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1 Annals of Clinical & Laboratory Science, vol. 45, no. 1, 2015 Available online at Congenital Peribronchial Myofibroblastic Tumor: Case Report of an Asymptomatic Infant with a Rapidly Enlarging Pulmonary Mass and Review of the Literature Katharine E. Brock 1,2, James Wall 3, Micaela Esquivel 4, Beverley Newman 5, Neyssa Marina 1,2, Craig Albanese 3, and Florette K. Hazard 1,6 Stanford University School of Medicine, 1 Department of Pediatrics, 2 Division of Pediatric Hematology/Oncology, 3 Department of Surgery, Division of Pediatric Surgery, 4 Department of Surgery, 5 Department of Radiology, and 6 Department of Pathology, Stanford, CA, USA Abstract. Background. Congenital peribronchial myofibroblastic tumor (CPMT) is a rare, benign lung tumor of infants, with only 19 reported cases worldwide. It is often diagnosed by prenatal imaging or in the immediate postnatal period due to co-morbidities like polyhydramnios, fetal hydrops, respiratory distress, and heart failure. Observation. We report the oldest known infant (8 weeks old) diagnosed with CPMT, and present his clinical course including the relevant radiographic and histopathologic findings. Conclusions. CPMT is a rare tumor that should be considered among other primary lung tumors of infancy (developmental, benign, and malignant) even if not detected prenatally or in the immediate postnatal period. Keywords: congenital peribronchial myofibroblastic tumor, neonatal, benign lung tumor, pleuropulmonary blastoma. 83 Introduction Congenital peribronchial myofibroblastic tumor (CPMT) is a rare, benign primary lung tumor of infants with no reported cases of local recurrence or distant metastases following complete surgical resection. Only 19 cases have been reported worldwide (Table 1) [1-17]. CPMT is most often detected by prenatal imaging, although affected patients can present in the immediate postnatal period. Presenting signs/symptoms include respiratory distress, heart failure, polyhydramnios, nonimmune hydrops fetalis, and intrauterine fetal death [4,6,9,11,13]. Historically, this tumor has been known by many names: bronchopulmonary leiomyosarcoma, bronchopulmonary fibrosarcoma, congenital fibroleiomyosarcoma, hamartoma, and congenital mesenchymal/adenomatoid malformation [18]. Address correspondence to Katharine E. Brock, MD; Division of Pediatric Hematology/Oncology, Stanford University School of Medicine; 1000 Welch Road, Suite 300, Palo Alto, CA, ; phone: ; fax: ; e mail: kebrock@stanford. edu We report the case of an 8-week-old infant with an incidental, rapidly-growing CPMT. We also review the common entities considered in the differential diagnosis of lung masses in infants, describe their clinical, radiographic and pathologic features, and recommended treatment. This patient s unusual presentation illustrates the need to maintain a broad differential diagnosis when evaluating lung masses in infants; CPMT should be considered, even if not detected prenatally or in the immediate postnatal period. Case Report We report an 8-week-old Swedish/Mexican male, born at 38 weeks gestation to a 36-year-old mother. No family history of cancer was noted. Regularly scheduled prenatal ultrasounds did not reveal a mass or polyhydramnios. Chorionic villous sampling (performed for abnormal quadruple screen) confirmed a normal 46, XY karyotype. The mother had an uneventful vaginal delivery, and the infant experienced no hydrops or respiratory distress. Physical exam revealed a left pre-auricular pit and partial heterochromia of the left iris /15/ by the Association of Clinical Scientists, Inc.

2 84 Annals of Clinical & Laboratory Science, vol. 45, no. 1, 2015 Table 1. Summary of case reports of congenital peribronchial myofibroblastic tumor. Author Age at Sex Tumor Tumor Nonimmune Diagnosis Treatment Outcome presentation Location size(cm) hydrops (weeks gestation) fetalis Jones [1] 28 F RUL Hamartoma None Died, 1 hour Robb [2] 40 M LLL Fibrosarcoma Lobectomy NED,10months Guccion [3] NS M LUL 6 - Leiomyosarcoma None Died at birth Haller [4] 40 F LLL CMT None Died, 8 hours Warren [5] F LUL, LLL CMM Pneumonectomy Died, 24 hours Jimenez [6] 36 M RLL Leiomyosarcoma Lobectomy NED, 34 months Pettinato [7] NS M LUL 6 - PBPF Lobectomy NED, 6 years Pettinato [7] NS M RLL PBPF Lobectomy NED, 3 months Khong [8] 27 M RUL CMM None Died at birth McGinnis [9] 33 M RUL 5 + CPBMT Pneumonectomy Intraoperative death Alobeid [10] 35 F RML, RLL 6 - CPMT Lobectomy NED, 12 months (middle and lower) Horikoshi [11] 30 M LLL 6 + CPMT None IUFD Reiss [12] 25 M L lung CPMT None Elective termination de Noronha [13] 24 M LLL 12 + CPMT None IUFD Huppman [14] 23 M LUL, LLL 6.6^ + CPMT Lobectomy & NED, 6.5 years completion pneumonectomy Kim [15] 4 postnatal F RML, RLL CPMT Bilobectomy NED, 2 years weeks (42) Chang [16] 32.5 F LLL 5.2 # - CPMT None Died, 17 days Chang [16] Full term F RLL 6.5 # - CPMT Surgical resection Intraoperative death Calvo-Garcia [17] 30 M LUL CPMT Lobectomy by NED, 17 months intrauterine surgery Current case 8 postnatal M RLL, RML CPMT Pneumonectomy NED, 16 months weeks (46) CMT, congenital mesenchymal tumor; CMM, congenital mesenchymal malformation; CPBMT, congenital peribronchial myofibroblastic tumor; IUFD; intrauterine fetal demise; LLL, left lower lobe; LUL, left upper lobe; NED, no evidence of disease; NS, not specified; PBPF, primary bronchopulmonary fibrosarcoma; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; ^Fetal MRI measurement; # CT measurement

3 Congenital peribronchial myofibroblastic tumor: a case and review 85 Figure 1. Imaging. A. Chest X-ray demonstrating a right parahilar and lower lobe rounded opacity with air bronchograms. The remaining lung appears normally aerated. B and C. MRI (B. axial STIR series, C. Coronal T1 post-gad) showing right parahilar, T2 bright, moderately enhancing lesion that includes fluidfilled cysts, with extension into the posterior mediastinum, encasement of central bronchi, air bronchograms extending peripherally (C) and mediastinal shift. D and E. Contrast enhanced CT (D. Mediastinal window, E. Lung window) confirming the cystic and solid nature of the lesion surrounding central vessels and bronchi and extending to the posterior mediastinum. A few air-filled cysts can be seen anteriorly in panel E (arrow). At 8 weeks of age, he presented to a local emergency department with fever, congestion, and cough for one day. His oxygen saturations remained above 95%, and he had no respiratory distress. Chest x-ray revealed a well-demarcated, rounded consolidation in the right lower lobe with air bronchograms and hilar lymphadenopathy (Figure 1A). Complete blood count, chemistry panel, lactate dehydrogenase, and uric acid were normal. Magnetic resonance imaging (MRI) of the chest (and subsequent computed tomography (CT)) showed a large enhancing, mixed solid and cystic lesion in the parahilar right lung extending to the mediastinum, causing mediastinal shift (Figure 1B,C). The radiographic differential included an infected congenital pulmonary airway malformation (CPAM), neoplasm such as pleuropulmonary blastoma (PPB), and round pneumonia. An infected CPAM or PPB were thought to be the most likely diagnoses, and the patient was taken for an open thoracotomy which revealed a large, predominately solid mass occupying the right upper, middle, and lower lobes without edema, purulence, effusion, or pleural nodularity. The mass firmly adhered to the esophagus, pericardium, and pulmonary hilar vessels. Frozen section evaluation was consistent with malignancy. A right pneumonectomy was performed, followed by segmental resection of a portion of the remaining right mainstem bronchus, to achieve complete resection. The infant recovered without complications and was discharged on postoperative day five. Based on concern for PPB, a metastatic work-up was completed (bone scan, brain MRI, CT of the chest/abdomen/pelvis, and ultrasound of the kidneys and urinary bladder). No imaging studies showed metastases. Within two months of the resection, the patient s breathing pattern normalized. Given the presence of tumor at the hilar resection margin, follow-up has included alternating chest CT and chest x-ray. He is currently 16 months post-resection with no evidence of disease recurrence. Pathologic examination. The right lung measured 10.0x8.5x4.5 cm and, upon sectioning, was noted to contain a 3.5 cm firm white mass involving the right upper, middle, and lower lobes without visceral pleural involvement. Histologic sections confirmed the presence of a highly cellular spindle-cell proliferation arranged in fascicles, with extension to the hilar surgical margin (Figure 2). The spindled tumor cells showed moderate nuclear pleomorphism, some nuclear membrane irregularities, moderate to high nucleus to cytoplasm ratios, vesicular chromatin, occasional prominent nucleoli, eosinophilic cytoplasm, and frequent mitotic figures. There were no atypical mitotic figures present. Abundant cartilage formation was noted throughout, with several irregular cartilaginous islands. Scattered atrophic-appearing bronchioles and variably sized cystic spaces were also noted. With appropriate controls, immunohistochemical stains for cytokeratin (AE1 and CAM5.2), actin, desmin, CD34, and myogenin were negative within the

4 86 Annals of Clinical & Laboratory Science, vol. 45, no. 1, 2015 Figure 2. Pathology, Congenital Peribronchiolar Myofibroblastic Tumor. A. Lung hilum showing tumor infiltration adjacent to the cartilage of the bronchus (H&E stain; 10X magnification). B. Cellular spindled proliferation with admixed irregular cartilage islands (H&E stain; 40X magnification). C. Neoplastic spindled cells with moderate nuclear pleomorphism and frequent mitotic figures (H&E stain; 400X magnification). tumor cells. Fluorescent in situ hybridization testing for ALK gene mutations was negative. Cytogenetic analysis and genomic sequencing were not performed. An initial diagnosis of PPB Type II (solid and cystic) was rendered. However, based on the patient s young age, a cystic Type I PPB would have been expected. Thus, no further adjuvant therapy was given while expert consultative review was obtained, and the diagnosis was revised to congenital peribronchial myofibroblastic tumor (CPMT). Discussion Clinically, CPMT is a benign primary lung tumor of infants that is generally detected by prenatal imaging studies or in the immediate postnatal period. There is no predilection for gender, lobe, or laterality. It is associated with respiratory distress, heart failure, polyhydramnios, nonimmune fetal hydrops, and intrauterine fetal demise [1-7,9-14,18]. Treatment is complete surgical resection; there have been no recurrences described, even in cases with positive resection margins [14,15]. Chemotherapy and/or radiotherapy are not indicated for this benign tumor. However, due to the tumor s intimate association with the bronchial tree, lobectomy or pneumonectomy is often required. Despite the excellent prognosis after surgical resection, clinicians should be aware of pneumonectomy-related morbidity, notably mediastinal shift and post-pneumonectomy syndrome. The mediastinum and residual lung shift over time to fill the contralateral potential space. Post-pneumonectomy syndrome occurs when chronic extreme mediastinal shift leads to dynamic airway compromise. The empty thoracic cavity may need to be filled with prosthetic material to counteract mediastinal shift prior to irreversible airway distortion [19]. This 8-week-old infant with CPMT is unique in that there was no mass on prenatal imaging studies, and he was asymptomatic. The diagnosis of CMPT was challenging on multiple levels: radiographically, air bronchograms initially created diagnostic confusion as these are atypical of most intrapulmonary neoplasms; pathologically, this lesion resembled a Type II PPB. While the diagnosis of CMPT is complicated by its extreme rarity and need for multiple pathologic reviews, ultimately, our patient s lack of significant cytologic atypia, the tumor s close association with the bronchial tree, and the young age of the patient all support the diagnosis of CPMT. When considering primary lung masses in infants, the differential diagnosis should remain broad and include developmental malformations such as intralobar sequestration and congenital pulmonary airway malformation (CPAM); benign tumors such as fetal lung interstitial tumor (FLIT), infantile myofibromatosis, and CPMT; and malignant tumors such as pleuropulmonary blastoma (PPB) and infantile fibrosarcoma (Table 2). CPMT is thought to arise from pleuripotent peribronchial interstitial mesenchymal cells found at 12 weeks of gestation, and may therefore

5 Congenital peribronchial myofibroblastic tumor: a case and review 87 share similar pathogenesis with other mesenchymal lesions such as FLIT and PPB [20]. CPMT tends to be a firm, yellow, rubbery mass with interlacing fascicles of spindle cells surrounding normal lobules of alveolated parenchyma, and extending along bronchovascular bundles, interlobular septa, and (less commonly) the pleura. Importantly, there is no destruction or invasion of the airways. Mitotic figures can be frequent, but there is no significant cytologic atypia or atypical mitoses. Generally, immunohistochemistry is diffusely positive for vimentin with focal positivity for muscle specific actin, smooth muscle actin, and desmin. The tumor is negative for alpha-fetoprotein (AFP), GFAP, MyoD1, CD99, ALK1, S100, and cytokeratin [18]. Cytogenetics have been scarcely reported in the literature, but one case did show a complex rearrangement of chromosomes 4, 8, and 10[10]. Pulmonary sequestrations may be intralobar (an aerated focus of lung parenchyma that developed separately from the surrounding lung, with its own arterial blood supply) or extralobar (a solid and non-aerated mass). Their histopathologic features are similar to normal lung parenchyma [21]. Congenital pulmonary airway malformation (CPAM) is characterized by a haphazard distribution of bronchioles with an incomplete branching pattern, variably sized cysts and occasional metaplastic changes. These malformations may regress through the first year of life. Large, symptomatic CPAMs are associated with increased fetal morbidity/mortality and may require resection. Postnatal surgical resection is recommended for lesions that do not regress, become infected, cause respiratory distress, or develop solid components, indicating possible malignancy [21]. Fetal lung interstitial tumor (FLIT) is a benign, well-demarcated tumor that recapitulates fetal canalicular stage development, occurring at weeks gestation. It is hypothesized that FLIT reflects focal regions of arrested lung development (Table 2) [20]. Pleuropulmonary blastoma (PPB) is a malignant tumor of interstitial cells that is associated with DICER1 gene mutations and may be familial or sporadic [20]. Infants usually present with the cystic form (Type I), and as they age, can progress to the cystic solid form (Type II) and solid form (Type III) (Table 2). Chemotherapy recommendations for Types II and III continue to evolve, but vincristine, actinomycin D, ifosfamide, and doxorubicin are thought to be active agents in the treatment of PPB. While complete surgical resection may be curative, close monitoring for local recurrence, distant metastases, and associated tumors (i.e. cystic nephroma, thyroid goiters, and ovarian sex cord stromal tumors) is required [18]. Distinguishing Type II PPB from CPMT by radiography and histopathology can be challenging. The distinction is largely based on age, as PPB in a child less than one-year-old should be purely cystic (Type I) with a mild expansion of septa and a uniform population of primitive mesenchymal cells. Type II PPB develops at a median of three years of age. Our patient, despite having a mixed cystic/ solid lesion consistent with Type II PPB, presented at 8 weeks of age. This is an important clinical distinction, as Type II/III PPB have metastatic potential and are generally treated with chemotherapy, whereas CPMT does not recur or metastasize after surgical resection. Infantile (congenital) fibrosarcoma is a malignant tumor of interstitial/mesenchymal cells that rarely occurs in the lung. It is characterized by t(12;15) (p13;q25) leading to a ETV6-NTRK3 fusion. Treatment with observation alone (in patients with a complete resection), or with vincristine/doxorubicin/cyclophosphamide, or vincristine/dactinomycin/cyclophosphamide (in patients with incomplete resection) yields five-year event-free survival rates near 70% [22]. In summary, we report a diagnosis, at the most advanced age known, of a CPMT that was not present on prenatal imaging studies or within the immediate postnatal period. CPMT is a benign primary lung tumor of infancy with complications that range from respiratory distress, heart failure, polyhydramnios, and nonimmune hydrops fetalis to intrauterine fetal death. Pathologic diagnosis is characterized by bland spindled cells and atypical cartilage islands with an infiltrative growth pattern arising from the peribronchial interstitial

6 Table 2. Clinical, radiographic and pathologic features of congenital lung lesions and their usual treatment. 88 Diagnosis Congenital Fetal Lung Pleuropulmonary Congenital Congenital Sequestration Peribronchial Interstitial Tumor Blastoma Infantile Pulmonary (Intralobar/ Myofibroblastic (FLIT) (PPB) Fibrosarcoma Airway Extrolobar) Tumor (CPMT) (CIFS) Malformation (CPAM) Annals of Clinical & Laboratory Science, vol. 45, no. 1, 2015 Clinical Features Respiratory +/-100% +/- (8/10 cases) [20] ++ +/- 2/3 of cases +/- insufficiency(%) Many detected 100% Type I - 54% (median 10 months) 80% 90% Likely majority for both Diagnosed in prenatally Often within first 10 Type II - 3% (median 34 months) Very rarely intralobar and extralobar first year of life days of life, up to Type III - 1% [18] type 3 (with increased utilization 3 months[20] (median 44 months) of prenatal ultrasound) Nonimmune fetal hydrops +/- (9/20 cases) +/- (rare) +/- (rare) +/- 5-10% of cases - Pleural effusion +/- (5/20 cases) - +/- (rare) +/- +/- +/- Polyhydramnios +/- (6/20 cases) - +/- (rare) - +/- - Radiographic Features Pneumothorax - +/- + +/- +/- +/- Other features Solid, enhancing Solid, enhancing Type 1- air filled, single cyst Generally a solid Lobar, single. Most often medial, left, mass. mass. or multicystic mass. Peripheral, mass. Types 1 and 2 lower lobe. Often mixed Can have cystic Generally single, lobar. multifocal lesions more common. Only rarely are aerated soon solid and cystic. Intralobar or necrotic May contain small cysts. Type 2- both cystic and solid reported in after birth. often aerated and hyperinflated. components. components or cysts with nodules the lung. Type 1-multiple, Extralobar usually solid. Often central Type 3- usually large and solid larger air filled Systemic artery(s) arise from in location. with pleural/mediastinal cysts >3.5cm aorta. Possible air extension Type 2-small cysts bronchograms Type 3-solid appearing with some enhancement Pathologic Features Spindled interstitial/ Yes No Yes Yes No No mesenchymal proliferation Systemic feeding artery No No No No No Yes Gene mutations None None DICER1 [20] ETV6-NTRK3 [22] None None TP53 mutations Cytogenetic abnormalities Rearrangements None Trisomy 8 t (12;15)(p13;q25) None None of ch. 4, 8 and 10 Trisomy 2 [23] in one patient [10] Treatment Most reported treatment Lobectomy or Wedge excision Lobectomy with complete Complete surgical Close observation, Close observation versus in the literature pneumonectomy or lobectomy resection of locally invasive disease resection, or if requires surgical resection when feasible, +/- chemotherapy resection, +/- chemotherapy +/- radiation therapy segmentectomy vs +/- radiation therapy lobectomy

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