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Congenital pulmonary lymphangiectasis: Report of an autopsy case masquerading as pulmonary interstitial emphysema
ARTICLE IN PRESS Pathology – Research and Practice 206 (2010) 522–526
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Teaching cases
Congenital pulmonary lymphangiectasis: Report of an autopsy case masquerading as pulmonary interstitial emphysema Sohsuke Yamada a,n, Masanori Hisaoka b, Tetsuo Hamada c, Shunsuke Araki d, Mika Shiraishi d a
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan Departments of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan c Department of Surgical Pathology, Kyushu Rosai Hospital, Kitakyushu, Japan d Departments of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan b
a r t i c l e in f o
a b s t r a c t
Article history: Received 9 December 2009 Received in revised form 9 February 2010 Accepted 13 February 2010
We describe the clinicopathologic features of a case of congenital pulmonary lymphangiectasis (CPL). A male Japanese infant born prematurely at 34 weeks of gestation developed a severe moaning sound, dyspnea, and prominent respiratory acidosis about 10 min after delivery. A chest X-ray film showed bilateral frosted glass-like infiltrates with an air bronchogram and an air leak around the cardiac shadow, suggesting pneumomediastinum. The patient died of hypoxemic respiratory failure 13 h after birth. The death was complicated by bilateral pneumothorax, despite the initiation of artificial ventilation and administration of a surfactant. At autopsy, small cystic lesions were noted in the visceral pleura, interlobular septa, and hilum of both lungs. A histologic examination of the lungs showed diffuse and marked dilation of the lymphatic channels in the subpleural, peribronchial, interlobular, and hilar areas. The channels were lined with flattened endothelium, which was immunohistochemically positive for D2-40. In addition, lymphangiectasis was found around the thymus and intra-abdominal organs, but no cardiovascular anomalies were seen. The findings conformed to a primary form of CPL, Noonan Group 3. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis because of the overlapping clinicopathologic features, a giant cell reaction surrounding the interstitial cystic lesions, a histologic hallmark of PIE, was absent in the present case. & 2010 Elsevier GmbH. All rights reserved.
Keywords: Congenital pulmonary lymphangiectasis (CPL) Neonate Pulmonary interstitial emphysema (PIE)
Introduction Congenital pulmonary lymphangiectasis (CPL) is a rare and poorly documented disease of neonates, and is characterized by prominent and diffuse microcystic lymphatic dilation in the septal, subpleural, and peribronchial tissue throughout both lungs. Although an accurate incidence of CPL is elusive, a previous autopsy study has suggested that approximately 1% of all infants stillborn or dead in the neonatal period have CPL [1], and at least 30 and 130 cases of CPL have been reported in Japan and in the world. According to previous CPL reports, males are affected more than females, and there is no familial predisposition in most cases. However, a few cases have described an association with genetic disorders, such as Noonan, Down, Turner, and Fryns syndromes [2,3]. CPL is generally divided into two groups: primary (congenital) and secondary. In addition, Noonan classified CPL into three groups:[4] group 1 is characterized by generalized lymphangiectasis (lymphedema with intestinal lymphangiectasis) [5,6]; in group 2, CPL is caused by pulmonary venous hypertention or obstruction associated with surgery, radiation, infection,
n
Corresponding author. Tel.: + 81 93 691 7426, fax: + 81 93 603 8518. E-mail address: [email protected] (S. Yamada).
0344-0338/$ - see front matter & 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2010.02.007
tumor, or cardiovascular anomalies, including anomalous pulmonary venous drainage or cor triatriatum [7,8]; and group 3 is due to a primary developmental defect of the pulmonary lymphatics [9,10]. Therefore, groups 1 and 3 of CPL are primary (congenital), and group 2 is secondary. In particular, group 3 CPL is characterized by severely disturbed pulmonary gas exchange and a poor prognosis [4–11], and some reports have shown that neonates with group 3 CPL have lymphatic dilation in lungs and multiple other organs, and pursue an adverse clinical course [12–14]. Because of the clinicopathologic similarities between group 3 CPL and pulmonary interstitial emphysema (PIE), CPL tends to be misdiagnosed as PIE [15,16]. Although a conclusive diagnosis of CPL can only be made pathologically or by autopsy, CPL should be distinguished from PIE because of their distinct treatments and prognoses [1,15,16]. In this paper, we describe an autopsy case of CPL group 3 with a special reference to distinction from PIE.
Clinical summary A male Japanese neonate was born at 34 weeks of gestation after pregestational treatment for infertility and medication for
ARTICLE IN PRESS S. Yamada et al. / Pathology – Research and Practice 206 (2010) 522–526
Fig. 1. Plain chest X-ray. A chest X-ray film about 10 min after birth shows bilateral frosted glass-like infiltrates with air bronchogram and an air leak (arrows) around the cardiac shadow, suggesting pneumomediastinum.
mild amniorrhexis, and was the second child born to nonconsanguineous parents. The parents’ first baby weighed 3,276 g and was born at 40 weeks of spontaneous gestation 5 years before this case. The patient weighed about 2,300 g at birth, and his Apgar scores were 7 and 8 at 1 and 5 min, respectively. The amniotic fluid was clear, and the amount was approximately 400 mL. The placenta, weighing 460 g, had no remarkable features. However, he developed a severe moaning sound and dyspnea about 10 min after birth, in spite of artificial oxygenation. A chest X-ray film showed bilateral frosted glass-like infiltrates with an air bronchogram and an air leak around the cardiac shadow, suggesting pneumomediastinum (Fig. 1). Despite artificial ventilation after intubation and surfactant substitution therapy, he died of hypoxemic respiratory failure 13 h after birth due to persistent pneumomediastinum and bilateral pneumothorax, which were resistant to the puncture by thoracostomy tubes and the intravenous administration of dopamine and bicarbonate. The blood cell counts and values of blood biochemistry were within normal limits, except for a venous blood sample when breathing was at 30% oxygen concentration in the incubator showing elevated partial pressure of carbon dioxide (PaCO2) (70.7 mm Hg), and decreased base excess ( 7.4 mEq/L) and pH (7.145), indicating marked respiratory acidosis. An autopsy was performed approximately 3 h after death.
Pathological findings At autopsy, the baby measured 45 cm in height and weighed 2,328 g. An external examination showed no detectable anomalies or abnormalities except for several needle marks on the chest wall and the extremities. In an internal examination of the thoracic cavity (Fig. 2A), there was a bilateral clear yellow pleural fluid (20 mL; 20 mL) without hemorrhage or chylothorax, and one cystic lesion was noted in the anterior mediastinum. In addition to the visceral pleura, both lungs demonstrated a network of dilated cystic spaces. The left and the right lungs weighed 21 and 23 g, respectively, and were firm in consistency. The cut surfaces of the congestive lungs (Fig. 2B) also showed numerous cystic spaces ranging from about 1 to 2 mm in size in the surface visceral pleura, as well as in the thickened interlobular septum and hilum, although the cystic changes were inconspicuous after
523
formalin fixation. These findings were well-recognized in a hematoxylin–eosin-stained scanning magnification of the lungs (Fig. 2C). The heart, weighing 18 g, showed no gross abnormalities. No specific findings were identified in the other internal organs or the brain, except for a clear yellow peritoneal fluid (150 mL). A histologic examination of the lungs showed diffuse and marked lymphatic dilation in the subpleural, peribronchial (Fig. 3A), interlobular (Fig. 3B), and hilar areas. The dilated lymphatic channels were invariably lined with flattened endothelium, which was immunohistochemically positive for D2-40 (Nichirei Bioscience Co., Tokyo, Japan, 1:1) (Fig. 3C), CD31 (Dako Cytomation Co., Kyoto, Japan, 1:20), and CD34 (IMMUNOTECH, Marseille, France, 1:50). No CD68-positive (Dako, 1:100) foreign-body type histiocytes were seen in these cystically dilated lesions. Most of the mature-looking alveolar spaces were collapsed, and the alveolar walls were close to each other with frequent deposits of hyaline membrane along the bronchioli or alveolar ducts, accompanied by accumulated basophilic amorphous materials (Fig. 3D), which were negative for Kossa staining and probably derived from the necrotic bronchioloalveolar epithelium [17]. In addition, mild lymphangiectasis was found around the mediastinum, including the thymus (Fig. 4A) and the intra-abdominal organs, such as the adrenal gland (Fig. 4B), kidney, pancreas, spleen, sigmoid colon, and abdominal aorta, all of which also lacked any foreign-body reaction. Pseudofollicular cysts were present in the definitive adrenal cortex (Fig. 4B). The diagnosis of CPL, a primary form, Noonan Group 3, was established based on these features.
Discussion Congenital pulmonary lymphangiectasis (CPL) was first described by Virchow in 1856 [18], demonstrating clinical manifestations of aggressive dyspnea after birth, cyanosis, and death. The lungs of CPL show grossly dilated lymph channels beneath the pleura and in the variably thickened interlobular septa, and these dilated lymph vessels are also recognized in the subpleura, interlobular septa, and peribronchial tissue throughout both lungs microscopically [1–16]. The mortality rate of neonatal CPL was considered to be nearly 100% more than 30 years ago. However, because neonatal care has advanced significantly since then, the outcome of the patients has improved, especially for those who present the symptoms after the neonatal period or for those belonging to Noonan classification of group 1 or 2 [4–10,12]. Nevertheless, Noonan group 3 CPL is usually associated with an adverse clinical course and high mortality [4–12]. It is well-known that group 3 CPL is due to a developmental error, probably resulting from a failure of pulmonary interstitial connective tissue to regress and leading to the dilation of pulmonary lymphatic vessels [16]. This usually occurs after the 16th week of fetal life [19,20], followed by insufficient dilatation of alveolar structures. These pathologic changes might result in severe pulmonary symptoms [12,21], probably including those due to respiratory distress syndrome (RDS). CPL is often difficult to differentiate from pulmonary interstitial emphysema (PIE) because of the clinicopathologic similarities between these two diseases [1,15,16]. PIE in the newborn is a frequent complication of RDS or hyaline membrane disease. The typical chest X-ray findings of PIE include multiple large cysts (0.8–3.0 cm) in a background of smaller cysts (0.2–0.4 cm) with uniform minute reticulogranular densities and abnormal airbronchograms caused by RDS [22]. The X-ray in the current case showed bilateral frosted glass- or cotton-like infiltrates with an air bronchogram and an air leak around the cardiac shadow due to
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Fig. 2. Gross findings of the lungs. (A) An internal examination of the thoracic cavity reveals one cystically dilated lesion (arrow) in the anterior mediastinum. Both lungs also demonstrate multiple cystically dilated spaces (arrowheads); (B) on the cut surface of both lungs, numerous microcystic spaces about 1–2 mm are seen from the surface visceral pleura to interlobular septum and hilum; (C) these gross findings are well-supported by the scanning magnification (H&E stain, rt. lower lobe), showing diffuse cystic dilation (arrowheads) of the subpleural, thickened interlobular and hilar areas. Bar= 10 mm.
RDS and pneumomediastinum, partly resembling the findings of PIE complicated by pneumomediastinum. Moreover, the patient suffered an uncontrollable bilateral pneumothorax after artificial ventilation was started. Therefore, a clinical distinction between these entities is not straightforward, and a definitive diagnosis of CPL can be made only by pathologic examinations [1,15,16]. The small cysts of PIE are invariably lined by mono- and multinucleated giant histiocytes displaying a foreign-body type reaction [22,23]. In contrast, cysts in CPL are lined with flattened endothelium without evidence of aggregated histiocytes [1–16]. Although our case demonstrated pneumothorax and pneumomediastinum, their etiologic mechanisms are not easy to explain. However, the bilateral pneumothorax might have been caused by the artificial ventilation, which often results in air leak to the extra airspaces, rather than by RDS itself. As to the pneumomediastinum prior to the ventilation and pneumothorax, a dilated lymphatic vessel might have been misunderstood as air leakage forming the persistent cystic lesion in the anterior mediastinum, in which not only the immunohistochemical result of D2-40 showed positive staining but also no giant cell reaction was identified. Furthermore, it is certain that RDS is sometimes accompanied by pulmonary lymphangiectasis, which might or might not lead to mediastinal lymphangiectasis, to a degree that
renders its distinction from CPL difficult [23]. However, in RDS, distended lymphatics are primarily interlobular in location, while in CPL they are also found in the subpleural and peribronchial areas and are wider in size [23], as in this case. From these viewpoints, it is suggested that this pulmonary to mediastinal lymphangiectasis is caused not only by CPL but also by RDS, although to a lesser degree. Besides PIE and CPL should be distinguished from diffuse pulmonary lymphangiomatosis (DPL) [12,24,25], because of their similar clinical manifestations and histologic features. In addition, an immunohistochemical approach cannot differentiate between CPL and DPL, both of which share positive staining for vimentin, CD31, CD34, factor VIII-related antigen, and D2-40 [26]. Histologically, DPL is characterized by an increased number of complex anastomosing lymphatic channels, in which variable dilation or expansion is a secondary phenomenon within the lungs and mediastinum, whereas in CPL, the lymphatics are not increased in number and are relatively more regular in size and shape [1–16,24,25]. Based on these features, DPL could also be excluded in our case. In summary, we herein reported a neonate case of group 3 CPL with pathologic findings of lymphangiectasis in or around multiple organs, including both lungs, the mediastinum, and those in
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Fig. 3. Histologic findings of CPL. (A–C) Low-power views of the lung show diffuse and marked lymphatic dilation of the peribronchial (A), subpleural, and interlobular (B) areas. They are invariably lined by flattened lymphatic endothelium (H&E stain), which is immunohistochemically positive for D2-40 (C). No foreign-body type monoor multi-nucleated histiocytes are seen in these cystically dilated lymph vessels; and (D) many mature-looking alveolar spaces are collapsed, and the alveolar walls are close to each other with deposits of hyaline membrane along the bronchioli to alveolar ducts, accompanied by accumulated basophilic amorphous materials (H&E stain).
Fig. 4. Histologic findings in the extrapulmonary organs. (A and B) Lymphangiectasis is found around the thymus (A) and adrenal gland (B) (H&E stain). No foreign-body reaction is recognized in these cystically dilated lymph vessels (A and B). Pseudofollicular cystic change is seen in the definitive adrenal cortex (B).
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the intra-abdominal cavity. Although CPL is a very rare disorder, we should be aware that CPL is a possible causal condition in the development of severe pulmonary symptoms in neonates.
References [1] K.M. Laurence, Congenital pulmonary cystic lymphangiectasis, J. Pathol. Bacteriol. 70 (1955) 325–333. [2] S. Jacquemont, S. Barbarot, M. Boceno, et al., Familial congenital pulmonary lymphangiectasia, non-immune hydrops fetalis, facial and lower limb lymphedema: confirmation of Njolstad’s report, Am. J. Med. Genet. 93 (2000) 264–268. [3] J.P. Fryns, P. Moerman, 46,XY/46,XX mosaicism and congenital pulmonary lymphangiectasis with chylothorax, Am. J. Med. Genet. 47 (1993) 934–935. [4] J.A. Noonan, L.R.B.N. Walters, J.T. Reeves, Congenital pulmonary lymphangiectasis, Am. J. Dis. Child. 120 (1970) 314–319. [5] J.E. Maclean, E. Cohen, M. Weinstein, Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy, Pediatrics 109 (2002) 1117–1180. [6] C. Bellini, E. Bonioli, N. Josso, et al., Persistence of Mullerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the urioste syndrome, Am. J. Med. Genet. 104 (2001) 69–74. [7] C.W.M. Verlaat, H.M. Peters, B.A. Semmekrot, et al., Congenital pulmonary lymphangiectasia, presenting as a unilateral hyperlucent lung, Eur. J. Pediatr. 153 (1994) 202–205. [8] M.K. Gilewski, C.C. Statler, G. Kohut, et al., Congenital pulmonary lymphangiectasia, and other anomalies in a child: provisionally unique syndrome?, Am J. Med. Genet. 66 (1996) 438–440. [9] A. Huber, D. Schranz, I. Blaha, et al., Congenital pulmonary lymphangiectasia, Pediatr. Pulmonol. 10 (1991) 310–313. [10] P. Moerman, K. Vandenberghe, H. Devlieger, et al., Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality, Am. J. Med. Genet. 47 (1993) 54–58.
[11] T. Hoehn, M. William, A.R. Mcphaden, Endothelial, inducible and neuronal nitric oxide synthase in congenital pulmonary lymphangiectasia, Eur. Respir J. 27 (2006) 1311–1315. [12] H. Hirano, T. Nishigami, A. Okimura, et al., Autopsy case of congenital pulmonary lymphangiectasis, Pathol. Int. 54 (2004) 532–536. [13] J. Frank, P.G. Piper, M. Wis, Congenital pulmonary cystic lymphangiectasis, JAMA 171 (1959) 1094–1098. [14] J.B.J. Mckendry, W.K. Lindsay, M.C. Gerstein, Congenital defect of lymphatics in infancy, Pediatrics 19 (1957) 21–35. [15] J. Finder, J. Steinfeld, Congenital pulmonary lymphangiectasia, N Engl. J. Med. 350 (2004) 948. [16] Z.Y. Xiao, Y. Tao, X.Y. Tang, et al., Congenital pulmonary lymphangiectasis, World J. Pediatr. 5 (2009) 68–70. [17] J.S. Wigglesworth (Ed.), Perinatal Pathology, 1st ed, W.B. Saunders Company, Philadelphia, 1984. [18] R. Virchow, Gesammelte abhandlungen zur wissenschaftlichen medicin, Farankfort: Meidinger (1856) 982. [19] K.M. Laurence, Congenital pulmonary cystic lymphangiectasis, J. Pathol. Bacteriol. 350 (1995) 948. [20] J.L. Faul, G.J. Berry, T.V. Colby, et al., Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome, Am. J. Respir. Crit. Care Med. 161 (2000) 1037–1046. [21] S.N. Janett, I. Webster, J.L. Braudo, Congenital dilatation of the pulmonary lymphatics, Pediatrics 31 (1963) 416–425. [22] J.T. Stocker, J.E. Madewell, Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome, Pediatrics 59 (1977) 847–857. [23] J.W. Keeling (Ed.), Fetal and Neonatal Pathology, 2nd ed, Springer-Verlag, London, 1993. [24] J.K. Bush, R.L. McLean, H.O. Sieker, Diffuse lung disease due to lymphangiomyoma, Am. J. Med. 46 (1969) 645–654. [25] M. Brown, T. Pysher, CM. Coffin, Lymphangioma and congenital pulmonary lymphangiectasis: a histologic, immunohistochemical, and clinicopathologic comparison, Mod. Pathol. 12 (1999) 569–575. [26] M. Fukunaga, Expression of D2-40 in lymphatic endothelium of normal tissues and in vascular tumors, Histopathology 46 (2005) 396–402.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Congenital pulmonary lymphangiectasis: Report of an autopsy case masquerading as pulmonary interstitial emphysema Sohsuke Yamada a,n, Masanori Hisaoka b, Tetsuo Hamada c, Shunsuke Araki d, Mika Shiraishi d a
Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan Departments of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan c Department of Surgical Pathology, Kyushu Rosai Hospital, Kitakyushu, Japan d Departments of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan b
a r t i c l e in f o
a b s t r a c t
Article history: Received 9 December 2009 Received in revised form 9 February 2010 Accepted 13 February 2010
We describe the clinicopathologic features of a case of congenital pulmonary lymphangiectasis (CPL). A male Japanese infant born prematurely at 34 weeks of gestation developed a severe moaning sound, dyspnea, and prominent respiratory acidosis about 10 min after delivery. A chest X-ray film showed bilateral frosted glass-like infiltrates with an air bronchogram and an air leak around the cardiac shadow, suggesting pneumomediastinum. The patient died of hypoxemic respiratory failure 13 h after birth. The death was complicated by bilateral pneumothorax, despite the initiation of artificial ventilation and administration of a surfactant. At autopsy, small cystic lesions were noted in the visceral pleura, interlobular septa, and hilum of both lungs. A histologic examination of the lungs showed diffuse and marked dilation of the lymphatic channels in the subpleural, peribronchial, interlobular, and hilar areas. The channels were lined with flattened endothelium, which was immunohistochemically positive for D2-40. In addition, lymphangiectasis was found around the thymus and intra-abdominal organs, but no cardiovascular anomalies were seen. The findings conformed to a primary form of CPL, Noonan Group 3. Although pulmonary interstitial emphysema (PIE) was considered an important differential diagnosis because of the overlapping clinicopathologic features, a giant cell reaction surrounding the interstitial cystic lesions, a histologic hallmark of PIE, was absent in the present case. & 2010 Elsevier GmbH. All rights reserved.
Keywords: Congenital pulmonary lymphangiectasis (CPL) Neonate Pulmonary interstitial emphysema (PIE)
Introduction Congenital pulmonary lymphangiectasis (CPL) is a rare and poorly documented disease of neonates, and is characterized by prominent and diffuse microcystic lymphatic dilation in the septal, subpleural, and peribronchial tissue throughout both lungs. Although an accurate incidence of CPL is elusive, a previous autopsy study has suggested that approximately 1% of all infants stillborn or dead in the neonatal period have CPL [1], and at least 30 and 130 cases of CPL have been reported in Japan and in the world. According to previous CPL reports, males are affected more than females, and there is no familial predisposition in most cases. However, a few cases have described an association with genetic disorders, such as Noonan, Down, Turner, and Fryns syndromes [2,3]. CPL is generally divided into two groups: primary (congenital) and secondary. In addition, Noonan classified CPL into three groups:[4] group 1 is characterized by generalized lymphangiectasis (lymphedema with intestinal lymphangiectasis) [5,6]; in group 2, CPL is caused by pulmonary venous hypertention or obstruction associated with surgery, radiation, infection,
n
Corresponding author. Tel.: + 81 93 691 7426, fax: + 81 93 603 8518. E-mail address: [email protected] (S. Yamada).
0344-0338/$ - see front matter & 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2010.02.007
tumor, or cardiovascular anomalies, including anomalous pulmonary venous drainage or cor triatriatum [7,8]; and group 3 is due to a primary developmental defect of the pulmonary lymphatics [9,10]. Therefore, groups 1 and 3 of CPL are primary (congenital), and group 2 is secondary. In particular, group 3 CPL is characterized by severely disturbed pulmonary gas exchange and a poor prognosis [4–11], and some reports have shown that neonates with group 3 CPL have lymphatic dilation in lungs and multiple other organs, and pursue an adverse clinical course [12–14]. Because of the clinicopathologic similarities between group 3 CPL and pulmonary interstitial emphysema (PIE), CPL tends to be misdiagnosed as PIE [15,16]. Although a conclusive diagnosis of CPL can only be made pathologically or by autopsy, CPL should be distinguished from PIE because of their distinct treatments and prognoses [1,15,16]. In this paper, we describe an autopsy case of CPL group 3 with a special reference to distinction from PIE.
Clinical summary A male Japanese neonate was born at 34 weeks of gestation after pregestational treatment for infertility and medication for
ARTICLE IN PRESS S. Yamada et al. / Pathology – Research and Practice 206 (2010) 522–526
Fig. 1. Plain chest X-ray. A chest X-ray film about 10 min after birth shows bilateral frosted glass-like infiltrates with air bronchogram and an air leak (arrows) around the cardiac shadow, suggesting pneumomediastinum.
mild amniorrhexis, and was the second child born to nonconsanguineous parents. The parents’ first baby weighed 3,276 g and was born at 40 weeks of spontaneous gestation 5 years before this case. The patient weighed about 2,300 g at birth, and his Apgar scores were 7 and 8 at 1 and 5 min, respectively. The amniotic fluid was clear, and the amount was approximately 400 mL. The placenta, weighing 460 g, had no remarkable features. However, he developed a severe moaning sound and dyspnea about 10 min after birth, in spite of artificial oxygenation. A chest X-ray film showed bilateral frosted glass-like infiltrates with an air bronchogram and an air leak around the cardiac shadow, suggesting pneumomediastinum (Fig. 1). Despite artificial ventilation after intubation and surfactant substitution therapy, he died of hypoxemic respiratory failure 13 h after birth due to persistent pneumomediastinum and bilateral pneumothorax, which were resistant to the puncture by thoracostomy tubes and the intravenous administration of dopamine and bicarbonate. The blood cell counts and values of blood biochemistry were within normal limits, except for a venous blood sample when breathing was at 30% oxygen concentration in the incubator showing elevated partial pressure of carbon dioxide (PaCO2) (70.7 mm Hg), and decreased base excess ( 7.4 mEq/L) and pH (7.145), indicating marked respiratory acidosis. An autopsy was performed approximately 3 h after death.
Pathological findings At autopsy, the baby measured 45 cm in height and weighed 2,328 g. An external examination showed no detectable anomalies or abnormalities except for several needle marks on the chest wall and the extremities. In an internal examination of the thoracic cavity (Fig. 2A), there was a bilateral clear yellow pleural fluid (20 mL; 20 mL) without hemorrhage or chylothorax, and one cystic lesion was noted in the anterior mediastinum. In addition to the visceral pleura, both lungs demonstrated a network of dilated cystic spaces. The left and the right lungs weighed 21 and 23 g, respectively, and were firm in consistency. The cut surfaces of the congestive lungs (Fig. 2B) also showed numerous cystic spaces ranging from about 1 to 2 mm in size in the surface visceral pleura, as well as in the thickened interlobular septum and hilum, although the cystic changes were inconspicuous after
523
formalin fixation. These findings were well-recognized in a hematoxylin–eosin-stained scanning magnification of the lungs (Fig. 2C). The heart, weighing 18 g, showed no gross abnormalities. No specific findings were identified in the other internal organs or the brain, except for a clear yellow peritoneal fluid (150 mL). A histologic examination of the lungs showed diffuse and marked lymphatic dilation in the subpleural, peribronchial (Fig. 3A), interlobular (Fig. 3B), and hilar areas. The dilated lymphatic channels were invariably lined with flattened endothelium, which was immunohistochemically positive for D2-40 (Nichirei Bioscience Co., Tokyo, Japan, 1:1) (Fig. 3C), CD31 (Dako Cytomation Co., Kyoto, Japan, 1:20), and CD34 (IMMUNOTECH, Marseille, France, 1:50). No CD68-positive (Dako, 1:100) foreign-body type histiocytes were seen in these cystically dilated lesions. Most of the mature-looking alveolar spaces were collapsed, and the alveolar walls were close to each other with frequent deposits of hyaline membrane along the bronchioli or alveolar ducts, accompanied by accumulated basophilic amorphous materials (Fig. 3D), which were negative for Kossa staining and probably derived from the necrotic bronchioloalveolar epithelium [17]. In addition, mild lymphangiectasis was found around the mediastinum, including the thymus (Fig. 4A) and the intra-abdominal organs, such as the adrenal gland (Fig. 4B), kidney, pancreas, spleen, sigmoid colon, and abdominal aorta, all of which also lacked any foreign-body reaction. Pseudofollicular cysts were present in the definitive adrenal cortex (Fig. 4B). The diagnosis of CPL, a primary form, Noonan Group 3, was established based on these features.
Discussion Congenital pulmonary lymphangiectasis (CPL) was first described by Virchow in 1856 [18], demonstrating clinical manifestations of aggressive dyspnea after birth, cyanosis, and death. The lungs of CPL show grossly dilated lymph channels beneath the pleura and in the variably thickened interlobular septa, and these dilated lymph vessels are also recognized in the subpleura, interlobular septa, and peribronchial tissue throughout both lungs microscopically [1–16]. The mortality rate of neonatal CPL was considered to be nearly 100% more than 30 years ago. However, because neonatal care has advanced significantly since then, the outcome of the patients has improved, especially for those who present the symptoms after the neonatal period or for those belonging to Noonan classification of group 1 or 2 [4–10,12]. Nevertheless, Noonan group 3 CPL is usually associated with an adverse clinical course and high mortality [4–12]. It is well-known that group 3 CPL is due to a developmental error, probably resulting from a failure of pulmonary interstitial connective tissue to regress and leading to the dilation of pulmonary lymphatic vessels [16]. This usually occurs after the 16th week of fetal life [19,20], followed by insufficient dilatation of alveolar structures. These pathologic changes might result in severe pulmonary symptoms [12,21], probably including those due to respiratory distress syndrome (RDS). CPL is often difficult to differentiate from pulmonary interstitial emphysema (PIE) because of the clinicopathologic similarities between these two diseases [1,15,16]. PIE in the newborn is a frequent complication of RDS or hyaline membrane disease. The typical chest X-ray findings of PIE include multiple large cysts (0.8–3.0 cm) in a background of smaller cysts (0.2–0.4 cm) with uniform minute reticulogranular densities and abnormal airbronchograms caused by RDS [22]. The X-ray in the current case showed bilateral frosted glass- or cotton-like infiltrates with an air bronchogram and an air leak around the cardiac shadow due to
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Fig. 2. Gross findings of the lungs. (A) An internal examination of the thoracic cavity reveals one cystically dilated lesion (arrow) in the anterior mediastinum. Both lungs also demonstrate multiple cystically dilated spaces (arrowheads); (B) on the cut surface of both lungs, numerous microcystic spaces about 1–2 mm are seen from the surface visceral pleura to interlobular septum and hilum; (C) these gross findings are well-supported by the scanning magnification (H&E stain, rt. lower lobe), showing diffuse cystic dilation (arrowheads) of the subpleural, thickened interlobular and hilar areas. Bar= 10 mm.
RDS and pneumomediastinum, partly resembling the findings of PIE complicated by pneumomediastinum. Moreover, the patient suffered an uncontrollable bilateral pneumothorax after artificial ventilation was started. Therefore, a clinical distinction between these entities is not straightforward, and a definitive diagnosis of CPL can be made only by pathologic examinations [1,15,16]. The small cysts of PIE are invariably lined by mono- and multinucleated giant histiocytes displaying a foreign-body type reaction [22,23]. In contrast, cysts in CPL are lined with flattened endothelium without evidence of aggregated histiocytes [1–16]. Although our case demonstrated pneumothorax and pneumomediastinum, their etiologic mechanisms are not easy to explain. However, the bilateral pneumothorax might have been caused by the artificial ventilation, which often results in air leak to the extra airspaces, rather than by RDS itself. As to the pneumomediastinum prior to the ventilation and pneumothorax, a dilated lymphatic vessel might have been misunderstood as air leakage forming the persistent cystic lesion in the anterior mediastinum, in which not only the immunohistochemical result of D2-40 showed positive staining but also no giant cell reaction was identified. Furthermore, it is certain that RDS is sometimes accompanied by pulmonary lymphangiectasis, which might or might not lead to mediastinal lymphangiectasis, to a degree that
renders its distinction from CPL difficult [23]. However, in RDS, distended lymphatics are primarily interlobular in location, while in CPL they are also found in the subpleural and peribronchial areas and are wider in size [23], as in this case. From these viewpoints, it is suggested that this pulmonary to mediastinal lymphangiectasis is caused not only by CPL but also by RDS, although to a lesser degree. Besides PIE and CPL should be distinguished from diffuse pulmonary lymphangiomatosis (DPL) [12,24,25], because of their similar clinical manifestations and histologic features. In addition, an immunohistochemical approach cannot differentiate between CPL and DPL, both of which share positive staining for vimentin, CD31, CD34, factor VIII-related antigen, and D2-40 [26]. Histologically, DPL is characterized by an increased number of complex anastomosing lymphatic channels, in which variable dilation or expansion is a secondary phenomenon within the lungs and mediastinum, whereas in CPL, the lymphatics are not increased in number and are relatively more regular in size and shape [1–16,24,25]. Based on these features, DPL could also be excluded in our case. In summary, we herein reported a neonate case of group 3 CPL with pathologic findings of lymphangiectasis in or around multiple organs, including both lungs, the mediastinum, and those in
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Fig. 3. Histologic findings of CPL. (A–C) Low-power views of the lung show diffuse and marked lymphatic dilation of the peribronchial (A), subpleural, and interlobular (B) areas. They are invariably lined by flattened lymphatic endothelium (H&E stain), which is immunohistochemically positive for D2-40 (C). No foreign-body type monoor multi-nucleated histiocytes are seen in these cystically dilated lymph vessels; and (D) many mature-looking alveolar spaces are collapsed, and the alveolar walls are close to each other with deposits of hyaline membrane along the bronchioli to alveolar ducts, accompanied by accumulated basophilic amorphous materials (H&E stain).
Fig. 4. Histologic findings in the extrapulmonary organs. (A and B) Lymphangiectasis is found around the thymus (A) and adrenal gland (B) (H&E stain). No foreign-body reaction is recognized in these cystically dilated lymph vessels (A and B). Pseudofollicular cystic change is seen in the definitive adrenal cortex (B).
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the intra-abdominal cavity. Although CPL is a very rare disorder, we should be aware that CPL is a possible causal condition in the development of severe pulmonary symptoms in neonates.
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