CASE REPORT

The Clinical Respiratory Journal

Lung squamous carcinoma with two paraneoplastic syndromes: dermatomyositis and Lambert–Eaton myasthenic syndrome Yuanrong Dai1, Ping Li2, Sunshun Yan1, Xiaodong Xia1, Zhixiong Li3 and Mengling Xia1 1 Department of Respiratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China 2 Department of Respiratory Medicine, The People’s Hospital of Yichun City, Yichun, China 3 Department of Respiratory Medicine, Xiaoshan No. 1 People’s Hospital, Hangzhou, China

Abstract Background and Aim: Paraneoplastic syndrome is a disease or symptom that is the consequence of cancer in the body but, unlike mass effect, is not due to the local presence of cancer cells. An overlap of two paraneoplastic syndromes secondary to lung cancer in a patient is very rare. In order to improve the diagnosis of two paraneoplastic syndromes secondary to lung cancer, we reported an overlap of two paraneoplastic syndromes secondary to lung squamous carcinoma in a patient. Methods: We reported a case of a 60-year-old male smoker who presented multiple erythematous lesions for 6 months with progressive proximal muscular weakness, and developed to dysphonia in 2 months. His chest computed tomography showed a spiculate pulmonary nodule near the hilar in the right upper lobe and mediastinal lymph nodes enlargement. Lung biopsy showed squamous cell carcinoma. The patient’s blood test revealed elevated creatine kinase levels. Electromyography results were consistent with moderate myopathy accompanied with a pattern suggestive of Lambert–Eaton myasthenic syndrome. Results: So we made the diagnosis of an overlap of two paraneoplastic syndromes (dermatomyositis and Lambert–Eaton myasthenic syndrome) secondary to lung squamous carcinoma. Conclusion: Recognition of paraneoplastic syndrome is crucial for early diagnosis of lung cancer because up to 80% of patients may present paraneoplastic syndromes before any other direct indication of malignancy. Early diagnosis and treatment of paraneoplastic syndrome is also important because delayed diagnosis may result in rapid disease progression and irreversible neurological damage. Please cite this paper as: Dai Y, Li P, Yan S, Xia X, Li Z and Xia M. Lung squamous carcinoma with two paraneoplastic syndromes: dermatomyositis and Lambert– Eaton myasthenic syndrome. Clin Respir J 2014; ••: ••–••. DOI:10.1111/crj.12229.

Conflict of interest We declared that we have no financial and personal relationships with other parties or organizations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in any product, service and/or company

that could be construed as influencing the position presented in, or the review of, the manuscript entitled, ‘Lung squamous carcinoma with two paraneoplastic syndromes: dermatomyositis and Lambert–Eaton myasthenic syndrome’.

Introduction Lung cancer is the most common cause of cancerrelated death in men and women. Paraneoplastic syn-

Key words dermatomyositis – Lambert–Eaton myasthenic syndrome – lung squamous carcinoma – paraneoplastic syndromes Correspondence Yuanrong Dai, MD, Department of Respiratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, Wenzhou 325027, China. Tel: +86 05 7788002724 Fax: +86 05 7788832693 email: [email protected] Received: 13 June 2014 Revision requested: 13 September 2014 Accepted: 13 October 2014 DOI:10.1111/crj.12229 Authorship and contributorship Yuanrong Dai and Sunshun Yan: Designed the study and performed the study, collected and analyzed the data and wrote the paper. Ping Li and Xiaodong Xia: Performed the study, collected and analyzed data and wrote the paper. Zhixiong Li: Designed the study, contributed important reagents and wrote the paper. Mengling Xia: Designed and performed the study, contributed important reagents and analyzed data. Ethics The study was approved by local ethics review committees, and the patient gave informed consent.

drome is a disease or symptom that is the consequence of cancer in the body but, unlike mass effect, is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors (by hormones or

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 1 © 2014 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Figure 1. Computed tomography of the chest showing a spiculate pulmonary nodule near hilar in the right upper lung lobe with mediastinal lymph nodes clumps.

cytokines) excreted by tumor cells or by an immune response against the tumor. But an overlap of two paraneoplastic syndromes secondary to lung cancer in a patient is very rare. We reported a clinical case of a patient with lung squamous carcinoma who had concomitant dermatomyositis (DM) and Lambert–Eaton myasthenic syndrome (LEMS).

Case report A 60-year-old male patient was admitted to the second affiliated Hospital of Wenzhou Medical University because his chest computed tomography (CT) showed a spiculate pulmonary nodule near the hilar in the right upper lung lobe and mediastinal lymph nodes enlargement. He worked at a power plant and had a smoking history of 40 pack-year. The patient had unexplained weight loss (10 kg) in the past 6 months. Six months ago, he noticed that his right leg was covered with erythematous lesion along with abnormal pain and itchy. The same erythematous rash spreaded to other places of the body, including face, shoulder, neck, anterior chest (in a ‘V’ shape), posterior neck and back area. Then he went to a clinic for help. He was diagnosed with ‘allergic dermatitis’ and was prescribed some medication. However, no improvement was seen after taking the medicine. Two months ago, he experienced progressive proximal muscle weakness with hoarseness. Muscle weakness could not relieve after rest. He was unable to grip his hand, lift his arms over his head or stand up after crouching. Then he went to a hospital and his chest CT showed a spiculate pulmonary nodule near the hilar in the right upper lung lobe and mediastinal lymph nodes enlargement. For further diagnosis and

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treatment, he was admitted to the second affiliated Hospital of Wenzhou Medical University. Physical examination: The patient’s body temperature was 36.5°C, pulse was 102/min, respiration rate was 21/min and blood presure was 125/84 mmHg by physical examination. Widespread violet red rash could be seen on the patient’s face, four limbs, back, shoulders, neck, upper chest and in a ‘V’ shape over the posterior neck and back. He had periorbital edema with purple patches. Muscle strength was graded as follows: grade 5 (worse than normal) distal muscle strength and grade 4 (active motion against gravity with some resistance) proximal muscle strength in the upper arms; grade 4 distal and grade 4 proximal muscle strength in the lower limbs. Laboratory tests: blood creatine kinase levels of 436 U/L (ref. ≤ 174 U/L); aspartate aminotransferase levels of 40 U/L (ref. ≤ 35 U/L); nonreactive antiSjogren’s syndrome A, antistreptolysin O, anti-cyclic citrullinated peptide and rheumatoid factor; normal range of blood tumor markers (carcino embryonic antigen, alpha-fetoprotein, cancer antigen-125). Chest CT revealed a spiculate pulmonary nodule near the hilar in the right upper lung lobe with mediastinal lymph nodes enlargement (Fig. 1). Muscle biopsy (left deltoid, striated muscle tissue) showed that horizontal and vertical lines of the muscle cells were blurry and disappeared. There are rupture, distortion, focal necrosis and inflammatory cell infiltration in some muscle fibers (Fig. 2). Electromyography (EMG) showed myogenic damage (upper and lower limbs are involved). Neurophysiological tests with adequate repetitive stimulation showed LEMS (Fig. 3). Sputum pathology: A group of severe dysplasia epithelial cells were identified by sputum pathology, which suggested carcinoma. Bronchoscopy showed neoplasm in the posterior

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd

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Lung squamous carcinoma, paraneoplastic syndromes

Discussion

Figure 2. Muscle biopsy (left deltoid, striated muscle tissue) showed that horizontal and vertical lines of the muscle cell were blurry and disappeared. Some muscle fibers were ruptured and distortional. There was focal necrosis with inflammatory cell infiltration (H&E, 100×).

segment of the right upper lobe. Bronchoscopic brush biopsy from the right upper lobe tumor showed lung squamous carcinoma (Fig. 4). Immunohistochemical analysis based on bronchoscopy indicated squamous carcinoma: CK7 (−), CK20 (−), CK15 (+), CEA (+), EMA (+), CgA (−), Syn (−), CD56 (−), TTF-1 (+). According to these examinations, the patient was diagnosed with lung squamous cell carcinoma (SCC) with clinical manifestations of two overlapping paraneoplastic syndromes: DM and LEMS. He underwent lung cancer operation. Immunohistochemical analysis indicated squamous carcinoma that was pathologically staged as tumor2 node2 metastasis x (T2N2Mx). Then he received one cycle of first-line chemotherapy. Other medical treatments such as methylprednisolone and calcium supplement were used for LEMS and DM therapy. After one cycle of chemotherapy, the violet red rash faded. Muscle weakness also improved, but still with hoarseness.

Polymyositis (PM)/DM is an uncommon inflammatory myopathy with characteristic rash accompanying with progressive muscle weakness. Application of catastrophic illness certificate for DM and PM requires a thorough clinical and laboratory examinations that fulfills the diagnostic criteria proposed by Bohan and Peter (1, 2). The diagnostic criteria for DM include: symptoms of proximal muscle weakness; abnormal results on EMG; abnormal results on muscular biopsy; elevated serum levels of muscle enzyme (creatine kinase), lactate dehydrogenase, aspartate transaminase and alanine transaminase; and typical skin rash compatible with DM. The patient was diagnosed with DM according to the laboratory examinations: elevated creatinine phosphokinase levels (436 U/L, normal ≤ 174 U/L), EMG showing myogenic disorders (upper and lower extremities are involved), and the muscle biopsy (left deltoid, striated muscle tissue) confirming muscle inflammation. DM is a high-risk factor for cancer, and was often considered as a paraneoplastic syndrome (3). It has been suggested that lung cancer is frequently associated with PM/DM. The prevalence of cancer in DM/PM patients is five to seven times higher than that in general population (4). A nationwide cohort study in Taiwan reported that DM was the highest risk factor for nasopharyngeal carcinoma, lung/mediastinum cancer, bone/joint cancer and lymphoma/leukemia (5). Most cancer cases were eventually confirmed within the first year after the diagnosis of DM (4). The onset of PM/DM is frequently observed before the detection of lung cancer. The association between PM/DM and malignancy has been reported with variable frequency, but it is likely to be more frequent in the elderly (5). Combining all the examinations, this patient was diagnosed with squamous carcinoma (pathologically staged as T2N2Mx). After lung cancer operation and one cycle of first-line chemotherapy, the violet red rash faded.

Figure 3. The result of neurophysiological tests with adequate repetitive stimulation: compound motor action potentials (CMAP) amplitude was up to a 63% decrement at low frequency repetitive stimulation (3 Hz supramaximal stimulation) and up to 420% increment at high frequency stimulation (20 Hz supramaximal stimulation).

The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd

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Figure 4. The pathological picture showing squamous epithelial dysplasia. The morphology of squamous epithelium indicated invasive growth of tumor nests. Their nuclei are large, pleomorphic and dark staining with a certain pleomorphic (H&E, ×100).

LEMS is one of the representative paraneoplastic syndromes and an autoimmune disease of the neuromuscular junction. LEMS is a rare but wellknown paraneoplastic disorder characterized by muscle weakness and fatigability predominantly involving the proximal lower limbs. Because of its scarcity, the exact incidence of LEMS is unknown. The pathophysiology is understood quite well; antibodies to voltage-gated calcium channels in motor and autonomic nerve terminals disrupt calcium influx and reduce acetylcholine release. The diagnosis depends on a combination of measurement of the serum anti-P/ Q-type voltage-gated calcium channel antibody levels and neurophysiological studies. EMG studies without repetitive stimulation at appropriate frequencies may well be non-specific. LEMS is known to be associated with malignant neoplasm, especially small cell lung carcinoma (SCLC). Approximately 50% to 75% of LEMS patients have SCLC (6). LEMS is rarely associated with other subtypes of lung cancer like lung SCC. A PubMed literature search (keywords, ‘Lambert-Eaton Myasthenic Syndrome’ and ‘lung adenocarcinoma’) found only one publication in the English literature (7). His EMG result showed myogenic damage (upper and lower limbs are involved). But the serum test of voltage-gated calcium channel antibodies was not available in our hospital. He did a repetitive stimulation of EMG; the result conformed LEMS: compound motor action potentials amplitude was 63% decre-

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ment at low frequency repetitive stimulation (3 Hz supramaximal stimulation) and 420% increment at high frequency stimulation (20 Hz supramaximal stimulation). Therefore, the patient’s diagnosis was an overlap of two paraneoplastic syndromes (DM and LEMS) secondary to lung squamous carcinoma. In China, data from statistical yearbook of the 2010 China Health Organization reveal that, in terms of cancer mortality, lung cancer was the first leading type of cancer in 2005 (8). Clinical manifestations of lung cancer include symptoms caused by the primary tumor, intrathoracic tumor spread, distant metastasis and non-metastatic symptoms. The main types of lung cancer are SCLC. SCC of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. It most often arises centrally in larger bronchi, and while it often metastasizes to locoregional lymph nodes. LEMS and DM could be paraneoplastic syndrome. Paraneoplastic syndromes are rare disorders associated with cancer, not caused by direct cancer invasion, metastasis or consequences of treatment, and it often precede the manifestations of cancer. LEMS is the symptom showing the neuromuscular junction impairment while DM is an inflammatory myopathy. Because most patients who were diagnosed as having an apparent paraneoplastic syndrome may not have concomitant cancer at the same time, screening for underlying cancer is strongly indicated. This process includes complete history collection and physical examination, as well as imaging analysis. If CT scanning in chest, abdomen and pelvis is negative, positron emission tomography-computed tomography may be useful to identify underlying tumor. Further study of paraneoplastic syndromes are important because up to 80% of patients present with paraneoplastic syndromes before there is any other direct indication of malignancy. Early recognition, diagnosis and treatment of paraneoplastic syndrome and underlying cancer is important because any delay can result in disease rapid progression and irreversible neurological damage.

Acknowledgments I would like to extend my sincere thanks to all those who have contributed to the project and manuscript.

References 1. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292: 344–7.

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2. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292: 403–7. 3. Castro AS, Barroso A, Parente B. Dermatomyositis as the first manifestation of a lung tumor. Rev Port Pneumol. 2013;2159(12): 163–8. 4. Ponyi A, Constantin T, Garami M, András C, Tállai B, Váncsa A, Gergely L, Danko K. Cancer-associated myositis: clinical features and prognostic signs. Ann N Y Acad Sci. 2005;1051: 64–71. 5. Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, Chang YT. Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan. Arthritis ResTher 2010;12(2): R70.

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6. Wirtz PW, van Dijk JG, van Doorn PA, et al. The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology. 2004;63: 397–8. 7. Katada E, Nakamura T, Watanabe H, Matsukawa N, Ojika K, Sobue G. Lambert-Eaton myasthenic syndrome associated with pulmonary squamous cell carcinoma and circulating anti-P/Q-type voltage-gated calcium channel antibody. Rinsho Shinkeigaku. 2010;50(1): 17–9. 8. Ministry of Health of the People’s Republic of China. Diagnosis and management of primary lung cancer (2011 edition). Clin Educ Gen Prac. 2011;9(5): 486–9.

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Lung squamous carcinoma with two paraneoplastic syndromes: dermatomyositis and Lambert-Eaton myasthenic syndrome.

Paraneoplastic syndrome is a disease or symptom that is the consequence of cancer in the body but, unlike mass effect, is not due to the local presenc...
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