Disseminated intravascular carcinomatosis, primary tumour never definitely identified Dr. Marian Malone Great Ormond Street Children's Hospital London WC1N 3JH, UK

Case History: A 13 year-old girl of Turkish background who was previously well presented to her local hospital in December 2005 with a 3 week history of severe, then moderate, left-sided headaches. These were associated with ataxia, slurred speech and progressive left lower limb weakness and a one week history of chorea. On examination, fundoscopy and cranial nerves were normal. She had choreiform movements, dysarthria, ataxic gait, power 4/5 and hemireflexia on the left. Full blood count, erythrocyte sedimentation rate C-reactive protein, anti-nuclear antibody, anti-streptolysin O titre and thyroid function tests were normal. Magnetic resonance imaging showed multiple white matter lesions in the cerebral hemispheres and infratentorially. A diagnosis of acute demyelinating encephalomyelitis (ADEM)) was made and she was treated with intravenous methylprednislone for 3 days followed by oral prednisolone. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer In January 2006 she presented to Great Ormond Street with headaches, confusion and deterioration in her speech. MRI showed new white matter lesions and a diagnosis of recurrence of ADEM was made. She was again treated with i.v. methylprednisolone then oral prednisolone. In March 2006, she complained of pain in her feet and lower legs, cold feet which had been progressing over two months, four episodes of epistaxis over one week and headaches. In retrospect at her initial presentation to her local hospital, she had a cold, pale pulseless right foot. She had no neurological symptoms apart from residual word-finding difficulties Examination showed cool feet with pulses present but difficult to feel. She had a new end-systolic murmur, maximum at the apex. She had systolic hypertension with pressures of 130 and 120 in the right and left upper limbs respectively and 60 and 80 in the right and left lower limbs. Respiratory, abdominal and neurological examinations were normal. Echocardiography showed a large vegetation on the mitral valve. She had a lymphopenia with a relatively low platelet count, low fibrinogen and raised D-dimers with a normal coagulation screen. She developed sustained hypertension and renal ultrasound scan showed a small left kidney which was poorly functioning on DMSA scan. Rheumatoid factor and anti-nuclear antibody were weakly positive. Chest X-ray was suggestive of hilar lymphadenopathy. Computerised tomography showed bilateral hilar lymphadenopathy, a small right pleural effusion, focal consolidation in the right lower lobe and a 1cm nodule in the basal segment of the right lower lobe. Quantiferon gold test for tuberculosis was positive and repeated Mantoux tests were positive. Her mother was known to have had TB in 1998.A biopsy of lung and pleura and sampling of the pleural effusion were carried out. Histopathology Cytological examination of the pleural effusion shows numerous reactive mesothelial cells admixed with enormous signet ring-like cells, with eccentric pleomorphic nuclei and central vacuolar clearing of the cytoplasm. The features are of a malignant pleural effusion. The lung biopsy shows essentially normal architecture with no abnormal infiltration of airspaces and no pneumonia.. However, numerous vessels are occluded by predominantly eccentric organising, apparent thrombotic areas, affecting both veins and arteries while large artery branches contain intraluminal clumps and clusters of pleomorphic cells with vesicular nuclei, prominent nucleoli and eosinophilic cytoplasm. In places these clumps of large abnormal cells are admixed with organising thrombus with lymphocytes and fibroblasts. An elastin stain shows eccentric intimal thickening of the pulmonary vessels. Immunohistochemical staining shows the abnormal intravascular cells to strongly express pancytokeratin (MNF 116). Staining for S 100, CD31, CD34, factor V1III- related antigen, CD 20 and CD 3 is negative. The features are highly suggestive of a disseminated malignant intravascular epithelial tumour (carcinoma). The pleural biopsy shows marked dense fibroblastic proliferation with areas of hylalinosis, macrophages, concentric abnormal calcifications and scattered signet ring-type cells. Immunostaining shows a similar phenotype with the large pleomorphic cells showing strong cytokeratin positivity The overall features are highly suggestive of disseminated malignancy, probable carcinoma,, likely adenocarcinoma. It is not possible to determine with any degree of certainty on such material the origin of the tumour, but breast carcinoma would be high on the list of differentials. Clinical course An entire body PET scan was carried out which was negative apart from a strongly avid nodule in the basal segment of the right lower lobe. This was presumed to be the primary tumour. She was transferred for palliative care to the Adolescent Oncology Unit at University College London Hospital . Palliative chemotherapy was commenced with Cisplatin and Etoposide. A Doppler ultrasound scan of the left leg showed no evidence of deep vein thrombosis. The differential blood pressure improved over time. She developed anorexia and lethargy. In May 2006, she developed a sudden right hemiplegia and aphasia. CT scan and MRI scan showed a "cerebrovascular accident". She became confused, and developed a contralateral lack of movement. At no time did she suffer from respiratory symptoms. She became anuric and died. Permission for autopsy was refused. Discussion Acute demyelinating encephalomyelitis. This is a rare condition of which there are no case reports in children. Adult cases have been described as a para-neoplastic phenomenon associated with leukaemia, non-Hodgkin's lymphoma, seminoma and adenocarcinoma of the lung. The pathology: is of sharply demarcated plaques of demyelination with no associated malignant infiltration. There is perivascular lymphocytic cuffing. Diagnosis:is by MRI. Acute multiple sclerosis should be excluded by searching for oligoclonal bands in CSF. Anti-neuronal antibodies are negative (when reported). An alternative explanation of the cerebral syndrome in the present case might be the presence of intravascular tumour thrombi similar to those seen in the lung. Differential diagnosis on the lung biopsy Epithelioid haemangioendothelioma. 80% of cases are reported in women. The age range is 12-61 years, mean 36 years. Clinical presentation,is indolent and half the patients are asymptomatic. It may rarely present as thromboembolic disease and may present as a solitary lung mass. The characteristic presentation is with multiple small bilateral lung nodules. Histopathological examination shows lung nodules with central sclerotic hypocellular zones and a cellular periphery. The centre can be calcified. Extensive lymphatic spread is characteristic. The intercellular stroma consists of abundant hyaline matrix. Intracellular vacuoles are common giving a signet- ring appearance. Tumour cells express CD31, CD34 and Factor VIII. Focal cytokeratin expression is seen in 20-30% of cases. Intravascular lymphomatosis. This is an uncommon variant of large cell lymphoma. Most patients are middle-aged or elderly although a congenital case has also been reported. Patients usually present with symptoms attributable to involvement of the skin or CNS. CNS involvement usually presents as confusing bizarre and non-specific neurological symptoms. Any organ or system can be involved. Histologically the key feature is filling of the lumina of small and intermediate –sized blood vessels by non-cohesive large atypical mononuclear cells. This can lead to multi-site infarction of many organs. Tumour cells usually possess round nuclei, vesicular chromatin, multiple prominent nucleoli and a moderate rim of amphophilic cytoplasm. Mitoses can often be seen. Tumour cells tend to be enmeshed in fibrin or platelet thrombi. Blood vessels can become thrombosed. Immunhistochemically almost all cases are of B-cell lineage. Disseminated melanoma is excluded in this case by negative immunostaining for S 100. Discussion point It is regrettable that an autopsy was not performed. The complexity of presentation and the challenge of establishing a diagnosis, even to the partial extent that was achieved, provide an exceptional "teaching case" in which a definitive pathological diagnosis was never established. An autopsy would have provided the best opportunity for doing so. In addition other ancillary questions might well have been answered. Final diagnosis Disseminated intravascular carcinomatosis, primary tumour never definitely identified.