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BMJ Case Rep. 2010; 2010: bcr11.2009.2495.
Published online 2010 May 4. doi:  10.1136/bcr.11.2009.2495
PMCID: PMC3047541
Rare disease

Diffuse primary leptomeningeal melanocytosis in a patient receiving a novel cancer cell vaccine for prostate cancer

Abstract

A 75-year-old man, undergoing treatment for metastatic prostate cancer with a novel cancer cell vaccine, presented with a 4 week history of poor balance, gait disturbance and cognitive decline. Blood tests including HIV and onconeuronal and voltage gated potassium channel antibodies were normal. Computed tomography and two magnetic resonance images of the brain showed possible non-specific meningeal or vascular enhancement. Two cerebrospinal fluid analyses, including cytology, were negative, other than six lymphocytes in the former. Despite intravenous aciclovir and dexamethasone the patient deteriorated over 16 days, with worsening confusion and involuntary movements, and died. Postmortem examination showed that the leptomeninges overlying the brain and spinal cord were diffusely infiltrated by a melanocytosis with a focal area of melanomatosis. Moreover, there were two sites of metastases of a highly malignant clone present in the pulmonary parenchyma.

Trial registration number:

NCT00133224

Background

Leptomeningeal melanocytomas are one of a rare group of tumours arising from melanocytes within the pia mater which are typically localised and benign with a good postoperative prognosis. Novel cellular vaccines are being increasingly utilised in trials to treat several cancers. We report the first case of a man treated with a cellular vaccine for prostate cancer who developed diffuse primary leptomeningeal melanocytosis with focal melanomatosis and pulmonary metastases which was fatal. Future research with cellular vaccines is required to determine if the diffuse melanocytosis in our case is related. Clinicians need to be aware of the potential for metastases and mortality with primary leptomeningeal melanocytic neoplasms.

Case presentation

A 75-year-old man with a prostate cancer presented with a history of vomiting for 1 month and poor balance, gait disturbance and cognitive decline for 2 weeks. Neurological examination was normal other than a positive Romberg’s test and non-specific ataxia.

Prostatic adenocarcinoma, diagnosed 3 years earlier, initially responded to goserelin (Zoladex) and bicalutamide (Casodex); however after 2 years he developed bone pain, his prostate specific antigen (PSA) increased, and computed tomography (CT) demonstrated new neoplastic vertebral and pulmonary lesions. There were no neurological symptoms. He enrolled in a phase III open label randomised controlled trial, Vital II, for metastatic hormone resistant prostate cancer (HRPC). He was randomised to receive two novel cancer cell vaccines PC-3 cells CG1940 and LNCaP cells CG8711 (GVAX) and docetaxel chemotherapy, for 10 cycles. The control arm received docetaxel and prednisolone. After the sixth cycle he was admitted with the above presentation. His bone pain had improved and his PSA had reduced from 245 ng/ml to 120 ng/ml. He had history of previous myocardial infarction and a testicular tumour successfully resected 40 years earlier.

Investigations

Blood tests including HIV, onconeuronal and anti-voltage gated potassium channel antibodies were normal. Cranial CT demonstrated a small serpinginous enhancement of the left parietal lobe thought to represent a vein. Magnetic resonance imaging (MRI) was normal. Two lumbar punctures (LPs) were performed, 2 weeks apart, both with normal protein, glucose and red cells, and six white cells (100% lymphocytes) in the former and three white cells in the latter. Both had negative cultures and only a few lymphocytes on cytology. After the former, intravenous aciclovir was commenced. PCR for herpes and JC viruses and toxoplasmosis was negative. Another MRI 7 days before his demise showed slight linear enhancement within the sulci (fig 1). This was attributed to vasculature as both cerebrospinal fluid (CSF) samples had negative cytology. Aspiration of the pulmonary lesions did not demonstrate abnormal cells.

Figure 1
Cranial magnetic resonance imaging (MRI) of a patient with diffuse leptomeningeal melanocytosis. T1 weighted MRI with contrast: small excess of linear enhancement within the sulci overlying the cranial aspect of both the cerebral hemispheres possibly ...

Differential diagnosis

The differential diagnoses during this patient’s investigation included encephalitis, paraneoplastic phenomena, and meningeal metastases of the prostatic tumour, although the above investigations were unable to confirm any of these differential diagnoses.

Treatment

After the former lumbar puncture, intravenous aciclovir was commenced to cover for viral encephalitis. As the patient continued to deteriorate despite this, intravenous dexamethasone was initiated.

Outcome and follow-up

Over 16 days the patient developed worsening confusion, dysarthria, involuntary twitching of all limbs and bilateral extensor plantars. Four days following the commencement of dexamethasone the patient died.

Macro- and microscopic postmortem examination revealed a well localised prostatic adenocarcinoma. Microscopic examination of the bilateral pulmonary nodules showed a different tumour composed of pleomorphic epithelioid multinucleated and spindle shaped cells forming sheets, with mitoses, vascular invasion and surrounding necrosis. There was no lymphadenopathy, a normal spleen, no evidence of bone or hepatic metastases, and no pigmented lesions of the skin or retina.

The fixed brain weighed 1372g and had a normal macroscopic appearance as did the spinal cord, tibialis muscle and attached nerve. However, microscopic examination revealed that the meninges, Virchow–Robin spaces, spinal cord, a spinal ganglion and nerve were all infiltrated by a neoplasm composed of moderately pleomorphic rounded or elongated, epithelioid, occasionally binucleated cells with an increased nucleus:cytoplasmic ratio which were occasionally pigmented (fig 2). Nuclei were pleomorphic, irregularly bordered or vesicular with an occasional mitosis. The tumour infiltrated CA1-4, the dentate gyrus granular cell layer, and the posterior insular cortex with focal parenchymal invasion, and expressed the immunohistochemical markers outlined in table 1.

Figure 2
Immunohistochemical findings in a patient with diffuse primary leptomeningeal melanocytosis.
Table 1
Histological and immunohistochemical features of the primary leptomeningeal melanocytosis and the pulmonary metastases

In the absence of a primary melanocytic lesion elsewhere, this is consistent with primary diffuse leptomeningeal melanocytosis, with a focal area of melanomatosis and metastatic deposits of a high grade malignant clone within the lungs.

Discussion

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).14 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.68 Theoretical advantages are increased tumour cell death and reduced rates of metastases.911 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.13,12 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 99mTc-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.13 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.

Learning points

  • 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.

Acknowledgments

We would like to acknowledge the intellectual input of Dr Geoff Keir (consultant neuro-immunologist, The Walton Centre for Neurology and Neurosurgery) in reviewing this case report.

Footnotes

Competing interests: None.

Patient consent: Patient/guardian consent was obtained for publication.

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