Acquired Platythorax, or Anteroposterior Flattening of the Chest Wall, as a Late Complication of Cyclophosphamide Treatment for Childhood Acute Lymphoblastic Leukemia, Presenting in a Young Man with Respiratory Failure

Background

Chest wall deformities can be congenital or acquired. The most common chest wall deformity is congenital pectus excavatum, which occurs in 88% of cases [1]. Platythorax, or flattening of the chest with a reduction in the anteroposterior (AP) diameter, is very rare [2]. Platythorax can be primary or secondary to diseases of the bone of the chest wall, including pectus excavatum [2] and scoliosis [3] or to pulmonary disease associated with pulmonary fibrosis or pulmonary hypoplasia including congenital diaphragmatic hernia, chronic bronchopulmonary dysplasia [4], pulmonary infection, autoimmune disease, drug-induced pulmonary fibrosis [5], and idiopathic pleuroparenchymal fibroelastosis [6].

Platythorax is very rare, and the prognosis is varied, depending on the degree of the deformity, its effects on respiratory function, and on any underlying disease. Because the condition is rare, the mechanism of its development, pathogenesis, and prognosis remain unknown.

This report is of a young man who developed platythorax due to cyclophosphamide-related pulmonary fibrosis eight years after the cessation of chemotherapy for acute lymphoblastic leukemia (ALL). This report also describes the method used determine the ratio of the chest wall AP diameter to lateral diameter to show the timeline of progression in the flattening of the chest wall in this patient, compared with twenty long-term survivors of childhood ALL. The pathogenesis of platythorax due to drug-induced pulmonary fibrosis is discussed with a review of the literature on cyclophosphamide-associated pulmonary fibrosis.

Case Report

A 20-year-old man began to experience cough, chest pain, and mild exertional dyspnea. He was admitted to the hospital at 23 years of age with respiratory failure. He had been successfully treated for acute lymphoblastic leukemia (ALL) at 3 years of age, with chemotherapy that included a cumulative dose of cyclophosphamide of 15.6 g/m2. His ALL relapsed six years later, when he was 9-years-old, and he was the treated again with cyclophosphamide and underwent a second and complete remission. During chemotherapy for ALL, he did not experience pulmonary adverse events, including pneumonia, and chest X-ray at the time of cessation of chemotherapy at 11 years of age was normal (Figure 1A). He was never treated with radiotherapy. Unfortunately, he was lost to follow-up for several years, until he presented to our hospital at the age of 20 years, due to a one-week history of non-productive cough.

On this most recent hospital admission, at the age of 23 years, he was in respiratory failure, and chest imaging showed pleural thickening and platythorax, or flattening of the chest with a reduction in the anteroposterior (AP) diameter, was prominent (Figure 1B). His respiratory rate was 52/min with 75% SpO2. No respiratory infections were identified. Chest computed tomography (CT) showed diffuse infiltrates and bilateral pleural thickening (Figure 1C). His pulmonary vital capacity was 0.56 L (13.3%) of the predicted value. No physical findings, blood tests, or family history suggested the presence of collagen or autoimmune diseases. Non-invasive positive pressure ventilation (PPV) with oxygen was commenced for respiratory failure. He developed severe dyspnea with New York Heart Association (NYHA) class IV heart failure, secondary to pulmonary fibrosis, which gradually worsened.

At 25 years of age, he died of cardiopulmonary failure, five years after the onset of respiratory symptoms. Permission for an autopsy was not obtained. It was assumed that his platythorax, or reduced AP diameter of the chest, might have been secondary to pulmonary hypoplasia with pulmonary fibrosis because the diaphragm in his chest X-ray films had been elevated. He had previously received a moderate dose of cyclophosphamide (cumulative dose, 15.6 g/m2) for the treatment of ALL. Finally, based on the clinical course and exclusion of other diseases, a clinical diagnosis was made of cyclophosphamide-related late-onset pulmonary fibrosis resulting in platythorax, or reduced AP diameter of the chest.

Discussion

Platythorax, or flattening of the chest with a reduction in the anteroposterior (AP) diameter, is rare and the mechanisms involved in the development of this condition remain unknown. Drug-induced pulmonary fibrosis is one of the pulmonary hypoplasia-related disorders associated with acquired platythorax. However, pulmonary fibrosis has many causes, including scleroderma (systemic sclerosis), sarcoidosis, infection, and exposure to drugs, toxins, or radiation, and the most common and most fatal type of idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF). Cyclophosphamide pulmonary toxicity is a rare cause of pulmonary fibrosis and is usually a diagnosis of exclusion, as blood examinations, bronchoalveolar lavage (BAL), or lung biopsy may not be diagnostic [7].

There have been 15 reported cases, including six children and nine adults, of late-onset pulmonary disease associated with cyclophosphamide therapy, including this case (Table 1) [5,7–13]. In many of these cases, late-onset pulmonary toxicity developed in patients who had received prolonged treatment over several months to years with relatively low doses of cyclophosphamide, and the prognosis was poor [5,7–13]. The interval from initiation of cyclophosphamide treatment to the onset of respiratory symptoms varied from 0.4–19 years (median, seven years), and the cumulative dose of cyclophosphamide ranged from 3.4–91 g/m2 [5,7–13]. Initial symptoms were nonspecific, including a cough and exertional dyspnea. Pulmonary function tests showed a severe restrictive ventilation defect and chest X-ray showed pleural thickening in most of the cases [5,7–13]. The major pathologic feature was pulmonary fibrosis [5,7–13]. Severe chest deformity developed only in the cases that received chemotherapy in childhood (cases 1 and 4).

Therefore, severe platythorax due to cyclophosphamide-related pulmonary fibrosis may occur predominantly in children. The patient in the present report received a moderate dose of cyclophosphamide intermittently (cumulative dose, 15.6 g/m2). Although the pathogenesis of pulmonary fibrosis due to cyclophosphamide is poorly understood, there may be genetic differences in local pulmonary drug metabolism that could be risk factors, but these remain to be identified. Among the cytochrome P450 (CYP) superfamily, CYP2B6 is a major enzyme that metabolizes cyclophosphamide and is expressed in lung tissues [14]. However, cyclophosphamide is also a substrate of other CYPs (including CYP2A6, CYP2C19, CYP2C9, and CYP3A4). Because platythorax, or flattening of the chest wall, with pulmonary fibrosis associated with cyclophosphamide treatment is very rare, it is possible to speculate that CYP polymorphism may have a role in the development of this condition.

Currently, there are few available treatments for pulmonary fibrosis and treatment is of limited efficacy. The profibrotic signaling inhibitors, pirfenidone and nintedanib, have been shown to slow the decline in lung function in patients with IPF, measured by forced vital capacity (FVC) and to reduce all-cause mortality [15,16]. However, the ability of pirfenidone and nintedanib to resolve fibrosis in IPF has not been demonstrated. Reddy et al. reported that depletion of the transcription factor PPARg in lung fibroblasts induced a profibrotic phenotype, and that activation of PPARg promoted dedifferentiation in lung myofibroblasts in an animal model in vivo [17].

The underlying mechanism for the development of platythorax, or flattening of the chest with a reduction in the AP diameter, and the association with pulmonary fibrosis has not been investigated. It is possible to hypothesize that pulmonary fibrosis that occurs at an early age has an adverse effect on the development of the thorax. The development of the chest wall occurs at the same time as the development of the lungs, including alveolarization with the expansion of the lungs, which continues from childhood to young adulthood [18]. Therefore, chemotherapeutic damage to the lungs may result in interruption of alveolar development and impaired pulmonary function followed by chest deformity in some children. Recently, Beynat-Mouterde et al. reported that platythorax, or flattening of the chest, with pleuroparenchymal fibroelastosis was a late complication of treatment with chemotherapy agents, similar to the case in this report [13].

We conducted a retrospective analysis of chest radiographs from two cohorts of children that included control subjects and patients with acute lymphoblastic leukemia (ALL). Control subjects included a total of 100 children and young adults (age range, 0–24 years). These control subjects were admitted to the hospital for various surgical procedures and preoperative chest radiographs were taken. Subjects with congenital anomalies and airway disorders were excluded from this study, and the remaining subjects were subdivided into five groups. Box plots analysis of the T (thickness)/W (width) ratio on chest radiographs were performed for 10 men and 10 women in each age group, which included 0–4 years, 5–9 years, 10–14 years, 15–19 years, and 20–24 years. Platythorax was defined as T/W <0.60 (0.703±0.103, mean ±2 SD), 0.55 (0.638±0.086), 0.50 (0.631±0.127), 0.50 (0.614±0.115), 0.51 (0.627±0.119), respectively (Figure 2A). There was no sex variation among all age groups (men, 0.654±0.128; women, 0.632±0.120, mean ±2 SD). Among each age group, an inter-patient variation of T/W ratio was seen. Mild, moderate, and severe platythorax were tentatively defined as, – 3 SD ≤T/W < – 2 SD, – 4 SD ≤T/W < – 3 SD, and T/W < – 4 SD, respectively.

In the ALL cohort, the T/W ratio in 21 long-term child survivors of ALL, with a median follow-up of eight years after cessation of chemotherapy (range, 2–12 years) was serially plotted. In this case report of a patient with platythorax, the T/W ratio gradually decreased from 0.61 (normal) to 0.43 (moderate), and to 0.35 (severe platythorax) over ten years (Figure 2B). The remaining patients with ALL had normal chest radiographs.

Conclusions

This report described a rare case of acquired platythorax, or flattening of the chest wall, in a young adult. The use of the ratio of the chest wall AP diameter to lateral diameter (the T/W ratio) may be used in the early detection of this chemotherapy-induced complication in children and adults. This case was also reported to draw attention to this rare but potentially lethal complication of cyclophosphamide treatment.