Primary leptomeningeal melanocytic tumours comprise a rare group of conditions resulting from neoplasia of the melanocytes within the pia mater of the central nervous system (CNS).1–4
The World Health Organization (2007) sub-classifies the primary meningeal lesions into malignant melanoma, melanomatosis, melanocytoma, and diffuse melanocytosis.5
In primary malignant melanoma tumour cells are well localised but invade the opposed cerebral cortex.2,3
Histologically, this should be distinguished from leptomeningeal melanocytoma which is typically a well localised benign neoplasia of abnormal melanocytes which does not invade the brain parenchyma, although this may rarely progress to involve extensive areas of the meninges in diffuse melanocytosis, as in this case.2,3
Published data report a 5 year survival of 82% following complete resection of a melanocytoma, as has been the management in half of cases in the literature.4
GVAX belongs to a novel group of therapies for prostate cancer, termed cancer cell vaccines, and involves intradermal injection of irradiated neoplastic cells genetically modified to secrete GM-CSF (granulocyte macrophage colony stimulating factor), which leads to secretion of cytokines and generates anti-tumour immunity.6–8
Theoretical advantages are increased tumour cell death and reduced rates of metastases.9–11
In preclinical and clinical phase I/II trials, the combination of docetaxol and cancer cell vaccines demonstrated a synergistic effect and prolonged survival has been reported in animal models.9,10
A favourable side effect profile has been reported, mainly limited to injection site reactions.10,11
While the melanocytic pulmonary metastases in this case were present before treatment with the cancer cell vaccine, there were no neurological symptoms at that time. We report the first case of a leptomeningeal melanocytic neoplasm in a patient receiving this novel therapy. Future research with cancer cell vaccines is needed to determine if the CNS extension of the melanocytoma in our case is related to treatment.
As highlighted by this case, the diagnosis of melanocytic neoplasia of the CNS is particularly difficult to make ante-mortem.1–3,12
The clinical features are non-specific, including seizures, raised intracranial pressure or disturbances of cognition, and may be mistaken for other diagnoses including encephalitis, hydrocephalus and psychiatric disturbance with potentially fatal consequences.1,3,4
Diagnosis is also made difficult by the inadequacy of routine investigations—notably, CT is only 42% sensitive and gadolinium enhanced MRI, the gold standard, has a sensitivity of 70%.1,2
Free radicals within melanin may be demonstrated and may represent the meningeal enhancement identified in this case.2
However, this is typically absent in early disease and is also found in other meningeal conditions such as infection, malignancy and amyloidosis.1,2 99m
Tc-MIBI SPECT imaging has been successfully utilised in one recent case report of primary leptomeningeal melanoma, although its role in clinical practice has yet to be determined.2
As CSF analysis is dependent on the number and degree of pigmentation of cells sampled the sensitivity is low, as demonstrated by the two negative CSF analyses in this case.1–3
Therefore, a histological diagnosis is often required, particularly as the immunohistochemical markers HMB-45 and S100, which were positive in this case, have a high degree of sensitivity and specificity when used together.2,3
However, brain or meningeal biopsies are much less frequently performed than lumbar punctures and neuroimaging due to the associated risks, and may not be considered indicated in cases in which the CSF cytology is negative.
We report a case of a man who developed testicular, prostatic and meningeal melanocytic neoplasia. As far as we are aware, this is the first reported case of this nature. This may be a fortuitous finding or it may represent a genetically determined polyneoplastic syndrome, although further case series are needed.
This case highlights the difficulties in establishing the diagnosis of leptomeningeal melanocytic neoplasms which is currently limited by the low sensitivity and specificity of routine investigations. Moreover, clinicians need to be aware of the potential for widespread CNS extension and death in patients with these neoplasms. Previous studies have described the extra-CNS distribution of leptomeningeal lymphoma at sites which may be more acceptable for biopsy than the brain or meninges.13
Future research is needed, both to assess whether the widespread leptomeningeal extension reported in this case is associated with the cancer cell vaccine utilised and also to describe the extra-CNS loci of meningeal melanocytic neoplasms, so that clinicians can be aware of the potential of these lesions to metastasise to sites which may be more accessible to biopsy and thus tissue diagnosis than brain or meninges.
- Although primary leptomeningeal melanocytosis is typically localised to the leptomeninges, our case highlights that they have the potential to develop focal melanomatosis and metastasise to distant sites.
- We report the first case of a patient undergoing treatment with a novel cancer cell vaccine for prostate cancer who developed a primary leptomeningeal melanocytic neoplasm which was fatal.
- Currently the diagnosis of primary leptomeningeal melanocytic neoplasms is limited by the low sensitivity and specificity of the clinical features, MRI findings, and CSF analysis.
- Further studies are needed both to determine if the treatment with novel cancer cell vaccines is associated with the extension of leptomeningeal melanocytic neoplasms and to describe the secondary distribution of these lesions at sites which may be more accessible to biopsy, and thus tissue diagnosis, than brain or meningeal biopsy.