Tumors Masquerading as Neurological Diseases: A Caution for Clinicians in Planning Diagnosis and Treatment
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.280647
Source of Support: None, Conflict of Interest: None
Keywords: Mass lesions, prognostic and therapeutic relevance, treatment-resistant neurology, TRIADKey Message: All age groups of patients can present with neurological disorders with hidden mass lesions. Children have well-defined syndromes with specific neoplasms and adults have a spectrum. Awareness of these syndromes is lifesaving.
Tumors as per definition are a group of abnormally proliferating cells which serve no useful function. They are commonly detected by the effects of the compromise of space in regions where ever they grow. There are benign tumors which have no other sequelae except when they produce hormones, interfere with the supply of nutrients by competing with the host, preventing absorption, by a set of features called paraneoplastic syndromes, and also by immune-mediated and treatment-related complications on the nervous system. The malignant lesions, in addition, produce the most serious complications due to metastasis. Most of these disorders are easy to diagnose. But paraneoplastic neurological disorders are a heterogeneous group of syndromes affecting any part of the neuraxis and some of these disorders can be great imitators closely mimicking pure primary neurological illness, which results in the diagnosis being totally missed for long, resulting in great morbidity to patients. In this article, we discuss our experience in this area of nonmetastatic features which are not attributable to tumor growth. The disease-related syndromes can be autoimmune, metabolic, nutritional, and hormonal. The common autoimmune manifestations are encephalitis, encephalomyelitis, cerebellar ataxia, opsoclonus myoclonus syndromes, disorders of peripheral nerves, muscles, and myoneural junction, including Eaton and Lambert syndrome (LEMS).,, The paraneoplastic LMN disorders carry the best prognosis with treatment. The presence of anti-HU as well as CNS manifestation carries bad prognosis. The auto antibody-like GAD65 to intracellular synaptic proteins carry intermediary response to immunotherapy.
Patients seen by the authors in the last five years with primary neurological illness who did not have any known neoplasm but later became evident as the epiphenomena of hidden tumors are discussed in the article. Broadly, the neurological features can be related to brain and spinal metastasis or paraneoplastic. Features secondary to metastasis which depends on the dynamics of tumor growth and its tropism were excluded in this study. Other manifestations are classified as those who presented with central nervous system features, basal ganglia features, cerebellar features, spinal cord features, features of muscle disease, and neuromuscular junction and peripheral nerve features for convenience and discussed. The subjects or caregivers were explained about the details and informed consent obtained as per institutional practice for use of their data for learning and publication purposes. As it is retrospective data, specially designed consent forms were not used. All of them underwent a thorough clinical evaluation, MRI, paraneoplastic work up, autoimmune and vasculitis workup, B12, VDRL. LFT, RFT, other evaluations like CT abdomen and thorax, PET MRI, and histopathology based on feasibility and need.
In the last five years, 28 patients seen by the authors presented with neurological disorders which were due to underlying general surgical conditions. There were 12 females and 16 males. Their age groups varied from less than 10 years to more than 60 years. Age wise distribution showed maximum patients in the 61 and above age group (8/28) followed by 7 patients in 21 to 40 years age. 41 to 60 age group had 6 patients (6/28). Least was in below 10 years age group and 11–20 years age group with four patients each. The commonest neurological presentation was muscle and nerve in 8/28 cases, seizures and opsoclonus in four cases each, ataxia and dementia in three patients each, and parkinsonism spectrum, NMDA encephalitis, and subacute combined degeneration of the cord were seen in two patients each. The commonest surgical condition in less than 20 age group was midline lipoma 4/28, suprarenal mass 4/28, carcinoma stomach 2/28 [Figure 1], thymic tumor 2/28 [Figure 2], ovarian teratoma 2/28, tendon xanthomas 1/28 [Figure 3].
Neoplasms produce neurological manifestations through several mechanisms. If the symptoms can be directly related to their location, the patient directly lands up with the surgeon. Therefore, diagnosis and management take place properly. However, the mechanisms by which the lesion remains in hiding but produces neurological features are many and can affect all parts of the nervous system. The usual clinical presentations are as follows: Immune-mediated encephalitis, ataxia, opsoclonus-myoclonus, brainstem encephalitis, peripheral neuropathy, myopathy, myositis, Eaten–Lambert syndrome, and antibody to ganglionic AChR receptor (by the mechanism of molecular mimicry due to cross-reacting onconeural antigens). Commonly detected antibodies are Anti-Hu which present with brainstem and limbic encephalitis, ataxia, and myeloneuropathy and the frequent tumors are small cell lung cancer (SCLC) and neuroblastoma. Anti-RI is seen with ataxia and rhombencephalitis. The common tumors associated are carcinoma breast and small cell lung cancer (SCLC). Anti-Yo presents with ataxia and is associated with female genital tract tumors. Anti-Cv2 presents as limbic encephalitis and the tumors seen are thymoma, SCLC. Anti-PNMA 2 presents with limbic and pan brain stem encephalitis. Tumors seen are non-SCLC and testicular tumors. Anti-PNMA 1 presents as brain stem encephalitis and is associated with breast carcinoma. Anti-amphiphysin presents with muscle and nerve features. The tumors associated are thymoma and lymphomas. PCA 2 presents with encephalopathy and neuropathy and associated with SCLC. Anti-TR presents with connective tissue disease and tumor associated is lymphoma. Anti-SOX1 presents with LEMS and tumor associated is SCLC. Anti-MAG presents as neuropathy and tumor association is protein secreting tumors. Anti-GAD 65 presents with Stiff person syndrome and is seen in SCLC. Anti-ZiC 4 presents with connective tissue disease and SCLC. Anti-titin presents as neuromuscular junction disorder and is associated with thymoma. Anti-recoverin is associated with retinopathy and tumor associated is SCLC. Other mechanism is by the effect of hormones secreted in an unregulated manner by these neoplasms. Identifying neoplasm as a part of the spectrum of a neurological disease has great diagnostic and therapeutic relevance. The effect due to specific nutritional deficiency like malignancies of GIT causing intrinsic factor deficiency lead to sub-acute combined degeneration of cord, peripheral neuropathy, and dementia. Treatment-related and disease-associated toxic and metabolic complications on the nervous system also can manifest as presenting features. These syndromes are defined as definite if they form classic syndromes with identified neoplasm; nonclassic syndromes include a) which improve with treatment of neoplasm, b) paraneoplastic antibody and neoplasm but relationship is not established, or c) neoplasm but no antibody detected. They are categorized as possible if classic syndrome is seen with no identified neoplasm or antibody, classic or nonclassic syndromes and noncharacterized antibody, and nonclassic syndrome and neoplasm but no antibody. Patients can also have problems due to multiple underlying co-morbidities like anemia, infections, and vascular and metabolic issues. The symptoms may be misdiagnosed resulting in serious consequences. The neurological complications of neoplasms can be more disabling and resistant to treatment unless the condition is identified. Therefore, we decided to share our experience in the last five years to enhance insight into these situations. This study reveals the following. There were 8 children and 20 adults in the study period seen by the authors. New onset and refractory seizures and psychosis were the commonest symptoms in children. Muscle and nerve problems were common in adults.
Mitochondrial encephalopathy with ragged red fibers (MERRF) and midline lipoma
Child was admitted with features of familial juvenile myoclonic epilepsy and progressive cognitive decline, deafness, and blindness while on sodium valproate. Incidental observation of mother and aunts showed huge midline lipomas, which is a marker of MERRF. Valproate is the drug of choice for juvenile myoclonic epilepsy but, being a mitochondrial poison, it aggravates the condition when JME is due to mitochondrial diseases. Withdrawal of the drug was done with moderate improvement. However, during subsequent years child also developed the lipoma and she passed away four years after the valproate-induced encephalopathy, while the other members who received safer drugs survived. In this condition, the tumor association helps in choosing the right pharmacotherapy.
NMDA encephalitis and ovarian teratomas
Two children presented with severe new-onset psychosis preceded by brief febrile illness. One of the children was incidentally bitten by a rabid dog and she had violently bitten herself and her brother [Figure 4]. She was labelled as rabies; however, diagnosis was confirmed as NMDA encephalitis based on the clue that contrary to the popular belief, patients with rabies do not bite. Timely evaluation was done based on our protocol applying the TRIAD in every case of new-onset psychosis. Typical EEG changes, NMDA antibody, and ovarian Teratoma was identified and treatment caused complete remission.
Neuroblastoma and opsoclonus-myoclonus syndrome
Four children all in the age group of less than 10 presented with features of opsoclonus myoclonus syndrome and investigation revealed neuroblastoma in three children and ganglioneuroma in one. With appropriate treatment all but one of the children could be saved.
Adults 21 to 40 and 61 and above age group had a maximum incidence. Muscle and nerve were the commonest presentations in adults.
Muscle and nerve manifestations
In most of these cases, autoantibodies directly affect the ion channels or related proteins in NMJ or peripheral nerves. Eight patients in this study had lower motor neuron features. Three patients had recurrent hypokalemic paralysis with suprarenal mass; one patient had POEMS syndrome with peripheral neuropathy and solitary plasmacytoma, polymyositis in 1 case with pancreatic mass, and two patients presented with limb girdle weakness due to parathyroid adenoma [Figure 5]. One patient with myasthenia gravis had later developed features of MND and thymic tumor. One patient with pancreatic mass presented with myasthenia gravis. Neuromuscular paraneoplastic syndromes are generally associated with autoantibodies, and our patients showed AChR AB in two, myositis panel showed anti-SRP strongly positive, positive myeloma band in POEMs and increased calcium in patients with parathyroid adenoma in two cases. (hypercalcemic myopathy2, POEMS 1, polymyositis 1, MG and MND 1, MG 1, hypokalemic paralysis 2) [Table 1].
Late middle-aged male presented with rapidly progressive ataxia and weight loss. The patient had become bedbound in a few months which is not usual in degenerative ataxias and thorough examination revealed left inguinal lymphadenopathy which turned out to be due to non-Hodgkin's lymphoma with strongly positive Anti-Ri antibody. The second patient had renal cell tumor, and the 3rd patient was a female in 5th decade with carcinoma lung.
Dementia with atypical features in the form of delirium, tremors, and skin tags and ichthyosis with weight loss was seen in a male patient of more than 60 age group and investigations revealed a malignant thymic tumor. Second patient presented with rapidly progressive memory loss due to limbic encephalitis and investigations revealed bilateral suprarenal metastatic deposits. The third patient had left supraclavicular deposits and unknown primary.
Thefirst patient in this group is an elderly male smoker who had significant weight loss in the preceding 6 months, followed by an imbalance while walking, slightly stooped posture, repeated falls, and upgaze palsy. He had swallowing difficulty and hoarse voice with evidence of right palatal palsy. He was diagnosed as a case of progressive supranuclear palsy and came for the second opinion. In view of his lifestyle, rapid progression, hoarse voice, and weight loss, paraneoplastic antibody screening was done which showed strongly positive anti-HU antibody. Therefore, whole-body PET was done. Nevertheless, it was inconclusive. He was treated symptomatically with plasmapheresis and showed improvement temporarily. Two years later, he was found to have an angiosarcomatous deposit in scalp with unknown primary. The second patient was a male in his fifth decade who presented with features of akinetic rigid parkinsonism of four months duration, fatigue, and severe sleepiness and found to have a malignant tumor of the parathyroid.
Subacute combined degeneration of cord
Two patients both males in their fourth decade presented with spasticity of both lower limbs for one month, ataxia of sensory nature with features of peripheral neuropathy of three months. They both had early satiety, weight loss, and anemia. Investigations revealed a leather bottle stomach in one patient and mass in the stomach in the second person. They both had low B12 in serum, macrocytic anemia. Neurological symptoms partly improved with vitamin B12 replacement. Unexplained and rapidly progressive evidence of subacute combined degeneration of cord always needs to be investigated for intrinsic factor deficiency due to mass lesions.
Neoplasms behave like chameleons changing the way they express themselves with great caution for the survival of the tumor. Clinician needs a lot of awareness so that right investigations are planned and early treatment is initiated.
In this study, both children and adults presented with a spectrum of neurological illnesses secondary to underlying malignancy. These malignancies were occult, and the diagnosis was of great therapeutic relevance. Though the number in the pediatric age group is relatively less, one patient could be saved from the fatal diagnosis of rabies (in the child with NMDA encephalitis), and the child with MERRF faced severe deterioration and fatality due to the use of contraindicated pharmacotherapy because of the lack of awareness of relationship between midline lipoma and MERRF. The children presenting as opsoclonus-myoclonus syndrome need treatment of the primary neoplasm for improvement apart from other symptomatic measures for the disabling neurological manifestations.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients/guardians have given their consent for their/patients images and other clinical information to be reported in the journal. The patients/guardians understand that their/patients names and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.
We acknowledge with gratitude that our patients and their families, as well as the teaching institutions in Trivandrum and NIMHANS for the cooperation tendered in completing this work.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]