Lambert-Eaton myasthenic syndrome associated with intravascular uterine leiomyoma

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neurologic disease with impaired transmission across neuromuscular junction [ 1 O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar , 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. 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) [ 1 O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar , 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. LEMS shares clinical features with myasthenia gravis; patients usually experience cranial, limb fluctuating weakness and autonomic signs [ 1 O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar , 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. Neurologic symptoms precede or concur with cancer diagnosis [ 1 O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar , 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. 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 [ 1 O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar , 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. 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 [ 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. 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 [ 2 Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar , 3 Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ]. 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 [ [4] Bodner-Adler B. Barti M. Wagner G. Intravenous leiomyomatosis of the uterus with pulmonary metastases or a case with benign metastazing leiomyoma?. Anticancer Res. 2009; 29: 495-496 PubMed Google Scholar ]. Interestingly, coexisting pulmonary and UL can exhibit identical immunohistochemical reactivity for estrogen, progesteron receptors supporting notion of monoclonal origin [ [4] Bodner-Adler B. Barti M. Wagner G. Intravenous leiomyomatosis of the uterus with pulmonary metastases or a case with benign metastazing leiomyoma?. Anticancer Res. 2009; 29: 495-496 PubMed Google Scholar ]. Paraneoplatic neurological syndromes previously associated with ovarian leiomyomas were polymyositis and epilepsy; both conditions resolved after tumour excision [ [5] Yumru A.E. Bozkurt M. Ayanoğlu Y.T. Ayhan I. Inci Coşkun E. Battal Havane S. The relation between the presence of a giant primary ovarian leiomyoma and the occurrence of epilepsy as a paraneoplastic syndrome. Arch Gynecol Obstet. 2010; 28: 531-534 Crossref Scopus (7) Google Scholar ]. Witz [ [3] Witz P.W. Wintzen A.R. Verschuuren J.J.G.M. Lambert-Eaton myasthenic syndrome has more progressive course in patients with lung cancer. Muscle Nerve. 2005; 32: 226-229 Crossref PubMed Scopus (41) Google Scholar ] reviewed 270 published cases of LEMS; 112 had pulmonary malignancies; 45 occurred with tumours not formerly associated with LEMS. O Neil [ [1] O Neil H. Murrat F M.F. Newsom Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988; 111: 577-586 Crossref PubMed Scopus (598) Google Scholar ] 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 [ [2] Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ] 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 [ [2] Pellkofer H.L. Armbruster L. Linke R. Schumm F. Voltz R. Managing non paraneoplastic Lambert-Eaton myasthenic syndrome: clinical characteristics of 25 German patients. J Neuroimmunol. 2009; 217: 90-94 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ]. 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 [ [5] Yumru A.E. Bozkurt M. Ayanoğlu Y.T. Ayhan I. Inci Coşkun E. Battal Havane S. The relation between the presence of a giant primary ovarian leiomyoma and the occurrence of epilepsy as a paraneoplastic syndrome. Arch Gynecol Obstet. 2010; 28: 531-534 Crossref Scopus (7) Google Scholar ]. 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 [ [5] Yumru A.E. Bozkurt M. Ayanoğlu Y.T. Ayhan I. Inci Coşkun E. Battal Havane S. The relation between the presence of a giant primary ovarian leiomyoma and the occurrence of epilepsy as a paraneoplastic syndrome. Arch Gynecol Obstet. 2010; 28: 531-534 Crossref Scopus (7) Google Scholar ]. 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.