.gov]
  • Abstract Leptomeningeal meningitis occurs in approximately 5% of metastatic breast cancers, and there is no standard treatment for this complication.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: Evaluation of intrathecal TM synthesis is a specific, sensitive, reliable, and reproducible diagnostic tool, and is useful to support diagnosis of carcinomatous meningitis.[ncbi.nlm.nih.gov]
  • Meningeal metastasis from this type of neoplasm is extraordinarily rare and the prognosis is abysmal.[ncbi.nlm.nih.gov]
  • The brain and the spinal cord are enveloped by distinct tissues referred to as meninges. The inner meninges, pia mater and arachnoid mater, may also be designated leptomeninges.[symptoma.com]
Headache
  • Abstract BACKGROUND: Leptomeningeal metastasis-related hydrocephalus causes distress to patients with end-stage cancer through headache and other symptoms by elevating intracranial pressure, thus reducing quality of life.[ncbi.nlm.nih.gov]
  • Abstract A patient with uvular cancer presented with lower limb weakness and paresthesiae, headache, neck stiffness and multiple cranial palsies. No malignant cells were found on lumbar puncture. CT, and MRI were normal.[ncbi.nlm.nih.gov]
  • Abstract The authors report on a 15-year-old girl presenting with headache and nausea.[ncbi.nlm.nih.gov]
  • Abstract A 60-year-old woman with a history of ovarian carcinoma and complaining of gait instability, dizziness, nausea, and a right temporal headache visited a neurologist.[ncbi.nlm.nih.gov]
  • When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures.[ncbi.nlm.nih.gov]
Seizure
  • When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures.[ncbi.nlm.nih.gov]
  • Symptoms including confusion, seizures, pain and paralysis may be a result of either metastases to the nervous system or one of several nonmetastatic complications of cancer.[books.google.com]
  • Additionally, focal or generalized seizures, as well as meningism, may be reported. Neither of the aforementioned symptoms is specific for LM. LM are typically associated with high tumor grades and other metastases.[symptoma.com]
  • LM can cause many different symptoms, such as: Difficulty thinking Double vision Headaches Difficulty speaking or swallowing Pain Weakness or lack of coordination in your arms and legs Loss of bladder or bowel control Seizures You may have 1 or more of[mskcc.org]
  • For his seizures, the patient was treated with a higher dose of levetiracetam and lacosamide, later titrated to phenytoin.[appliedradiationoncology.com]
Radiculopathy
  • CONCLUSION: Spinal leptomeningeal metastasis needs to be suspected in patients with a past history of intracranial glioblastoma multiforme, who present with the clinical features of radiculopathy or myelopathy.[ncbi.nlm.nih.gov]
  • After 11 weeks, patient B had developed an organic psychiatric syndrome and multifocal radiculopathy. At that time, a second CSF examination was diagnostic for LMM.[clinchem.aaccjnls.org]
  • For example, a person may have symptoms (described below) of encephalopathy as well as a radiculopathy.[verywellhealth.com]
  • […] cranial nerve palsies * diplopia * facial numbness/paresis * hearing impairment or loss * sensory deficits * vertigo * vision impairment or loss Spinal cord * back pain * bladder and bowel dysfunction * lower motor weakness * neck pain * paresthesias * radiculopathy[nursingcenter.com]
Altered Mental Status
  • Patients may present with an altered mental status. Additionally, focal or generalized seizures, as well as meningism, may be reported. Neither of the aforementioned symptoms is specific for LM.[symptoma.com]
  • Thirty-six weeks after intrathecal treatment initiation, he presented to the hospital with altered mental status.[karger.com]

Workup

LM are typically associated with high tumor grades and other metastases. Thus, in patients previously diagnosed with advanced-stage cancer, clinical findings may prompt a suspicion of parenchymal brain tumors or neoplastic meningitis. Rarely, symptoms related to LM constitute the first manifestation of cancer. Diagnosis of LM is based on gadolinium-enhanced magnetic resonance imaging and cytological analyses of CSF specimens, and the former technique may also be employed to visualize parenchymal brain lesions [12]. Neuroimaging is preferentially performed before lumbar puncture to obtain CSF samples since the latter procedure may provoke misleading meningeal enhancement.

Indeed, enhancement of the outer meninges is a very common, yet unspecific finding in LM patients. Enhancement of the pia mater and nodular lesions are less frequently observed, but are considered to be more specific for neoplastic meningitis. Imaging procedures should encompass the entire neuroaxis because the majority of individuals who develop LM present with multiple metastases unevenly distributed throughout the subarachnoidal space. Besides LM, affected individuals may present parenchymal brain tumors and hydrocephalus. While hydrocephalus is readily observed in computed tomography scans, this technique does often yield unaltered images with regards to the meninges.

At least 10 ml of CSF should be examined for tumor cells to avoid false-negative results. Furthermore, a second sample may be obtained and analyzed in the case of the first specimen yields negative results. Morphological features of tumor cells largely depend on the origin of the primary tumor and it may be a challenge to distinguish malignant cells from merely atypical ones, particularly in the case of lymphoma or leukemia. Here, flow cytometric analyses may be necessary to identify a monoclonal population of immune cells. Immunohistochemical and molecular analyses may also aid to relate LM with a determined solid primary tumor and set the basis for target-oriented therapy. Finally, it has to be noted that LM is frequently associated with pleocytosis, enhanced protein levels, and low glucose concentrations in CSF.

Lymphocytic Infiltrate
  • The T lymphocyte infiltration, documented in all CSF samples, suggests a possible involvement of the CNS lymphatic system in both lymphoid and cancer cell migration into and out of the meninges, supporting the extension of a new form of cellular immunotherapy[ncbi.nlm.nih.gov]

Treatment

A thorough workup including an analysis for further metastases, an association of LM with a primary tumor, and a pathohistological classification of both is the basis of therapy. Determined molecular properties, e.g., hormone receptor expression and enzymatic activity, may render neoplasms susceptible to certain therapeutics, but they may differ between the primary tumor and LM [13]. While systemic chemotherapy is generally indicated to treat malignancies and metastases in peripheral tissues, an alternative route of administration has to be chosen to deliver drugs to the subarachnoid space. Intrathecal drug application via an intraventricular reservoir is preferred, but mechanical obstruction of the subarachnoid space by metastases may prevent compounds from reaching the entire neuroaxis. Lumbar punctures may be required to deliver active agents to the leptomeninges surrounding the inferior segments of the central nervous system. Of note, certain chemotherapeutics are neurotoxic and cannot be applied as described above. This is the case for vincristine; methotrexate, cytarabine, liposomal ara-C, and thiotepa, and are rather well-tolerated, though, and are most commonly used in LM patients. Pharmacodynamic and pharmacokinetic properties of those drugs have been reviewed elsewhere [1].

In patients with a high-performance status, craniospinal axis irradiation is recommended to target the entire neuroaxis. In contrast, a low-performance status indicates irradiation of symptomatic sites or sole palliative care.

Additional measures may be taken to relieve symptoms, e.g., the positioning of a ventriculoperitoneal shunt to lower intracranial pressure and application of corticosteroids to reduce spinal cord compression.

Prognosis

Despite diagnostic advances that allow for an earlier recognition of LM, they are still associated with a poor prognosis. In general, patients suffering from hematological malignancies that spread to the leptomeninges have a better outcome than those diagnosed with solid primary tumors. Median survival times of few months and two months have been reported, respectively [10].

Etiology

LM may arise after the spread of malignant cells originating from solid tumors, lymphoma or leukemia [3]. While the possibility of spread to the leptomeninges cannot be ruled out in any cancer, most cases of LM are associated with the following primary tumors [1]:

  • Carcinoma of the breast (up to a third of all cases)
  • Carcinoma of the lung (about a fourth of all cases)
  • Malignant melanoma (about a fourth of all cases)
  • Malignancies of the gastrointestinal tract
  • Adenocarcinoma of unknown origin

Epidemiology

Although reported incidences of LM are increasing, this complication of cancer is still assumed to be largely underdiagnosed. Epidemiological data provided should thus be interpreted with care.

As has been indicated in the previous section, certain malignancies are associated with an increased risk of LM. According to current knowledge, the individual risk of cancer patients for developing LM is as follows [4]:

  • About 3% of patients suffering from carcinoma of the breast develop LM. Negativity for estrogen and progesterone receptors may predispose for LM, while highest incidence rates have been reported for triple-negative breast carcinoma (negativity for estrogen and progesterone receptors and lack of overexpression of human epidermal growth factor receptor 2 HER2/neu) and tumors of the lobular subtype [5]. Of note, prognostic factors for brain parenchymal metastases and LM don't necessarily coincide.
  • Small cell carcinoma of the lung spreads to the leptomeninges in about 6% of cases, while other malignancies of the lung are associated with LM in only about 1% of affected individuals.
  • The likelihood of LM in malignant melanoma patients is less than 2%.
  • Malignancies of the gastrointestinal tract spread through the CSF in less than 1% of patients.
  • Adenocarcinomas of unknown origin metastasize to the leptomeninges in approximately 3% of cases.
Sex distribution
Age distribution

Pathophysiology

Infiltration of the subarachnoid space allows for an extensive distribution of tumor cells along the entire neuroaxis. Considerable research efforts have been undertaken to clarify how degenerated cells reach this privileged area, and the following routes of metastatic spread have been identified [6]:

  • Hematogenous spread of tumor cells, adherence to the endothelium of vessels supplying the leptomeninges and subsequent infiltration of those tissues and the subarachnoid space is assumed to be the most common form of spread to the leptomeninges in the case of solid primary tumors.
  • LM may also arise after spread via perivascular lymph vessels [7].
  • The leptomeninges envelops the roots of cranial and spinal nerves, while peripheral segments of those nerves are sheathed by the perineurium. The continuity between leptomeninges and perineurium, between the subarachnoid and perineural spaces facilitates the perineural spread of tumor cells [8].
  • Brain tumors may infiltrate the leptomeninges and the subarachnoid space and spread along the neuroaxis. Of note, tumor cells originating from carcinoma of the breast or lung have been shown to invade and degrade the leptomeninges, while cells stemming from glioma may not be able to do so [9].
  • Finally, surgical interventions may result in the iatrogenic spread of tumor cells to the CSF.

Predilection sites of tumor cell accumulation and metastatic growth are determined by CSF flow and gravity and comprise basal cisterns, cerebellopontine angle, posterior fossa and lumbar cistern. Here, LM exert local mass effects and interfere with the brain, spinal cord, and nerve function. At the same time, tumor cells may form mechanical obstacles that hinder CSF drainage, and this condition may result in hydrocephalus.

Prevention

General measures to reduce carcinogen exposure may lower the individual risk of developing malignancies; detection of cancer during early stages may prevent metastatic spread. In this context, patients should be advised to refrain from tobacco consumption, to put safety measures into practice, and to regularly undergo preventive medical check-ups. Treatment of certain subtypes of cancer (e.g., T-cell lymphoblastic lymphoma) comprises prophylactic brain irradiation or intrathecal application of chemotherapeutics.

Summary

Brain and spinal cord are surrounded by the meninges, namely by pia mater, arachnoid mater and dura mater. The former two are also referred to as leptomeninges. The subarachnoid space, i.e., the more or less extensive space between pia mater and arachnoid mater, is filled with cerebrospinal fluid (CSF). Tumor cells may infiltrate this space by crossing the boundaries of vessels or adjacent tissues and may then be distributed within the CSF. Accordingly, patients may develop a single leptomeningeal metastasis (LM) or present with multiple secondary tumors to be encountered in pia mater and arachnoid mater.

For a long time, LM have been considered uncommon. Most types of cancer are expected to spread through hematogenous route or through lymphogenic route, and metastases most frequently form in regional lymph nodes, lungs, liver, and spleen. However, the incidence of LM is increasing [1], possibly due to prolonged survival times and improvements of therapeutic regimens directed against neoplasms in the aforementioned tissues. Chemotherapeutic drugs differ with regards to their pharmacokinetic properties and may or may not reach certain compartments. To date, most chemotherapeutics are unable to penetrate into privileged areas because they cannot overcome physiological and functional barriers like the blood-brain barrier and the blood-CSF barrier [2]. Consequently, tumors may proliferate in these regions despite otherwise effective systemic chemotherapy. Tumor growth may be associated with secondary inflammation and this fact that has lead to using the terms carcinomatous and neoplastic meningitis to refer to LM.

Although those barriers may display increased permeability in close proximity to tumors, they do pose a major obstacle to LM treatment. In general, chemotherapeutics have to be administered intrathecally. Furthermore, affected individuals may be subjected to radiotherapy. Despite all efforts, LM are associated with a poor prognosis and median survival times of less than half a year.

Patient Information

The brain and the spinal cord are enveloped by distinct tissues referred to as meninges. The inner meninges, pia mater and arachnoid mater, may also be designated leptomeninges. They enclose the subarachnoid space, which is filled with cerebrospinal fluid (CSF). If tumor cells reach the leptomeninges and the CSF, they may easily spread to multiple sites along the neuroaxis. Consequently, few patients present with a single leptomeningeal metastasis (LM) - the majority of affected individuals suffer from several metastases that interfere with brain and spinal cord function. Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.

Tumor cells that spread to the leptomeninges may originate from any type of cancer but are most commonly detected in patients previously diagnosed with carcinoma of the breast or lung, malignant melanoma, malignancies of the gastrointestinal tract and adenocarcinoma of unknown origin. These are aggressive neoplasms, and LM generally develop during advanced stages of these diseases. At this time, metastases may already affect other tissues, too. Thus, any therapeutic regimen should target the primary tumor as well as leptomeningeal and other metastases. In most cases, only palliative care can be offered. Patients may be administered chemotherapeutics, may undergo radiotherapy and additional measures to relieve symptoms in order to maintain life quality during the following months. To date, there is no cure for LM.

References

Article

  1. Le Rhun E, Taillibert S, Chamberlain MC. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int. 2013; 4(Suppl 4):S265-288.
  2. Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol. 2009; 31(4):497-511.
  3. Nolan CP, Abrey LE. Leptomeningeal metastases from leukemias and lymphomas. Cancer Treat Res. 2005; 125:53-69.
  4. Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006; 5(5):443-452.
  5. Scott BJ, Kesari S. Leptomeningeal metastases in breast cancer. Am J Cancer Res. 2013; 3(2):117-126.
  6. Taillibert S, Laigle-Donadey F, Chodkiewicz C, Sanson M, Hoang-Xuan K, Delattre JY. Leptomeningeal metastases from solid malignancy: a review. J Neurooncol. 2005; 75(1):85-99.
  7. Gonzalez-Vitale JC, Garcia-Bunuel R. Meningeal carcinomatosis. Cancer. 1976; 37(6):2906-2911.
  8. Dunn M, Morgan MB, Beer TW. Perineural invasion: identification, significance, and a standardized definition. Dermatol Surg. 2009; 35(2):214-221.
  9. Pedersen PH, Rucklidge GJ, Mork SJ, et al. Leptomeningeal tissue: a barrier against brain tumor cell invasion. J Natl Cancer Inst. 1994; 86(21):1593-1599.
  10. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal metastases in the MRI era. Neurology. 2010; 74(18):1449-1454.
  11. Damek DM. Cerebral edema, altered mental status, seizures, acute stroke, leptomeningeal metastases, and paraneoplastic syndrome. Hematol Oncol Clin North Am. 2010; 24(3):515-535.
  12. Perkins A, Liu G. Primary Brain Tumors in Adults: Diagnosis and Treatment. Am Fam Physician. 2016; 93(3):211-217.
  13. Grewal J, Zhou H, Factor R, Kesari S. Isolated loss of hormonal receptors in leptomeningeal metastasis from estrogen receptor- and progesterone receptor-positive lobular breast cancer. J Clin Oncol. 2010; 28(13):e200-202.

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Last updated: 2018-06-21 21:23