Dermatomyositis (DM) is an idiopathic inflammatory connective tissue disease characterized by muscular and cutaneous inflammation (1). Since the delineation of the association between DM and malignancy by Stertz in 1916, there have been increasing research interests on DM with co-morbid carcinoma. DM complicated with non-small cell lung cancer (NSCLC) is not rare (2), and could rapidly develop into severe lung cancer [performance-status score (PS) between 2 and 4]. Previous literature reports mainly focused on the comorbidity, pathogenesis, clinical manifestations and diagnostic criteria. However, the principles of management of symptom exacerbation during the course of chemotherapy remain poorly elucidated.
We retrospectively analyzed the diagnosis and treatment of a patient with DM complicated with NSCLC. The profiles consisted of symptoms onset, treatment courses, physician consultation, final diagnosis, complications, exacerbation and alleviation of symptoms. Furthermore, we have first proposed the concept of “severe lung cancer”, which was referred to a state in advanced NSCLC patients with PS score between 2 and 4. There may be reversibility and fluctuation of the PS score. We addressed that in patients with severe lung cancer, both the cancer and factors associated with exacerbation should be simultaneously managed to reduce the PS score and avoid unnecessary delay. More importantly, a second biopsy is important for proper management of the tumor with heterogeneity, especially when there is a deterioration of the disease after chemotherapy. These will lead to greater insights into the management of DM complicated with lung cancer.
A 51-year-old female never-smoker, presenting with productive cough, chest tightness and shortness of breath upon exertion, was referred from several hospitals. She was diagnosed as having pulmonary infection and interstitial pulmonary fibrosis. Following treatment with intravenous moxifloxacin and oral corticosteroids, she was admitted to our hospital in Nov 26, 2013 because of having low-grade fever (37.5 °C < T <38.0 °C) for 4 days which was accompanied by aggravated symptoms. The patient was diagnosed as DM complicated with NSCLC, according to the results of the following physical, lab examinations and biopsies. Chest auscultation indicated coarse respiratory sounds with crepitant rale in the right middle-lower lobe. Punctuate red rashes scattering on the extremities were noted. Pulse oxygen saturation (SPO2) was 85% (breathing air). Erythrocyte sedimentation rate (ESR) 45 mm/h; C-reactive protein (CRP) 1.07 mg/dL; creatinine kinase (CK): 860 U/L; blood gas analysis (O2 4 L/min) showing type I respiratory failure with an oxygen index (OI) of 253. Pulmonary function tests showed mild restrictive ventilatory dysfunction and moderately decreased diffusing capacity. Findings of positron emission tomography-computed tomography (PET-CT) are shown in Figure 1. Muscle biopsy of the right thigh is shown in Figure 2A. Bronchoscopic biopsies from the lower right lung suggested the diagnosis of interstitial inflammation. Biopsies from subcarinal lymph nodes showed visible massive cancer cells in the lymphoid tissue (Figure 2B). The immunohistochemistry assay of subcarinal lymph node results were as follows: EMA (focus), P63(+), CK5/6(+), CgA(−), TTF1(−), Syn(−), CD56(−), LCA(−), which collectively suggested metastatic squamous cell carcinoma (Figure 2C).
Methylprednisolone was prescribed for DM; chemotherapy with TP-based protocol [nanoparticle albumin bound-paclitaxel: 175 mg/m2, carboplatin area under the curve (AUC): 5.0 mg/mL/min] was prescribed for NSCLC. The area of pulmonary patchy shadows was reduced after a course of TP compared with baseline, accompanied by a reduction in PS score (by 1–2 points). This was followed by the second treatment course with TP-based protocol after a 21-day interval. Ten days after the second course of TP-based chemotherapy protocol, the patient was readmitted because of developed dyspnea with a PS score of 3–4 and emerging hypoxemia, suggesting the complication of infection or “severe lung cancer”. Chest radiography showed slightly increased multiple patchy lesions with increased density (Figure 3A). Meropenem and voriconazole were empirically prescribed, along with oxygen non-invasive ventilation for 4 days. Chest radiography showed reduced multiple patchy nodules compared with those in the previous 4 days (Figure 3B). But CT showed increased patchy ground-glass opacity and grid-like shades in the lower bilateral lobes compared with those before chemotherapy (Figure 4A). Two weeks later, her symptoms were ameliorated and the prescription was switched to INP-based protocol (vinorelbine: 25 mg/m2, ifosfamide: 3,500 mg/m2 and cisplatin: 75 mg/m2) after multidisciplinary consultation, we speculated the follow interpretations: (I) following infection controlled by effective antibiotics, symptoms of DM or tumor per se predominated; (II) ifosfamide and vincristine are effective anti-neoplastic and anti-DM agents. Navelbine belongs to vincristine family and may be more suitable for lung cancer with DM than paclitaxel; (III) cisplatinum was included for advanced NSCLC though its damage to kidney. In this case, the elevated PS score was mainly due to pneumonia, precluding complications of gastrointestinal or urinary tracts and neural function remained intact. After two courses of INP-based therapy, chest CT showed reduced lesions (Figure 4B). After six courses of INP-based chemotherapy, she remained clinically stable during follow-up (PS score 0–1) and her pulmonary function has been improved. Her CT scan showed reduced sizes of mediastinal lymph nodes, multiple pulmonary patchy shadows (Figure 5A).
Six months later, the lesions increased (Figure 5B), she was discharged home but failed to adhere to maintenance therapy. Two courses of INP and one course of GD-based protocols (gemcitabine + docetaxel) were administered; however, the improvement was unremarkable. The prescription was switched to tegafur/gimeracil/oteracil (S-1) 40 mg twice daily. The patient became clinically stable and the CT scan upon reassessment showed reduction of interstitial inflammation (Figure 5C). Having received S-1 triple therapy for approximately 1 year, there were signs of slightly increased lesions (Figure 6A).
To assess the progression and guide further treatment, the patient underwent the secondary percutaneous biopsy of the right lower lung. Results were as follows: P40(+), P63(+), CK(+), EMA(+), Vim(part +), CgA(−), Syn(−), CD56(−), TTF-1(−), NapsinA(−); in situ hybridization: EBER(+), which was consistent with pulmonary lymphoid-like carcinoma [ALK(−), C-Met(+), ROS1(−), PI3K(−); EGFR(−)]. In light of the new pathological type, chemotherapy was switched to AP-based protocol [Avastin (bevacizumab: 7.5 mg/kg) + pemetrexed disodium: 500 mg/m2]. After three courses, the CT scan showed reduced lesions (Figure 6B).
DM associated with lung cancer has been described in various publications. It was believed to occur in 7–15% of all patients with cancer (2-5). Lung cancer could be confirmed prior to, concurrently, or following the diagnosis of DM. In this case, the age interval, increased levels of ESR and CK, and concomitant interstitial abnormalities, should prompt the suspicion of tumor-related DM.
Our experience for treatment
The concept of and treatment for “severe lung cancer”
Based on our experiences and literature review, we have first proposed the concept of “severe lung cancer” which has not been mentioned in major lung cancer guidelines (ASCO, ESMO and NCCN). Severe lung cancer refers patients who are in more advanced stage of lung cancer per se or, patients present with more co-morbidity such as cardio-vascular diseases, chronic obstructive pulmonary disease (COPD) or respiratory infection.
In this case, the patient developed dyspnea after two courses of TP, with a PS score of 3–4 and emerging hypoxemia, suggesting the complication of infection or “severe lung cancer”. In our opinion, treatments of cancer and causes underlying exacerbations are equally important, including ventilation support and appropriate chemotherapy. It is important to resolve the major contradiction for the management of patients with “severe lung cancer”, especially when patient’s status was deteriorating. Priority should be given to improve the PS score before chemotherapy.
There may be reversibility and fluctuation of the PS score. Reversibility is more significant in certain subtypes of severe lung cancer, for instance, those with target genes susceptible to chemotherapy, treatment-naïve co-morbid pericardial effusion or pleural effusion, or major airway obstruction sensitive to initial local treatment. These patients may demonstrate significant reduction in PS score after appropriate therapy and may prompt further anti-cancer treatment. The fluctuations may be present in patients with co-morbidities such as COPD or cardiovascular disease, retreated pericardial effusion or pleural effusion, major airway obstruction resistant to initial local treatment. Treatment of this subtype may be complicated, requiring sufficient duration for controlling complications.
Heterogeneity of the tumor and necessity of performing rebiopsy
Dating back to 1976, Nowell and colleagues (6) proposed a landmark concept that the incidence of malignant tumors development is an evolutionary process due to somatic mutation and clonal selection. It is likely that malignant cells share common ancestor-cancer stem cells. The gene variants that caused by genomic instability progressively accumulated, which caused the malignant cells to differentiate into different subsets with varying genetic footprints. These clones of cancer cells coexist and continue to differentiate. Tumor growth is inseparable from its micro-environment. The relation of tumor heterogeneity with systemic chemotherapy drugs has not been systematically studied; however, after systemic chemotherapy the genetic profiles of cancer cells changed and the tumor heterogeneity increased (7-9). The drug resistance was reversible when a second biopsy was performed, which may confirm the nature of the lesions and prompt better treatment (10,11). In this case, having received S-1 triple therapy for approximately 1 year, there were signs of slightly increased lesions. Heterogeneity of the tumor pathology was shown in the two biopsies, with squamous cell carcinoma in the first time and pulmonary lymphoid-like carcinoma in the second time. Therefore, the treatment regimen has been changed accordingly. A clear pathological classification is of great value in choosing suitable and more effective medication.
Clinical characteristics of DM with co-morbid lung cancer may be non-specific, and missed diagnosis readily occurred. In case of severe lung cancer, both lung cancer and factors contributing to exacerbation should be simultaneously treated. There may be reversibility and fluctuation of the PS score, depending on the patient’s status. A second biopsy is necessary when tumor behavior changes.
Funding: This study was supported by Science and Technology Planning Project of Guangdong Province, China (No. 2014A020212562); National Natural Science Foundation of China (No. 81670036).
Conflicts of Interest: The authors have no conflicts of interest to declare.
Informed Consent: Informed consent was obtained from the patient for publication of this manuscript and any accompanying images.
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