Lambert-Eaton myasthenic syndrome associated with intravascular uterine leiomyoma

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neurologic disease with impaired transmission across neuromuscular junction [ , , ]. LEMS is thought to be caused by antibodies directed against presynaptic P/Q-type voltage-gated calcium channels (VGCC), most likely associated with small cell lung cancers (SCLC) [ , , ]. LEMS shares clinical features with myasthenia gravis; patients usually experience cranial, limb fluctuating weakness and autonomic signs [ , , ]. Neurologic symptoms precede or concur with cancer diagnosis [ , , ]. This 40 year old woman experienced (September 2006) dry mouth, fluctuating fatiguability. On examination, patient exhibited unreactive pupils, dysphonia, proximal and distal extremity weakness, abolished deep reflexes. Haematological screenings revealed only elevated cancer antigen 125 (60 U/ml, normal below 25). Chest X-rays, total body computed tomography were unremarkable; antibodies to onconeural antigens, muscletyrosinkinase, acetylcholine receptors were absent. 50 Hz repetitive nerve stimulation produced 200% increment of compound muscle action potential amplitude [ , , ]. 24-h ECG Holter monitoring and treadmill exercise test revealed altered autonomic balance. Patient was treated symptomatically with oral pyridostigmine bromide. Courses of intravenous immunoglobulin (IVIg, 2 g/kg/bw) were repeated without benefit. Oral prednisone (50 mg daily) was given for a year. In April 2009, patient experienced continued vaginal bleeding. Pelvic CT scans showed enlarged, multilobulated uterus with irregularly shaped submucosal mass 75 mm × 60 mm sized. Abdominal hysterectomy was performed. Dissection of uterine corpus revealed pale, spherical, firm nodules with distinct margins. Nodule sections demonstrated aggregates of whorled anastomosing fascicles of spindle-shaped cells, with abundant eosinophilic cytoplasm, fusiform nuclei with fine chromatin, without nuclear atypia. Dilated, slit-like spaces were noted in the myometrium. Mitotic index was low (less than 1 per 10 high-power fields) and labelling index defined by MIB1 immunostaining was less than 1%. Immunohistochemical staining for CD31 revealed that the intravascular tumour mass was covered with single layer of endothelial cells (Fig. 1a and b ). Spindle cells showed immunopositivity for vimentin and smooth muscle actin. Estrogen and progesterone receptors were diffusely, strongly positive through the entire mass. The tumour was classified as uterine leiomyoma (UL) with microscopic intravascular growth. On follow up, 16 months after surgery, patient limb weakness had improved greatly; 50 Hz RNS and 24-h Holter showed normal findings. A second malignancy in lungs or elsewhere was excluded by serial CT-scans. Paraneoplastic neurological syndromes are remote effects of cancer not caused by metastasis [ , ]. According to recommended diagnostic criteria, detection of onconeural antibodies is not required if a classical syndrome and a cancer develop within 5 years after neurological onset [ , ]. Intravascular UL are rare, histologically benign smooth muscle tumours, characterized by intraluminal growth in venous vessels; intravascular UL are capable of metastasizing distantly to lungs [ ]. Interestingly, coexisting pulmonary and UL can exhibit identical immunohistochemical reactivity for estrogen, progesteron receptors supporting notion of monoclonal origin [ ]. Paraneoplatic neurological syndromes previously associated with ovarian leiomyomas were polymyositis and epilepsy; both conditions resolved after tumour excision [ ]. Witz [ ] reviewed 270 published cases of LEMS; 112 had pulmonary malignancies; 45 occurred with tumours not formerly associated with LEMS. O Neil [ ] argued that antigenic determinant on cancer cells may initiate an autoimmune response but association of LEMS with tumours other than SCLC may be fortuitous. Pellkofer [ ] addressed the issue of non paraneoplastic LEMS; 23 of their 25 patients had no cancer detected within period of 4–17 years after diagnosis, whereas 2 suffered from an histologically confirmed tumour, one oesophageal and the other one cervix carcinoma. Both were not considered paraneoplastic because they did not occur within 5 years and did not improved after cancer therapy [ ]. Insuline-like growth factors (IGFs) are polypeptides exhibiting a role in cellular, somatic growing; IGFs regulate steps of angiogenesis in uterine vascular adaptation during pregnancy and in UL [ ]. In UL as in some lung cancers, overexpression of IGFs regulate metastasis cascade, invasion, transformation of benign and malignant smooth muscle cell; the role of IGFs in paraneoplastic syndromes deserves attention [ ]. We hypothesize that an antigenic similarity exists between UL and some lung cancers, which makes both potentially capable of triggering the same type of paraneoplastic syndrome, in this case LEMS. The fact that UL resection was associated with clinical improvement suggests a relationship between tumour and LEMS, as well as the absence of a second malignancy 5 years after the neurological onset. Based on indolent behavior of UL, it is possible that a small neoplasm was already present at onset of LEMS in our patient. Our report alerts physicians to detect and treat occult cancers in patients with LEMS.