To the Editor:
Cancer-associated mutations are identified in some congenital pulmonary malformations (CPMs), including mutations of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene in particular (1, 2). They were described in cystic malformations, with or without mucinous islets (1, 2). The theoretical risk of a link between CPMs and cancer risk is fueling the debate about whether preventive surgery should be performed for asymptomatic CPM.
We used the large French prospective population-based MALFPULM cohort to evaluate the actual prevalence of cancer-associated mutations in CPMs and to correlate CPM phenotype with the presence of at least one oncogenic mutation. This cohort has been described in detail elsewhere (3, 4). Briefly, all pregnant women whose fetus had a prenatal diagnosis of CPM were invited to participate in the study, whatever the ultrasonic phenotype of the CPM: cystic, purely hyperechoic, or mixed. This study received institutional review board approval (Comité de Protection des Personnes Ile-de-France IV, U.S. Department of Health and Human Services Agreement no. 00003835). Follow-up of this cohort was performed up to 2 years of age and had no impact on the decision as to whether or not to perform elective surgery. When compared with children with elective surgery, nonoperated children had fewer cystic malformations but as many malformations with systemic vascularization or emphysematous images. Postnatal thoracic computed tomography description and final histological diagnosis (5) were prospectively collected in a online database. Tumor DNA was extracted from macrodissected tissue samples from the area of the malformation. The 22 gene Ion AmpliSeq Colon and Lung Cancer Research Panel v2 (Life Technologies–Thermo Fisher Scientific) was used. Mutations in DNA were detected at allele frequencies as low as 0.001 for insertions or deletions >2 bp and 0.003 for single-nucleotide variants (6). For CPMs with mutation, tissue samples from apparently normal lung parenchyma, collected at some distance from the malformation sample, were also tested, when available. A blind histological review of slides from CPMs with mutation, together with randomly selected slides from 15 tissues without mutation, was performed using a standardized grid that was created by the review panel of four pathologists from three centers.
Univariate analysis compared the following parameters between malformations with mutations and those without mutations: pre- and postnatal imaging appearance of the malformation; maximum value during pregnancy of the ratio of CPM volume to head circumference (CVRmax); severe fetal compression; and neonatal respiratory distress (3, 4). χ2 tests, Fisher’s exact tests, t tests, and univariate logistic regression were used.
Of the 426 live-born infants in the MALFPULM cohort, 285 underwent surgery before the age of 2 years, and 195 of them were genotyped. The main reason for the absence of genomic analysis was the omission of the additional consent collection. The characteristics of CPMs sent for analysis did not differ from the ones not sent. A KRAS mutation was identified in 17 cases and an fibroblast growth factor receptor 2 (FGFR2) mutation in one case (Table 1). Seven CPMs with mutation had a concomitant analysis of histologically healthy tissue. In four of them, the same mutation was identified as in the area of the malformation, with similar or lower allelic ratios.
Table 1.
Description of the 18 Cases with Mutation
| Case Number | Age at Surgery (d) | Mutation in Malformed Tissue | Allelic Ratio (%) | Mutation in Surrounding Healthy Tissue | Allelic Ratio (%) | Prenatal Imaging | Birth Weight (kg) | Neonatal Respiratory Distress* | Largest Cyst Diameter on Postnatal CT (mm) | Mucinous Component |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 641 | KRAS p.Gly12Asp c.35G>A | 13.2 | KRAS p.Gly12Asp c.35G>A | 15 | Hyperechoic | 2.8 | No | 9 | No |
| 2 | 1 | KRAS p.Gly12Asp c.35G>A | 13 | KRAS p.Gly12Asp c.35G>A | 4 | Cystic | 3.3 | Yes | 41 | No |
| 3 | 0 | KRAS p.Gly12Asp c.35G>A | 23 | NA | Cystic | 3.5 | Yes | 45 | Yes | |
| 4 | 217 | KRAS p.Gly12Asp c.35G>A | 10 | None | — | Cystic | 3.7 | No | 12 | Yes |
| 5 | 320 | KRAS p.Gly12Val c.35G>T | 4 | NA | Hyperechoic | 3 | Yes | 7 | No | |
| 6 | 192 | KRAS p.Gly12Asp c.35G>A | 11 | NA | Cystic | 3.5 | No | 33 | No | |
| 7 | 211 | KRAS p.Gly12Asp c.35G>A | 20 | NA | Cystic | 3.2 | No | 34 | Yes | |
| 8 | 410 | KRAS p.Gly12Val c.35G>T | 3 | NA | Cystic | 4.1 | No | 11 | No | |
| 9 | 783 | KRAS p.Gly12Asp c.35G>A | 12 | NA | Cystic | 3.5 | No | 21 | Yes | |
| 10 | 364 | KRAS p.Gly12Val c.35G>T | 20 | NA | Cystic | 3.4 | Yes | 40 | No | |
| 11 | 118 | KRAS p.Gly12Asp c.35G>A | 19.4 | None | — | Cystic | 3.1 | No | 17 | No |
| 12 | 4 | KRAS p.Gly12Asp c.35G>A | 18.7 | KRAS p.Gly12Asp c.35G>A | 0.7 | Cystic | 2.6 | Yes | 20 | Yes |
| 13 | 13 | KRAS p.Gly12Asp c.35G>A | 33 | KRAS p.Gly12Asp c.35G>A | 9 | Cystic | 3.3 | No | 35 | Yes |
| 14 | 391 | KRAS p.Gly12Asp c.35G>A | 4.2 | NA | Cystic | 3 | No | 26 | Yes | |
| 15 | 190 | KRAS p.Gly12Asp c.35G>A | 7.9 | None | — | Cystic | 3.8 | No | 33 | No |
| 16 | 234 | KRAS p.Gly12Arg | 27 | NA | Cystic | 3.6 | No | 24 | No | |
| 17 | 2 | KRAS p.Gly12Cys | 17 | NA | Cystic | 2.9 | Yes | 53 | Yes | |
| 18 | 0 | FGFR2 p.Cys382Arg c.1144T>C | 34 | NA | Hyperechoic | 3.2 | Yes | NA | No |
Definition of abbreviations: CT = computed tomography; NA = not applicable.
Neonatal respiratory distress was defined by having at least one of the following criteria: polypnea > 60/min or signs of retraction; need for oxygen therapy, noninvasive ventilatory support, or invasive ventilatory support; need for surgical congenital pulmonary malformation removal before the age of 7 days (3).
CPMs with mutation demonstrated higher prenatal CVRmax values (odds ratio, 1.08; 95% confidence interval, 1.02–1.14 for every 0.1 cm2 increase in CVRmax; P = 0.007), higher rate of prenatal compressive complications (P = 0.037), higher rate of neonatal respiratory distress (P = 0.024), higher rate of surgery in the first week of life (P < 0.001), and higher rate of surgery because of symptoms (P < 0.001) (Table 2). All CPMs with mutation were cystic in appearance on postnatal imaging (P = 0.001), with no difference in postnatal mean diameter of the largest cyst between CPMs with or without mutation. In 3 of the 18 CPMs with mutation, the cysts were not detected on prenatal imaging. The histological diagnosis was congenital pulmonary airway malformation (CPAM) for all CPMs with mutations (P = 0.01). Of the 66 CPMs with postnatal systemic vascularization, including 17 who were also cystic, none had a mutation (P = 0.002). Microscopically, a mucinous component was identified only in tissues with mutation (P < 0.005). However, 56% of the mutated tissues had no identifiable mucinous component on the slides reviewed. Inflammation was noted in more than half the tissues, with no association with the presence of mutations. Microscopy findings were consistent with the diagnosis of type 2 CPAM in five cases with mutations.
Table 2.
Characteristics of Patients and Lesions by Mutation Status
| No Mutation | With Mutation | P Value | |
|---|---|---|---|
| Prenatal data | |||
| Prenatal US | |||
| Hyperechogenic | 61 (34.5) | 3 (16.7) | 0.126 |
| Cystic image | 116 (65.5) | 15 (83.3) | |
| CVRmax, cm2 | 0.67 ± 0.59 | 1.24 ± 1.35 | 0.004 |
| Compression* | |||
| No | 166 (93.8) | 14 (77.8) | 0.037 |
| Yes | 11 (6.2) | 4 (22.2) | |
| Neonatal and postnatal data | |||
| Birth weight, kg | 3.3 ± 0.5 | 3.3 ± 0.4 | 0.830 |
| Prematurity | |||
| No | 164 (92.7) | 15 (83.3) | 0.172 |
| Yes | 13 (7.3) | 3 (16.7) | |
| Neonatal respiratory distress† | |||
| No | 149 (84.2) | 11 (61.1) | 0.024 |
| Yes | 28 (15.8) | 7 (38.9) | |
| Cystic image | |||
| No | 72 (40.7) | 0 | 0.001 |
| Yes | 105 (59.3) | 18 (100) | |
| Cyst diameter, mm | 22.1 ± 14.8 | 27.1 ± 13.6 | 0.200 |
| Cyst diameter > 20 mm | |||
| No | 56 (59.6) | 6 (35.2) | 0.064 |
| Yes | 38 (40.4) | 11 (64.7) | |
| Systemic vascularization | |||
| No | 110 (62.1) | 17 (100) | 0.002 |
| Yes | 66 (37.3) | 0 | |
| Median age at surgery, d | 265 | 202 | <0.001 |
| Age at surgery | |||
| ⩽7 d | 2 (1.1) | 5 (27.8) | <0.001 |
| >7 d | 175 (98.9) | 13 (72.2) | |
| Surgery indication | |||
| Symptomatic | 21 (12.0) | 8 (44.4) | <0.001 |
| Elective | 154 (88.0) | 10 (55.6) | |
| Histology by local pathologist | |||
| CPAM | 81 (45.8) | 18 (100) | 0.010 |
| Sequestration | 55 (31.1) | 0 | |
| Bronchial atresia | 3 (1.7) | 0 | |
| Congenital lobar emphysema | 5 (2.8) | 0 | |
| Bronchogenic cyst | 9 (5.1) | 0 | |
| CPAM + sequestration (hybrid) | 11 (6.2) | 0 | |
| Other | 6 (3.4) | 0 | |
| Pathological data with histological review‡ | |||
| Cuboidal epithelial cells | 3 (20) | 8 (44) | 0.174 |
| Columnar ciliated epithelial cells | 10 (71) | 17 (94) | 0.075 |
| Mucinous epithelial cells | 0 | 8 (44) | 0.004 |
| Cartilaginous nodules | 3 (20) | 0 | 0.047 |
| Chronic inflammation | 9 (60) | 10 (56) | 0.797 |
Definition of abbreviations: CPAM = congenital pulmonary airway malformation; CVRmax = maximum value during pregnancy of the ratio of CPM volume to head circumference; US = ultrasound.
Data are presented as n (%) or mean ± SD unless otherwise noted.
Presence of hydrops, hydrothorax, ascites, or hydramnios during pregnancy.
Neonatal respiratory distress was defined by having at least one of the following criteria: polypnea > 60/min or signs of retraction; need for oxygen therapy, noninvasive ventilatory support, or invasive ventilatory support; need for surgical congenital pulmonary malformation removal before the age of 7 days (3).
n = 15 tissues without mutation for histological review.
In our prospective cohort, we demonstrate that mutations of cancer-associated genes are identified only in CPMs with a cystic component on postnatal imaging, with a prevalence of 15% within these cystic CPMs. All cystic CPMs are at risk of mutation, regardless of cyst size, type of CPAM, or identifiable mucinous epithelial cells by microscopy. This is concordant with the previous description of KRAS mutations away from mucinous islets of type 1 CPAMs or in type 2 CPAMs (1). Among the 22 genes tested on our panel, only KRAS and FGFR2 were identified with mutations. The FGFR2 mutation in one case was the first to be described in a CPM. As one-third of tissues with mutation were obtained from neonates, the results suggest that these mutations are prenatally acquired, consistent with the description of neonatal mucinous adenocarcinoma associated with CPAM and KRAS mutations (7).
The fact that mutations are associated with larger and more symptomatic CPMs raises questions about their role in the pathophysiology of CPMs. KRAS gain of function has been shown to result in an increase in the branching program, with a cystic airway branch phenotype, and the suppression of alveolar differentiation (8). Similarly, the p.Cys382Arg FGFR2 mutation is known to result in receptor activation, and high FGF10/FGFR2 activity in embryonic lungs has been shown to lead to cyst formation in both rodents (9) and human fetal explants (10).
Cancers other than mucinous adenocarcinomas have been associated with CPMs, including rhabdomyosarcoma or pleuropulmonary blastoma. However, these lesions are now believed to differ fundamentally from CPMs because of the lack of prenatal diagnosis (11) and a different genetic and molecular background (12). Thus, the discussion of tumor risk of prenatally diagnosed malformations remains focused on mucinous adenocarcinomas, which are themselves mostly associated with a KRAS mutation.
The detection of KRAS mutations in apparently healthy areas distant from the cystic area raises questions about the need for systematic searches for these mutations in surgical specimens and for long-term monitoring in children with mutations. However, to our knowledge, there are no published cases of mucinous adenocarcinoma occurring during follow-up after surgery for CPM in the absence of an initial cancerous lesion. Thus, although our findings support specific management of cystic CPMs, either preventive removal or long-term follow-up, they do not support systematic searches for cancer-associated mutations in surgical specimens or particular follow-up for children undergoing surgery with a mutation that would have been identified in the malformative tissue.
Acknowledgments
MALFPULM Study Group members: Guillaune Thouvenin, Michele Larroquet, Sabine Irtan, Sabah Boudjemaa, Lucie Guilbaud, Anne-Marie Darras, Jean-Marie Jouannic, and Erik Hervieux, Laure Choupeaux, Insaf Berrazaga, Sophie Collardeau-Frachon, Cecile Picard, and Jérôme Massardier, Virginie Fouquet, Clementine Vigier, Edouard Habonimana, Gwenaelle Le Bouar, Isabelle Bertorello, Nathalie Lelong, Isabelle Monier, Guillaume Levard, Thierry Jo Molina, Julien Stirnemann, Philippe Roth, Thierry Bultez, Laurent J. Salomon, Yves Ville, Catherine Llerena, Catherine Thong-Vanh, Christophe Piolat, Rony Sfeir, Caroline Thumerelle, Thameur Rakza, Antoine Deschildre, Florence Biquard, Guillaume Podevin, Jean-Paul Bory, Elisabeth Alanio, Mickael Pomedio, Francis Lefebvre, CHU Reims, France; François Goffinet and Vassilis Tsatsaris, AP-HP, Cochin-Port Royal, Paris, France; Anne-Sophie Valat-Rigot and Héloise Ducoin, Centre Hospitalier, Lens, France; Caroline Parico, Stephan Denapolicocci, Norbert Winer and Nathalie Banaszkiewicz, CHU Nantes, France; Eve Mousty and Edith Sabatier, CHU Nîmes, France; Bernard Romeo, Philippe Buisson, Charles Muszynski and Jean Gondry, CHU Amiens, France; Alexandra Benachi, Julien Saada and Alexandra Letourneau, AP-HP, Clamart, France; Valérie Goua, CHU Poitiers, France; Marie-Noelle Lebras, Christine Grapin, Jonathan Rosenblatt and Jean-Francois Oury, AP-HP, Robert Debré, Paris, France; Agnès Sartor, Mathieu Morin, Léa Roditis, CHU Toulouse, France; Fabienne Prieur, Cecile Fanget and François Varlet, CHU St Etienne, France; Thibaud Quibel, CH Poissy, France; Olivier Jaby, Claudine Touboul and Vanina Castaigne, Centre Hospitalier Intercommunal, Créteil, France; Loic Sentilhes, Frederic Coatleven, Hala Feghali, Rafaelle Mangione and Frédéric Lavrand, CHU Bordeaux, France; Valérie Bonfiglioli and Lionel Carbillon, AP-HP, Bondy, France; Isabelle Petit, Adam Kandem Simo, Maguelonne Pons, Helene Laurichesse, Carole Egron and Loren Deslandes, CHU Clermont-Ferrand, France; Claire Dazel-Salonne, Centre Hospitalier, Le Mans, France; Romain Favre, Jacqueline Matis and François Becmeur, CHU Strasbourg, France; Anne Paris, France, Talence, France; Franck Perrotin, Isabelle Gibertini and Hubert Lardy, CHU Tours, France; Cynthia Trastour, Jean Breaud and Jean-François Lecompte, CHU Nice, France; Nicolas Mottet and Arnaud Fotso Kamdem, CHU Besançon, France; Louis Lemelle, Olivier Morel and Estelle Perdriolle, CHU Nancy, France; Jean-Vladimir Gomola and Marie-Laure Eszto-Cambon, Centre Hospitalier Régional, Metz, France; Anne-Helene Saliou, Pierrick Cros and Philine Devries, CHU Brest, France; Jacques Brouard and Thierry Petit, CHU Caen, France; Frédéric Elbaz, CHU Rouen, France.
Footnotes
Supported by the Assistance Publique–Hôpitaux de Paris (Département de la Recherche Clinique et du Développement) and a grant from the French Ministry of Health Programme Hospitalier de Recherche Clinique–PHRC 2013 grant PHRC AOM130581 – NI13005.
Author Contributions: C.D. and B.K. conceptualized and designed the study, supervised the analysis, drafted the initial manuscript, and reviewed and revised the manuscript. M.R. designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. S.G. and H.B. carried out the genomic analyses, supervised genomic analysis, and reviewed and revised the manuscript. L.G.-R. supervised tissue sample collection, reviewed tissue slides, contributed to data interpretation, and critically reviewed the manuscript for important intellectual content. O.A., A.B., F.H., and N.K.-D. coordinated and supervised data collection, contributed to data interpretation, and critically reviewed the manuscript for important intellectual content. All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Clinical trial registered with www.clinicaltrials.gov (NCT02352207).
Originally Published in Press as DOI: 10.1164/rccm.202208-1573LE on October 26, 2022
Author disclosures are available with the text of this letter at www.atsjournals.org.
Contributor Information
for the MALFPULM study group:
Sabah Boudjemaa, Laure Choupeaux, Sophie Collardeau-Frachon, Virginie Fouquet, Edouard Habonimana, Erik Hervieux, Nathalie Lelong, Guillaume Levard, Thierry Jo Molina, Cecile Picard, Christophe Piolat, Rony Sfeir, Florence Biquard, Jean-Paul Bory, François Goffinet, Valat-Rigot As, Norbert Winer, Eve Mousty, Charles Muszynski, Alexandra Benachi, Laurent J. Salomon, Valérie Goua, Jean-Marie Jouannic, Gwenaelle Le Bouar, Jérôme Massardier, Jonathan Rosenblatt, Agnès Sartor, Catherine Thong-Vanh, Fabienne Prieur, Thibaud Quibel, Claudine Touboul, Jean Gondry, Loic Sentilhes, Valérie Bonfiglioli, Lionel Carbillon, Anne-Helene Saliou, Julien Saada, Alexandra Letourneau, Helene Laurichesse, Carole Egron, Loren Deslandes, Vanina Castaigne, Claire Dazel-Salonne, Julien Stirnemann, Philippe Roth, Thierry Bultez, Yves Ville, Vassilis Tsatsaris, Lucie Guilbaud, Anne-Marie Darras, Jean-Francois Oury, Cecile Fanget, Romain Favre, Anne Paris, Franck Perrotin, Nathalie Banaszkiewicz, Thameur Rakza, Mathieu Morin, Cynthia Trastour, Nicolas Mottet, Frederic Coatleven, Elisabeth Alanio, Olivier Morel, Estelle Perdriolle, Marie-Laure Eszto-Cambon, Insaf Berrazaga, Guillaume Podevin, Hala Feghali, Caroline Thumerelle, Rafaelle Mangione, Marie-Noelle Lebras, Héloise Ducoin, Bernard Romeo, Philippe Buisson, Pierrick Cros, Léa Roditis, Hiline Devries, Jacques Brouard, Thierry Petit, Isabelle Petit, Adam Kandem Simo, Maguelonne Pons, Olivier Jaby, Catherine Llerena, Edith Sabatier, Guillaune Thouvenin, Michele Larroquet, Sabine Irtan, Christine Grapin, Caroline Parico, François Varlet, Jacqueline Matis, François Becmeur, Isabelle Gibertini, Hubert Lardy, Stephan Denapolicocci, Antoine Deschildre, Jean Breaud, Jean-François Lecompte, Arnaud Fotso Kamdem, Frédéric Elbaz, Frédéric Lavrand, Mickael Pomedio, Francis Lefebvre, Jean Louis Lemelle, Vladimir Gomola, Clementine Vigier, and Isabelle Monier
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