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A paraneoplastic syndrome is a phenomenon or complex of symptoms that can occur with malignancy, without this being the result of tumour cells in the affected area. In this article, we describe the following paraneoplastic syndromes: thrombophlebitis migrans, clubbing, pemphigus, acanthosis nigricans, blue fingers, dermatomyositis, and myasthenia gravis.

Dermatomyositis is an idiopathic inflammatory myopathy with an incidence of 1 in 100,000. Clinically, it features typical skin abnormalities and muscle weakness. In a subset of cases an underlying malignancy may be present; in such instances the term paraneoplastic syndrome is used.We saw a 75-year-old male with progressive skin abnormalities, especially on the chest and hands. In addition, he experienced weakness in his arms and legs. Three months earlier, he was diagnosed with prostate cancer. Following additional investigations, the diagnosis of dermatomyositis was made and treatment with prednisone proved successful.In a patient with typical skin abnormalities one should consider dermatomyositis and it is important to investigate for the presence of muscle disorders and occult malignancy. The muscle symptoms often respond well to prednisone, but the skin abnormalities are usually harder to resolve, Treatment of a possible underlying malignancy also influences the dermatomyositis.

Asteatotic eczema is rarely associated with an underlying malignancy. The condition as paraneoplastic syndrome is characterised by glucocorticoid resistance.A 66-year old woman came to the emergency room with symptoms of dehydration resulting from diarrhoea due to cyclosporine therapy for treatment-resistant eczema. CT scan of thorax and abdomen showed multiple, pathologically enlarged lymph nodes. Histological examination of a lymph node biopsy from the right axilla showed an ALK-negative, anaplastic large T-cell lymphoma.Asteatotic eczema is usually innocuous but may also be linked to malignancy. A careful physical examination and early referral to second-line care are needed for rapid diagnosis and treatment of the underlying condition.

Establishing the presence of paraneoplastic antibodies is important in identifying an often severe neurological syndrome as paraneoplastic and hence directing the search for an underlying neoplasm. A paraneoplastic neurological syndrome was diagnosed in 3 patients. The first was a 64-year-old woman in whom paraneoplastic encephalomyelitis was diagnosed. The diagnosis was strongly supported by a high titre of serum anti-Hu antibodies, despite three negative biopsies from a mediastinal mass. The patient died of a non-convulsive status epilepticus; autopsy revealed not only paraneoplastic encephalomyelitis but also small-cell lung cancer. The second patient was a 55-year-old woman with metastatic breast cancer. After a three-year period of progressive neurological deterioration, a high titre of anti-CV2/CRMP5 antibodies was detected, on the basis of which the clinical syndrome was diagnosed as paraneoplastic. She received immunotherapy and her condition stabilised. The third patient, a 41-year-old man, presented with severe limbic encephalitis. Biopsy from a paraaortic mass was positive for undifferentiated carcinoma. The patient had a high titre ofanti-Ma2 antibodies and was subsequently tested positive for serum alpha-foetoprotein (AFP) and beta-human-chorionic gonadotrophin (bta-HCG). During chemotherapy for a non seminoma testicular cancer, the limbic encephalitis improved both clinically and radiologically, but the patient died as a result of the toxicity of the treatment.

Autoimmune retinopathy (AIR) is a rare disorder which may present as a paraneoplastic syndrome. AIR is associated with the presence of anti-retinal antibodies. These antibodies are assumed to cause damage to the retina, resulting in progressive vision loss.A 74-year-old man visited the ophthalmologist with a serious, progressive loss of vision, without any noteworthy abnormalities at routine ophthalmological examination. The electroretinogram was characteristic of loss of photoreceptor function. Anti-retinal antibodies against recoverin were detected in serum. After referral to an internist on account of a suspected diagnosis of paraneoplastic AIR, the patient was diagnosed with a lung carcinoma, confirming the diagnosis of cancer-associated paraneoplastic AIR.An unexplained loss of vision is highly suggestive of paraneoplastic AIR, even in patients without a known malignancy. Laboratory techniques for the detection of the anti-retinal antibody against recoverin have recently been implemented in the Netherlands, facilitating the diagnosis of AIR.

Paraneoplastic dermatoses may be the first manifestation of a malignancy. Rapid recognition is therefore important.A 72-year-old woman who had been treated in the past for metastasised neuroendocrine carcinoma and had undergone curative treatment for stage-1c endometrial carcinoma developed three paraneoplastic dermatoses over a 2-year period: acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa. Half a year later, cutaneous metastases derived from the endometrial carcinoma treated 12 years prior were discovered.The development of three paraneoplastic dermatoses in a short period of time is rare. Acanthosis nigricans, tripe palms and acquired hypertrichosis lanuginosa can develop in association with both neuroendocrine and endometrial carcinoma. The sudden development of paraneoplastic dermatoses is frequently a forewarning of progression of the malignancy.

A thymoma arises from the epithelial cells of the thymus. Local tumour growth may cause symptoms like coughing, dyspnoea or chest pain. Paraneoplastic phenomena can also occur in patients with a thymoma; myasthenia gravis is a well-known example. Other neurological, dermatological, cardiological and haematological disorders are not always recognised as being paraneoplastic phenomena. There is no clear relationship between tumour activity and the clinical course of paraneoplastic phenomena. The three cases in this article illustrate how the clinical presentation of these phenomena can vary.

A 53-year-old man with non-Hodgkin lymphoma developed red, flaky skin, which was initially suggestive of a drug reaction. He also had pneumonia, for which he was admitted for antibiotic treatment. During admission the skin picture changed and blisters and erosions appeared on his body. Skin biopsy and immunological examination led to the diagnosis of paraneoplastic pemphigus (PNP). The patient died five months after the diagnosis of PNP due to PNP pneumonia. PNP is a rare and often aggressive bullous disease with an autoimmune pathogenesis, associated with underlying lymphoproliferative disease. It is characterised by a polymorphous skin rash, painful mucosal erosions, sometimes with respiratory complications due to bronchiolitis obliterans. Diagnosis is based on clinical, histological and immunological findings. The prognosis is unfavourable; death occurs in 90 percent of patients. This case illustrates the importance of histology, immunofluorescence microscopy, and immunoserology in misunderstood skin disorders in patients with lymphoproliferative disease.

A 53-year-old man with non-Hodgkin lymphoma developed red, flaky skin, which was initially suggestive of a drug reaction. He also had pneumonia, for which he was admitted for antibiotic treatment. During admission the skin picture changed and blisters and erosions appeared on his body. Skin biopsy and immunological examination led to the diagnosis of paraneoplastic pemphigus (PNP). The patient died five months after the diagnosis of PNP due to PNP pneumonia. PNP is a rare and often aggressive bullous disease with an autoimmune pathogenesis, associated with underlying lymphoproliferative disease. It is characterised by a polymorphous skin rash, painful mucosal erosions, sometimes with respiratory complications due to bronchiolitis obliterans. Diagnosis is based on clinical, histological and immunological findings. The prognosis is unfavourable; death occurs in 90 percent of patients. This case illustrates the importance of histology, immunofluorescence microscopy, and immunoserology in misunderstood skin disorders in patients with lymphoproliferative disease.

A 53-year-old man with non-Hodgkin lymphoma developed red, flaky skin, which was initially suggestive of a drug reaction. He also had pneumonia, for which he was admitted for antibiotic treatment. During admission the skin picture changed and blisters and erosions appeared on his body. Skin biopsy and immunological examination led to the diagnosis of paraneoplastic pemphigus (PNP). The patient died five months after the diagnosis of PNP due to PNP pneumonia. PNP is a rare and often aggressive bullous disease with an autoimmune pathogenesis, associated with underlying lymphoproliferative disease. It is characterised by a polymorphous skin rash, painful mucosal erosions, sometimes with respiratory complications due to bronchiolitis obliterans. Diagnosis is based on clinical, histological and immunological findings. The prognosis is unfavourable; death occurs in 90 percent of patients. This case illustrates the importance of histology, immunofluorescence microscopy, and immunoserology in misunderstood skin disorders in patients with lymphoproliferative disease.

A 14-year-old neutered female cat was presented for a second opinion regarding hair loss, anorexia, and lethargy. Examination revealed alopecia of the ventral chest, abdomen, axilla, and groin. The footpads were encrusted. The liver was enlarged and nodular. Investigation revealed an enlarged liver with multiple nodules, and small and atrophic hair follicles. Paraneoplastic alopecia due to hepatocellular carcinoma was diagnosed and subsequently confirmed postmortem.

A 65-year-old woman was referred with a mass in the right popliteal fossa, fever and leucocytosis reaching 105 x 10(9)/l. Her medical history included the excision of a melanoma from the right ankle more than 20 years before. Ultrasound, CT and positron-emission tomography showed the mass in the right knee but no other lesions. The process was drained. Histological examination ofa subcutis biopsy indicated malignancy. Due to deterioration in her clinical condition amputation of the right leg was performed after which her leucocyte count normalized. The pathology specimen revealed a high-grade undifferentiated soft tissue tumour of unclear origin. Preoperatively assessed serum levels of granulocyte-stimulating factor (G-CSF), interleukin 6 and interleukin 8 were elevated to 241, 91 and 82 pg/ml respectively. After the amputation these levels returned to almost normal. This extreme leucocyte count may be explained by a paraneoplastic leukemoid reaction. It is hypothesized that the tumour cells produce G-CSF and other cytokines causing leucocytosis. Normalisation of the cytokine levels postoperatively supports this hypothesis.

Establishing the presence of paraneoplastic antibodies is important in identifying an often severe neurological syndrome as paraneoplastic and hence directing the search for an underlying neoplasm. A paraneoplastic neurological syndrome was diagnosed in 3 patients. The first was a 64-year-old woman in whom paraneoplastic encephalomyelitis was diagnosed. The diagnosis was strongly supported by a high titre of serum anti-Hu antibodies, despite three negative biopsies from a mediastinal mass. The patient died of a non-convulsive status epilepticus; autopsy revealed not only paraneoplastic encephalomyelitis but also small-cell lung cancer. The second patient was a 55-year-old woman with metastatic breast cancer. After a three-year period of progressive neurological deterioration, a high titre of anti-CV2/CRMP5 antibodies was detected, on the basis of which the clinical syndrome was diagnosed as paraneoplastic. She received immunotherapy and her condition stabilised. The third patient, a 41-year-old man, presented with severe limbic encephalitis. Biopsy from a paraaortic mass was positive for undifferentiated carcinoma. The patient had a high titre ofanti-Ma2 antibodies and was subsequently tested positive for serum alpha-foetoprotein (AFP) and beta-human-chorionic gonadotrophin (bta-HCG). During chemotherapy for a non seminoma testicular cancer, the limbic encephalitis improved both clinically and radiologically, but the patient died as a result of the toxicity of the treatment.

Establishing the presence of paraneoplastic antibodies is important in identifying an often severe neurological syndrome as paraneoplastic and hence directing the search for an underlying neoplasm. A paraneoplastic neurological syndrome was diagnosed in 3 patients. The first was a 64-year-old woman in whom paraneoplastic encephalomyelitis was diagnosed. The diagnosis was strongly supported by a high titre of serum anti-Hu antibodies, despite three negative biopsies from a mediastinal mass. The patient died of a non-convulsive status epilepticus; autopsy revealed not only paraneoplastic encephalomyelitis but also small-cell lung cancer. The second patient was a 55-year-old woman with metastatic breast cancer. After a three-year period of progressive neurological deterioration, a high titre of anti-CV2/CRMP5 antibodies was detected, on the basis of which the clinical syndrome was diagnosed as paraneoplastic. She received immunotherapy and her condition stabilised. The third patient, a 41-year-old man, presented with severe limbic encephalitis. Biopsy from a paraaortic mass was positive for undifferentiated carcinoma. The patient had a high titre ofanti-Ma2 antibodies and was subsequently tested positive for serum alpha-foetoprotein (AFP) and beta-human-chorionic gonadotrophin (bta-HCG). During chemotherapy for a non seminoma testicular cancer, the limbic encephalitis improved both clinically and radiologically, but the patient died as a result of the toxicity of the treatment.

Renal cell carcinoma was diagnosed in three male patients, 45, 53 and 52 years of age. In addition, they had paraneoplastic symptoms: hypercalcaemia, hyperglycaemia and elevated hepatic enzyme levels, respectively. All three patients underwent tumour nephrectomy, after which the paraneoplastic symptoms disappeared. The first patient died 16 months postoperatively, while the other two were alive and free of symptoms after a follow-up of nine months and four years, respectively. Many patients with renal cell carcinoma remain asymptomatic for a long period of time and 30% of all patients have metastatic disease at the time of diagnosis. The classic triad of flank pain, haematuria and an abdominal mass occurs in only 10% of all cases. However, 20-40% of all patients present with signs of a paraneoplastic syndrome, of which anaemia (20-40%), fever (30%), hypertension (24%), hypercalcaemia (10-15%) and hepatic dysfunction (3-6%) are the most common.

A 59-year-old man presented with polyarthritis and noduli on fingers and buccal mucous membrane due to multicentric reticulohistiocytosis. This was a paraneoplastic manifestation of a renal cell carcinoma, and regression of noduli was seen after nephrectomy.

In two patients, women aged 73 and 46 years, gastrointestinal symptoms were initially not recognised as a paraneoplastic syndrome due to small-cell lung cancer. This led to redundant diagnostics as well as a delay in final diagnosis. The anti-Hu syndrome is characterised by the presence of anti-Hu antibodies and neurological symptoms. About a quarter of the patients with the anti-Hu syndrome will develop gastrointestinal motility disorders in the course of their illness. The primary tumour is usually a small-cell lung cancer. Whereas the presence of anti-Hu antibodies appears to be beneficial for the oncological prognosis, the neurological outcome is less favourable.

A 13-year-old girl and a 3-year-old boy presented with the clinical symptoms of nephrotic syndrome. Both patients developed a nodular mass in the cervical region, which appeared to be due to Hodgkin's disease. The renal disease was a paraneoplastic phenomenon of Hodgkin's disease. Chemotherapy given for Hodgkin's disease also cured the nephrotic syndrome. A few years later one of the patients experienced a recurrent episode of nephrotic syndrome in conjunction with a recurrence of Hodgkin's disease but this was once again treated successfully. Nephrotic syndrome is a known but rare paraneoplastic syndrome accompanying Hodgkin's disease. It is thought that T cell dysfunction leads to a secretion of cytokines which alters the permeability of the glomerular basement membrane. This dysfunction is not only apparent during the period of active disease and this could clarify why paraneoplastic syndrome can exist or recur outside the period in which the malignancy is overt. The clear recognition of a paraneoplastic syndrome is important, as it is often only necessary to treat the malignancy.

Paraneoplastic neurological syndromes are believed to result from ectopic expression of onconeural antigens by tumours. The resulting immune response is not only directed against the tumour but also cross-reacts with the same or similar antigens in the nervous system. The immune response generates high titred autoantibodies that are associated with specific tumours and neurological syndromes. Paraneoplastic autoantibodies help diagnose neurological syndromes and help direct the search for an underlying tumour. In paraneoplastic syndromes, the course of the tumour is relatively mild. Detection of the autoantibodies might lead to early diagnosis and immunomodulation and anti-tumour treatment before irreversible neuronal cell loss and deficits set in.

Bilateral acute lower limb ischaemia is rare. Usually the diagnosis is based on clinical findings. In four patients, three women aged 51, 48, and 72 and a man aged 64 years, bilateral acute ischaemia of the lower limbs was diagnosed, due to different causes: arterial cardiac myxoma embolism, arterial thrombosis probably due to paraneoplastic coagulopathy, aortic dissection, and arterial thrombosis due to cardiac insufficiency, respectively. The management of these conditions includes restoring the circulation as soon as possible. Reperfusion can be achieved by thromboembolectomy or thrombolysis. In patients with underlying atherosclerosis angiography is useful, but time loss must be avoided. The outcome in patients with bilateral ischaemia of the lower limbs depends on the preoperative ischaemia time and the cardiac situation. The mortality varies between 20 and 50%.

So many conditions, both hereditary and acquired, can lead to polyneuropathy that a systematic approach is needed to identify the cause. Finding a cause is necessary to inform the patient about prognosis, handicap and chances of treatment. Three patients with polyneuropathy are described. The first was a man aged 34 with a predominantly motor neuropathy who appeared to have a duplication in the pmp-22 gene on chromosome 17PII.2. The diagnosis was hereditary sensorimotor neuropathy type IA (hypertrophic form of Charcot-Marie-Tooth disease). The second was a woman of 58 years; she had a sensory polyneuropathy as the first manifestation of Hodgkin's disease. The last patient, a 67-year-old man, had polyneuropathy due to vasculitis. He showed a prompt response to treatment.

A 64-year-old former civil servant consulted his general practitioner because of severe fatigue. Later he began to lose weight and gradually developed chronic sensorimotor polyneuropathy characterized by sensory nerve loss which started in his legs. After a year he needed a wheel chair and developed cachexia. IgG paraprotein was detected. Morbid-anatomical examination of enlarged supraclavicular lymph nodes revealed plasma cell angiofollicular hyperplasia, characteristic of Castleman's disease. Treatment with corticosteroids led to marked improvement of the patient's condition. He was able to walk again, using an ankle orthosis on both legs.

Lambert-Eaton myasthenic syndrome was diagnosed in three patients, two men aged 55 and 57 and one woman aged 66 years. After a variable time interval a small cell carcinoma of the lung was detected in all three patients. Two already had metastases outside the thorax and died, the other patient was doing well after treatment with chemotherapy and radiotherapy. The short survival of patients with a small cell carcinoma requires early diagnosis, and paraneoplastic phenomena such as the Lambert-Eaton myasthenic syndrome can be the earliest presenting sign. The syndrome can be diagnosed by electromyography.

Dementia is a frequent cause of mental or cognitive impairment in elderly patients. Sometimes elderly patients are unjustly diagnosed as being demented. Two such cases are reported in this article. Both patients were referred to a geriatric outpatient clinic with a diagnosis of dementia. The first patient had auditory hallucinations as a feature of a presumed paraneoplastic syndrome. The other patient experienced auditory agnosia as a result of an as yet unrecognized stroke. To recognize supposed dementia a thorough anamnesis and clinical evaluation are a prerequisite and often indicative of the correct diagnosis.

To inventory neurological complications in patients with cancer.Descriptive study.University Hospital Vrije Universiteit, Amsterdam.Data were collected from 718 neurological consultations with 610 admitted oncological patients from 1990 to 1992.In 203 cases backache, sometimes radiating to the leg, prompted the request for neurological consultation. In 142 cases a metastasis in the vertebrae could be detected; in 64 cases there were signs and/or symptoms of compression. Cerebral metastasis occurred in 133 patients in which eventuality neurological dysfunctions were the main initial manifestations. In all, 32 cases of leptomeningeal metastasis were diagnosed, mostly associated with carcinoma of the breast or haematological system. In 30 cases there was growth of a primary tumour or metastasis into a plexus or peripheral nerve. Non-metastatic complications consisted of paraneoplastic, iatrogenic and other (mostly metabolic or toxic encephalopathy) causes. A paraneoplastic complication was seen in only 6 cases. Iatrogenic complications were most frequently caused by cytotherapy.Numerous neurological complications can occur in patients with cancer. Timely treatment of metastatic complications can prevent serious disablement in a terminal stadium of the disease.

A 53-year-old man with non-Hodgkin lymphoma developed red, flaky skin, which was initially suggestive of a drug reaction. He also had pneumonia, for which he was admitted for antibiotic treatment. During admission the skin picture changed and blisters and erosions appeared on his body. Skin biopsy and immunological examination led to the diagnosis of paraneoplastic pemphigus (PNP). The patient died five months after the diagnosis of PNP due to PNP pneumonia. PNP is a rare and often aggressive bullous disease with an autoimmune pathogenesis, associated with underlying lymphoproliferative disease. It is characterised by a polymorphous skin rash, painful mucosal erosions, sometimes with respiratory complications due to bronchiolitis obliterans. Diagnosis is based on clinical, histological and immunological findings. The prognosis is unfavourable; death occurs in 90 percent of patients. This case illustrates the importance of histology, immunofluorescence microscopy, and immunoserology in misunderstood skin disorders in patients with lymphoproliferative disease.