Paraneoplastic syndromes

Paraneoplastic syndromes (i.e. organ/tissue disorders associated with cancer) affecting the nervous system are thought to be the result of an autoimmune response triggered by specific cancer antigens. Several of these antigens have recently been identified and include the Hu, Yo and Ri proteins, with the Hu antigens being the best studied. Immunization of animals with HuD has been shown to retard the growth of HuD-positive neuroblastomas. In addition, the presence of anti-HuD antibody in humans with small-cell lung cancer predicts the slow growth of the tumor. The associated neurological disorders, however, limit the use of these and other antigens with similar characteristics in cancer vaccines.     

Paraneoplastic syndromes

Anisodamine is an alkaloid isolated from a Chinese plant, which was subsequently synthesized. Its chemical structure is similar to atropine. It inhibits cholinergic nerve function, improves microcirculation, and was reported to have a protective effect on reperfusion injury in various organs. We used anisodamine in a rabbit model with ischemia and reperfusion injury of hind limb muscles. We evaluated its effect on skeletal muscle cells, using transmission electron microscopy, and analyzed lipid peroxidation by measuring malondialdehyde and lactate dehydrogenase blood concentrations. We found that malondialdehyde and lactate dehydrogenase concentrations after 1 hour of reperfusion were lower in animals treated with anisodamine than in controls. Damage to membrane structures and myofilaments in muscle cells was less severe after anisodamine treatment. Our findings indicate that anisodamine protects skeletal muscles with ischemia and reperfusion injury.     

Paraneoplastic syndromes

The importance of paraneoplastic syndromes is often underestimated in the horse. Clinically, paraneoplastic syndromes can cause greater morbidity than the actual physical presence of the malignant tumor. The appearance may be the first sign of a malignancy and may be so severe that appropriate therapy for the underlying cancer is not initiated. This article reviews some of the most common paraneoplastic syndromes that are likely to occur in the horse.     

Paraneoplastic limbic encephalitis

BACKGROUND: Polymorphonuclear elastase is an early and sensitive indicator of neonatal infection when performed at the beginning of clinical symptoms. PATIENTS AND METHODS: To investigate the diagnostic value of elastase measurement in cord blood immediately after birth, 211 neonates (103 boys vs 108 girls, 154 vaginal delivery vs 57 cesarean section). Mean gestational age 38.9 weeks (range: 30-42), mean birth weight 3,260 g (range: 1,430-4,920 g). After clinical, bacterial and biological screening, the infants were classified in three groups. Group A (n = 118): none infectious risk factor neither clinical signs of infection; group B (n = 79): one or more risk factors but no evidence of infection; group C (n = 14): proved or probable infection. Polymorphonuclear elastase was measured in cord blood of all infants using an heterogeneous enzyme-linked-immunosorbent assay. RESULTS: We observed higher elastase values in group C (176 +/- 67 micrograms/L) than in group A (91 +/- 64 micrograms/L) and B (67 +/- 61 micrograms/L) (mean +/- SD, P = 0.0001). With a cutoff value fixed at 80 micrograms/L, the sensitivity of this test applicated to neonates presenting materno-fetal infectious risk factor(s) was 85% (12/14), specificity 74% (59/79), positive predictive value 37%, and negative predictive value 96%. CONCLUSION: Because two of the 14 infected infants (15%) were not detected by elastase dosage in cord blood, this test cannot be used as an early indicator of materno-fetal infection.     

Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration (PCD) is a rare manifestation of cancer, characterized clinically by subacute progressive ataxia, dysarthria and nystagmus. The pathological hallmark of PCD is a severe, diffuse loss of Purkinje cells. PCD occurs most frequently in association with small cell carcinoma of the lung and adenocarcinoma of the ovary, but it has also developed in patients with carcinoma of the breast, malignant lymphoma, and various cancers. Autoantibodies against cerebellar Purkinje cells have been frequently observed in the serum or cerebrospinal fluid (CSF) from patients with PCD. The cause of PCD is unknown, but the presence of these autoantibodies in some patients suggests that the pathogenesis may be immune mediated. The potential role of the autoantibody in the pathogenesis of PCD is discussed.     

Paraneoplastic pemphigus with tracheobronchial involvement

BACKGROUND: Paraneoplastic pemphigus is a bullous skin disease with characteristic polymorphous clinical presentation and precise histological and immunological features. We report a case of paraneoplastic pemphigus associated with chronic lymphoid leukemia involving the tracheobronchial epithelium. CASE REPORT: A patient with chronic lymphoid leukemia developed pluriorificial lesions. There were several conjunctival, buccal and genital erosions associated with erosive plaques on the trunk, Nikolski's sign and bullous lesions suggestive of paraneoplastic pemphigus. Histology examination of a bulla showed intraepidermal blistering and suprabasal acantholysis. Direct immunofluorescence evidenced intercellular IgG and C3 deposits. Search for anti-intercellular substance antibodies was positive with fluorescence on specific paraneoplastic pemphigus substrates. At immunotransfer, the serum recognized several bands corresponding to 250, 230, 210 and 190 kD antigens, confirming the diagnosis of paraneoplastic pemphigus. Several days later, the patient's general condition deteriorated with bronchorrhea. Bronchial endoscopy visualized ulceronecrotic plaques. Tracheal biopsy evidenced acantholytic cells and intraepithelial cleavage. General corticosteroid therapy was initiated and led to improvement of the skin lesions but the patient died rapidly from pneumonia. Autopsy confirmed the presence of epithelial cleavage and acantholysis involving the trachea and bronchi. DISCUSSION: This case illustrates the difficulty of diagnosing paraneoplastic pemphigus in the early stages. The pluriorificial lesions were suggestive of a Stevens-Johnson syndrome. Besides the genital, conjunctival and buccal mucosa, other mucosa can be involved. In our case, despite the absence of an immunological element, histology was highly suggestive of specific tracheobronchial localizations. The presence of such lesions, which should be searched for in all cases with bronchopulmonary manifestations, worsens the prognosis.     

Paraneoplastic digital clubbing and hypertrophic osteoarthropathy

Previous work has shown that exposure to many non-mutagenic stresses causes greater UV resistance in Escherichia coli K12 via an error-free, excision repair-dependent process. Induction of the latter should enhance liquid holding recovery in the bacteria. The results in this paper show that this is the case and that the increased UV-resistance is due entirely to an increase in the capacity of the cells for DNA excision repair. The latter arises wholly or in part from an increase in the intracellular level of the key enzyme of the pathway, UvrABC endonuclease.     

Paraneoplastic pemphigus associated with Hodgkin''s disease

Highly emetogenic drugs such as cisplatin induce an increase in the urinary 5-hydroxyindoleacetic acid (5-HIAA) level, the main metabolite of serotonin (5-HT), within the first 24 h following a single infusion, thus providing a possible cause for acute emesis and an explanation for the action of 5-HT3 antagonists. No further excretion peaks have been observed, suggesting that additional or serotonin-independent mechanisms cause delayed emesis. Our aim was to study the mechanisms behind emesis seen during a highly emetogenic chemotherapy regimen given as a continuous infusion over several days. Seven women treated with a 4-day high-dose chemotherapy (HDCT) regimen for breast cancer entered the study. Pooled urine samples were collected prior to and during chemotherapy for determining 5-HIAA excretion. An excretion peak in the urinary 5-HIAA level was observed within the first 24 h with no further peaks thereafter. Thus, the mechanisms behind the emesis experienced during this highly emetogenic multiple-day chemotherapy regimen from days 2-3 onwards would appear to be at least partially serotonin independent and would not be expected to be completely relieved by 5-HT3 antagonists alone.     

Paraneoplastic syndromes affecting the nervous system

Paraneoplastic syndromes can affect virtually any portion of the nervous system. Most paraneoplastic syndromes are believed to be caused by an autoimmune reaction to an "onconeural" antigen shared by the cancer and the nervous system. The immune reaction may retard growth of the cancer, but it also damages the nervous system. Specific autoantibodies found in some individual paraneoplastic syndromes are usually associated with specific tumors. Neurological disorders, clinically and pathologically identical to paraneoplastic syndromes, may occur in some patients without cancer, but paraneoplastic antibodies are not found in these patients. The diagnosis of a paraneoplastic syndrome is based on its increased incidence in patients with cancer, the occasional response of the neurological syndrome to treatment of the underlying cancer, or the presence of specific autoantibodies. Some paraneoplastic syndromes respond to treatment of the underlying cancer or to immunosuppression but, for most syndromes, no effective treatment exists.     

Paraneoplastic cerebellar degeneration in Hodgkin's disease

HISTORY AND CLINICAL FINDINGS: A 30-year-old previously healthy man suddenly developed double vision, unsteady gait and some difficulty in speech articulation. Within 4 weeks he had become markedly ataxic, unable to walk, stand or sit down unaided. Neurological examination indicated a severe cerebellar syndrome. There were no other abnormal findings on physical examination. INVESTIGATIONS: There was no pleocytosis and no oligoclonal bands in cerebrospinal fluid (CSF). A test for anti-Purkinje cell antibodies was negative in both CSF and serum. Computed tomography and nuclear magnetic imaging (NMI) of the brain were normal. TREATMENT AND COURSE: As a para- or postinfectious or paraneoplastic process was suspected. I.v. immunoglobulin and oral corticosteroids were administered, but without improvement. 13 month later, a mediastinal mass was noted on a chest radiogram. This led to the diagnosis of a stage IA Hodgkin's disease. Retrospectively the cerebellar degeneration was most likely a paraneoplastic change related to the Hodgkin's disease. However, an independent second disease cannot be excluded. While the treatment of Hodgkin's disease was successful, the neurological symptoms remained unchanged. Severe cerebellar atrophy was demonstrated on NMI. CONCLUSION: In case of cerebellar atrophy of undetermined aetiology a paraneoplastic cause should be considered and an underlying malignant disease looked for.     

Paraneoplastic neurologic syndrome--neoplasms and neuroimmune system

Although the relationship between hyoid bone shape and fracture pattern figures prominently in forensic investigations of strangulation, few quantitative data exist on age and sex differences in hyoid morphology. An image analysis system was used to take a series of 30 measurements on digitized radiographs of 315 hyoid bones from people of known age and sex. The degree of fusion of the greater cornua to the hyoid body was also recorded. Statistical analysis of these data shows that there is a continuous distribution of hyoid bone shapes and the most bones are highly symmetrical. Based on smaller samples, previous researchers have suggested that non-fusion is more common in women than in men. In contrast, our data suggest that men and women have similar non-fusion rates. Analysis of sexual dimorphism shows that the greatest length differences are in the greater cornua. There are also significant sex differences in hyoid shape. For example, the distal ends of the greater cornua of women are significantly longer than those of men.     

Paraneoplastic syndromes in patients with ovarian neoplasia

The prevalence of several paraneoplastic syndromes associated with ovarian cancer was determined from a clinicopathological study of 908 patients with primary ovarian malignancy in the North East Thames Region. The diversity and rarity of these manifestations are great and the explanation for them is difficult. Circumstantial evidence suggests that in some cases an autoimmune phenomenon is the most plausible cause.     

Paraneoplastic cerebellar degeneration with asymmetrical pan-cerebellar syndrome

INTRODUCTION: Paraneoplasic cerebellar degeneration is seen clinically as a pancerebellar condition which is usually symmetrical. Different families of tumours are associated with this, particularly (in view of its frequency) oat cell pulmonary carcinoma, gynecological tumours and Hodgkin's lymphoma. CLINICAL CASE: Signs of cerebellar atrophy were seen on MR and cortical hypoperfusion was seen on Single Photon Emission Computerized Tomography (SPECT). We present the case of a 76 year old woman who presented with an asymmetrical pancerebellar disorder of gradual onset, with positive anti-self antibodies and undifferentiated carcinoma of the breast. CONCLUSIONS: Paraneoplasic cerebellar degeneration should be suspected in a patient with symmetrical, progressive cerebellar disease. The syndrome characteristically starts with a slightly uncoordinated gait. This progresses over a period of weeks or months to an ataxic gait with incoordination of the limbs, dysarthria and frequently nystagmus with oscilloscopy. No satisfactory treatment has been found for DCP in spite of trials with vitamins, corticosteroids, plasmapheresis and immunoglobulin infusion. Slight improvement may be seen after treatment of the primary tumour.     

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.     

Paraneoplastic cerebellar degeneration--characterization of anti-Yo antibody and underlying cancer

A group of patients with paraneoplastic cerebellar degeneration (PCD) have shown to produce autoantibody to both neurons and tumor cells (anti-Yo antibody). More than 60% of these patients have shown neurological symptoms and anti-Yo antibody production before the underlying cancers were found, which suggests that the test for anti-Yo antibody is important for the early detection and treatment of cancer. Originally, anti-Yo antibody has been characterized as 1) labelling the cytoplasm of cerebellar Purkinje cells immunohistochemically, 2) binding to the 62 and 34kDa bands on immunoblots of Purkinje cell extracts, 3) being present in female patients with gynecological or breast cancers. Recently, the common binding-epitope of anti-Yo antibody has been reported as leucine-zipper protein. In order to detect the anti-Yo antibody precisely, we examined the immunohistochemical and western blot characters of the recombinant leucine-zipper protein-reactive (anti-Yo) antibody. The results were, 1) sera containing leucine-zipper protein-reactive antibody labels both cerebellar Purkinje cells but some sera might contain other antibodies together with anti-Yo that confuse the immunostaining character of anti-Yo antibody, 2) the antibody binds to 58 kDa band and sometimes co-binds to 34kDa on immunoblots of cerebellar tissue extracts. The underlying cancers are mainly adenocarcinoma in the ovary, fallopian tube, uterus, or breast but occasionally large cel lung and bile duct cancers have been found. Interestingly, a male patient had an antibody similar in character to be anti-Yo antibody immunohistochemically and on immunoblots, that did not recognize leucine-zipper protein and the underlying carcinoma was small cell lung cancer. These results suggest that 1) the diagnosis of anti-Yo antibody should be based on the antibody's reactivity with leucine-zipper protein, 2) some sera with the anti-Yo antibody label other tissues besides the Purkinje cell cytoplasm because of the co-existence of other antibodies seen immunohistochemically and on immunoblots, 3) the search for underlying cancers should not be limited to gynecological or breast carcinomas.