Case 4 -

Congenital Pulmonary Myofibroblastic Tumor Megan K. Dishop Assistant Professor, Baylor College of Medicine Texas Children's Hospital Houston, TX

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Case History: Newborn boy, twin A, delivered at 28 weeks gestation to a 31-year-old mother with respiratory distress and severe hydrops, requiring intubation, high frequency oscillatory ventilation, and nitric oxide therapy. Maternal history and obstetric history were unremarkable, except for discordant fetal growth (twin A larger, twin B smaller). Chest x-ray showed a hyperinflated right lung and a mass in the right upper lung field, displacing the heart. No pleural or pericardial effusions were detected at delivery. Echocardiogram showed evidence of persistent pulmonary hypertension. He had rapid deterioration despite support and died less than 24 hours after delivery. A similar mass was not detected in Twin B. At autopsy, the baby was hydropic and non-dysmorphic. The lungs were discrepant in size, with a very large right lung weighing 70 grams (12 grams expected) and a hypoplastic left lung. The right upper lobe was enlarged, covering the anterior mediastinum, and replaced by a firm solid pale tan mass. The right lower lobe was hemorrhagic. No other visceral anomalies were identified. A section of the right upper lobe is provided. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Gross. A section of the right upper lobe mass showed a solid tan tumor with a fascicular pattern. Case 4 - Figure 2 Microscopic (H&E, 2x). The mass is composed of broad bundles of spindled cells dissecting the lung parenchyma along interlobular septa and along bronchovascular bundles. Abnormal proliferation of cartilage plates is associated with the small bronchi. Case 4 - Figure 3 Microscopic (H&E, 4x). The spindle cell proliferation distorts the architecture of the lung and compresses some bronchioles. Case 4 - Figure 4 Microscopic (H&E, 20x). The spindled cells shows a haphazard arrangement of fascicles and uniform bland cytologic features. Case 4 - Figure 5 Microscopic (H&E, 20x). There are occasional mitotic figures and no significant inflammatory cell infiltrates. Pathologic Features: Examination of the left lung mass shows a bland spindle cell proliferation expanding the bronchovascular bundles, interlobular septa, and pleura. The fascicles of spindled cells subdivide the alveolated lung parenchyma, accentuating the architecture of the lobules, but distorting the bronchovascular bundles. The cartilage plates entrapped within the spindle cell proliferation are distorted with irregular, enlarged, and elongated forms. The cells have elongated tapered nuclei with eosinophilic fibrillar cytoplasm. Although occasional typical mitotic figures are noted throughout, the cytologic features are bland, without cellular pleomorphism, nuclear hyperchromasia, cytologic atypia, atypical mitotic figures, or necrosis. Immunohistochemical staining shows the following profile: vimentin (diffuse strong +), smooth muscle actin (focal +), muscle specific actin (-), S100 (-), MyoD1 (-), CD99 (-), bcl2 (rare cytoplasmic +), ALK1 protein (-). Diagnosis: Congenital Pulmonary Myofibroblastic Tumor Differential Diagnosis: Inflammatory myofibroblastic tumor Myofibromatosis Fibromatosis Fibrous hamartoma of infancy Smooth muscle tumor, EBV-associated Lymphangioleiomyomatosis Pulmonary hamartoma Congenital (infantile) fibrosarcoma Bronchopulmonary fibrosarcoma Synovial sarcoma Embryonal rhabdomyosarcoma Discussion: Congenital pulmonary myofibroblastic tumor (CPMT) is a very rare benign lesion of the fetus and neonate which typically results in intrauterine fetal demise, hydrops fetalis, or respiratory distress at birth. Approximately 10 cases of CPMT have been described in the literature, including cases reported as "bronchopulmonary leiomyosarcoma", "bronchopulmonary fibrosarcoma", "congenital fibroleiomyosarcoma", "hamartoma", "congenital mesenchymal malformation", and "congenital peribronchial myofibroblastic tumor". The tumor is thought to arise from the pluripotent peribronchial mesenchyme, a precursor to the myofibroblastic phenotype. McGinnis et al. have proposed analogy of CPMT with congenital mesoblastic nephroma and congenital spindle cell tumor of the intestinal tract, two other fibroblastic/myofibroblastic tumors of infancy. There is no apparent predilection for gender (6M:4F), laterality, or lobe. Despite typically large size (3.5-7.5 cm), somewhat infiltrative appearance histologically, and mitotic activity, CPMT has otherwise benign cytologic features and should not be confused for malignancy. Mortality is dependent on adequacy of ventilatory support and ability to achieve surgical resection. Outcomes in reported cases have included intrauterine fetal demise and early neonatal death, as well as prolonged survival after surgical resection, without further recurrence or metastasis. Pathologic features are distinctive and typically allow diagnosis by histologic pattern alone. The lesion is composed of interlacing fascicles of spindle cells, surrounding normal lobules of alveolated parenchyma, and extending along bronchovascular bundles, interlobular septa, and occasionally along the pleura. Hypercellular areas, focal necrosis, calcification, and a hemangiopericytomatous vascular pattern have been reported. Malformed cartilage plates and "cartilagenous metaplasia" within spindle cell fascicles have also been described in CPMT. Immunohistochemistry is positive for vimentin and may be focally positive for smooth muscle actin, muscle specific actin, and desmin positivity. Focal S100 positivity has been reported in spindle cells surrounding foci of "cartilagenous metaplasia", raising the possibility of both myofibroblastic and chondrocytic differentiation. The lesion is otherwise negative for cytokeratin, GFAP, and alpha-fetoprotein. Electron microscopy has shown evidence supporting myofibroblastic differentiation. The spindled cells are limited by a cell membrane with a disrupted basal lamina, and have scant surrounding collagen. Bundles of fine cytofilaments with focal peripheral condensations and attachment plaques have been noted. Occasional cytoplasmic lipid droplets and myelin figures have been observed. Cytogenetic analysis in one case showed a complex rearrangement of chromosomes 4, 8, and 10. The differential diagnosis of neonatal intrathoracic masses includes primarily developmental cystic lesions (bronchogenic cyst, congenital pulmonary airway malformation, intralobar or extralobar pulmonary sequestration, bronchial atresia), extrapulmonary/mediastinal lesions (teratoma, lymphoma, thymic cysts), and only rarely primary neoplasms of the lung (pleuropulmonary blastoma, sarcomas, hamartoma). Fibroblastic and myofibroblastic tumors are common in infants and children, most often occuring in soft tissues but also involving the viscera in some cases. Inflammatory myofibroblastic tumor (IMT) is a benign primary lesion of the lung in both adults and children, typically occurring as a solitary nodule of either the tracheobronchial tree or alveolar parenchyma. In contrast to CPMT, the lesion forms a localized mass without the infiltrative septal pattern and is typically associated with a lymphocytic or lymphoplasmacytic inflammatory infiltrate. Infantile myofibromatosis refers to multifocal myofibroblastic proliferations of the skin and/or viscera occurring in infants and children. Lung involvement produces multiple separate lesions with variable hyalinization and cellularity, rather than the more monotonous and diffuse growth pattern with bronchovascular entrapment seen in CPMT. Fibromatoses occur most often in soft tissues of older children and adolescents, but other sites of involvement include the intestinal mesentery, abdomen, and mediastinum. Desmoid fibromatosis may be associated with APC mutations (Gardner syndrome). These lesions are poorly circumscribed and have infiltrative growth, but typically are less cellular than CPMT, and show more abundant collagen deposition and areas of hyalinization. Lung involvement is unusual and is most likely due to direct extension from the mediastinum, rather than primary origin in the lung. Fibrous hamartoma of infancy is a benign soft tissue tumor with a fibroblastic component resembling that seen in CPMT, but it also shows mature adipose tissue and immature mesenchymal components, and has not been reported as a primary lesion of the lung. Other benign spindle cell lesions which enter the differential diagnosis include smooth muscle tumors and lymphangioleiomyomatosis. Smooth muscle tumors (leiomyomas and leiomyosarcomas) rarely occur in the lung. A subset occur as solitary or multiple spindle cell nodules in immunocompromised or immunosuppressed children and are driven by Epstein-Barr virus, similar to post-transplant lymphoproliferative disorders. These lesions from circumscribed round masses, sometimes with a mild inflammatory component similar to IMT, and EBV expression can be demonstrated by in situ hybridization. Lymphangioleiomyomatosis (LAM) is characterized by multifocal spindle cell proliferations in the pleura, interlobular septa, and bronchovascular bundles in association with lymphatic channels. These lesions characteristically express HMB45. In contrast to CPMT, LAM typically develops in adolescent and young adult women, and is associated with tuberous sclerosis. The component of abnormally formed cartilage in many cases of CPMT might also prompt consideration of a pulmonary hamartoma. Unlike CPMT, these lesions typically form solid circumscribed nodules associated with the bronchial tree, and may have variable admixture of fibrous, cartilagenous, and adipose elements. The differential diagnosis also includes primary sarcomas of the lung, including: congenital-infantile fibrosarcoma, bronchopulmonary fibrosarcoma, synovial sarcoma, and rhabdomyosarcoma. Congenital (infantile) fibrosarcoma is a highly cellular malignant spindle cell neoplasm associated with a characteristic chromosome translocation resulting in fusion of the ETV6 and NTRK3 genes (t(12;15)(p13;q25). Although most often localized to soft tissue, visceral involvement may occur. For example, cellular mesoblastic nephroma is a morphologically equivalent primary renal tumor of infancy that demonstrates the same translocation as congenital fibrosarcoma of soft tissue. Bronchopulmonary fibrosarcoma(BPFS) is a rare spindle cell tumor of the lung in older children which shows more aggressive behavior than CPMT. While some cases of CPMT were initially described in a large series of bronchopulmonary fibrosarcomas, the neonatal presentation and bland cytologic features warrant distinction of this tumor from BPFS. Having said that, some theorize that BPFS may be the malignant counterpart of CPMT, similar to the histogenetic spectrum of the cellular and classic forms of mesoblastic nephroma. Although rare, synovial sarcoma is one of the most common primary lung sarcomas in children. It is a highly cellular primitive spindle cell tumor with monophasic and biphasic forms, and is associated with a characteristic translocation resulting in fusion of the SYT and SSX genes (t(X;18)(p11;q11)). Embryonal rhabdomyosarcoma may occur at any organ site and, although rare in the lung, enters the differential diagnosis of a spindle cell tumor in a child. Embryonal rhabdomyosarcoma typically shows a loose "cell-culture" growth pattern of small round and spindled hyperchromatic cells with only focal eosinophilic cytoplasm, and lacking a collagenous background. References: Alobeid B, Beneck D, Sreekantaiah C, Abbi RK, Slim MS. Congenital pulmonary myofibroblastic tumor: A case report with cytogenetic analysis and review of the literature. Am J Surg Path 1997. 21(5): 610-4. McGinnis M, Jacobs G, el-Naggar A, Redline RW. Congenital peribronchial myofibroblastic tumor (so-called "congenital leiomyosarcoma"). A distinct neonatal lung lesion associated with non-immune hydrops fetalis. Mod Pathol 1993 Jul. 6(4): 487-92. Pettinato G, Manivel JC, Saldana MJ, Peyser J, Dehner LP. Primary bronchopulmonary fibrosarcoma of childhood and adolescence: Reassessment of a low-grade malignancy. Hum Pathol 1989. 20: 463-71. Guccion JG, Rosen SH. Bronchopulmonary leiomyosarcoma and fibrosarcoma. Cancer 1972. 30(3): 836-47.