- Email: [email protected]
Solitary intrapulmonary cystic lymphangioma in an infant: A case report with literature review
Pathology – Research and Practice 206 (2010) 851–856
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Solitary intrapulmonary cystic lymphangioma in an infant: A case report with literature review Hiroshi Minato a,∗ , Sachiko Kaji a,1 , Eriko Kinoshita a , Nozomu Kurose a , Takayuki Nojima a , Miyuki Kohno b , Kunio Konuma b,2 , Hiromichi Ikawa b a b
Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Japan Department of Pediatric Surgery, Kanazawa Medical University, Japan
a r t i c l e
i n f o
Article history: Received 26 May 2010 Received in revised form 5 September 2010 Accepted 9 September 2010 Keywords: Lymphangioma Lung Cyst Giant cells Immunohistochemistry
a b s t r a c t Lymphangioma rarely presents as a solitary pulmonary lesion. We encountered a case of solitary cystic lymphangioma and present its clinicopathologic and immunohistochemical findings. A 2-month-old boy was referred to the hospital after developing a persistent cough. Chest X-ray showed a large cyst in the right lung. Under the preoperative diagnosis of bronchogenic cyst, he underwent right lower lobectomy at the age of 11 months. The resected specimen contained a 5.5-cm septate cystic lesion. Microscopically, the lesion consisted of a large cystic space and interconnected slit-like spaces surrounding bronchovascular islands. The cyst was lined by a monolayer of flat cells with focal multinucleated giant cells. Immunohistochemically, the cells lining the cystic lesion were positive for D2-40, Prox1, CD34, and CD31, and weakly positive for VEGFR-3, but were negative for AE1/3, HMB45, VEGF-A, VFGF-C, VEGFR-1. Differential diagnoses included lobar or interstitial emphysema, bronchogenic cyst, congenital pulmonary airway malformation and alveolar adenoma. D2-40 and Prox1 were useful in differentiation and in determining the extent of the lesion. A review of the literature found only 15 cases of solitary pulmonary lymphangioma. In younger patients, the lesions tend to occupy more of the lung. Focal giant cell reaction has not been described in the reported papers. © 2010 Elsevier GmbH. All rights reserved.
Introduction Lymphangiomas are much less common than hemangiomas and comprise <5% of all vascular tumors [2,3,29]. It is generally believed that most are developmental anomalies rather than true neoplasms. Lymphangiomas can affect any site in the body, but 75% occur in the head and neck, followed by 20% in the axilla. Less than 1% of lymphangiomas are mediastinal [31], and pulmonary lesions are even less common. Primary pulmonary lymphatic disorders or neoplasms are rare and are often difficult to diagnose and classify [6]. The abnormal lymphatic vessels may be cavernous or cystic. Only 15 solitary pulmonary lesions have been reported in the English literature to our knowledge [5,7,8,13–15,21–27,30,32]. We encountered an infant with large solitary cystic lymphangioma and present the clinico-
∗ Corresponding author at: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 9200293, Japan. Tel.: +81 76 218 8017; fax: +81 76 218 8440. E-mail address: [email protected] (H. Minato). 1 She is now in the Department of Pathology, Toho University Sakura Medical Center, Japan. 2 He is now in the Department of Pediatric Surgery, Fuji Heavy Industries Health Insurance Corporation Ota General Hospital, Gunma, Japan. 0344-0338/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2010.09.004
pathological and immunohistochemical findings. The differential diagnoses are also discussed.
Clinical summary A 2-month-old boy was referred to our hospital because of a persistent cough. Chest X-ray had shown a large cyst in the right lung. He had been born at full-term by a normal delivery, and no skeletal or cardiovascular anomaly was apparent at birth. On admission, chest X-ray revealed a large cyst in the middle to upper field of the right lung (Fig. 1a). No clear air-fluid level was seen. Computed tomography (CT) (Fig. 1b) and magnetic resonance imaging (MRI) studies (Fig. 1c) showed a septate cystic lesion occupying the right lung. The mediastinum had shifted to the left. No other intraor extrapulmonary cystic lesions were found. A Tc-99m macroaggregated albumin (MAA) pulmonary perfusion study revealed that right-to-left pulmonary blood flow ratio was 44.2–55.8%, which suggested a decrease in the right lung blood flow resulting from compression by the cystic lesion. Under a preoperative diagnosis of bronchogenic cyst or congenital pulmonary airway malformation (CPAM), the patient underwent right lower lobectomy at the age of 11 months. The postoperative course was uneventful, and the patient has remained well and free of recurrence for 47 months.
852
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
Fig. 1. (a) Chest X-ray shows a large cystic lesion in the right middle field of the lung. No air-fluid level is apparent. (b) CT reveals a few septa within the large cystic lesion in the lung parenchyma. (c) MRI reveals that the lesion compressed the right lung with shift of the mediastinum to the left.
Pathological findings The resected specimen contained a septate cystic lesion measuring 5.5 × 5.5 × 4.5 cm (Fig. 2). The cyst contained a small amount of serous fluid, and the inner surface was smooth. Microscopically, the lesion was composed of large cystic spaces compressing the lung parenchyma and bronchovascular bundles (Fig. 3a). The compressed lung tissue comprised the wall of the cyst and contained many slit-like spaces interconnected with the cystic lumen. These slit-like spaces occasionally surrounded bronchovascular islands (Fig. 3b). The inner surface of the cyst was lined
with a monolayer of flat cells, the nuclei of which were bland and elongated without mitosis (Fig. 3c). Occasionally, erosion of the surface was observed with focal proliferation of fibromuscular tissue and multinucleated giant cells (Fig. 3d). Hemosiderin-laden alveolar macrophages were distributed in the cyst wall. No significant mature smooth muscle proliferation or lymphoid follicles were seen. Immunohistochemically, the cells lining the cystic lesion were diffusely positive for D2-40 (Signet, MA, USA), Prox1 (abcam, Tokyo) (Fig. 4), CD34 (Nichirei, Tokyo, Japan), and CD31 (DAKO, Grostrup, Denmark), but they were negative for cytokeratin AE1/AE3 (DAKO), HMB45 (DAKO), estrogen receptor (ER) (DAKO), and progesterone receptor (PgR) (DAKO). Ki-67(MIB-1) (DAKO) labeling index was <1%. Based on the morphological findings and the results of immunohistochemical studies, a diagnosis of intrapulmonary cystic lymphangioma was made. As for the markers of vascular endothelial growth factors, VEGFR-3 (FLT-4) (Santa Cruz, CA, USA) was very weakly positive (Fig. 4), while VEGF-A (Santa Cruz), VEGF-C (IBL, Gunma, Japan), and VEGFR-1 (FLT-1) (Santa Cruz) were negative for the lining endothelial cells. Discussion
Fig. 2. Cut surface of the right lower lobe shows a large cystic lesion, measuring 5.5 × 5.5 × 4.5 cm, with septa and a few vessels. The lesion contained little serous fluid.
We have presented the clinicopathological and immunohistochemical findings of a solitary cystic lymphangioma of the lung. The patient had a large cystic lesion with a lining of flat endothelial cells. The cystic lumen interconnected with slit-like spaces in the lung parenchyma. The interstitial, perivascular, and peribronchial distributions of the spaces were consistent with the localization of lymphatic vessels. The cyst and slit-like spaces did not contain erythrocytes. The cells lining the lesion were immunohistochemically positive for endothelial markers: D2-40, Prox1, CD31, and CD34, but negative for cytokeratin AE1/AE3. D2-40 is a monoclonal antibody to podoplanin which is a 40-kDa O-linked sialoglycoprotein detected on a variety of tissues including fetal testis and testicular germ cell tumors [19]. D2-40 is a highly reliable lymphatic endothelial marker used in tissues that
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
853
Fig. 3. Microscopical feature of the lesion (HE staining). (a) The cyst wall is composed of the compressed lung parenchyma. (b) The cystic spaces are interconnected with peribronchial and perivascular slit-like spaces. (c) The inner surface of the cysts are lined by a monolayer of flat endothelial cells (arrows). (d) Multinucleated giant cells are seen focally in the cyst wall.
are fixed with formalin and embedded in paraffin [10]. In normal vessels, D2-40 stains the endothelium of lymphatic channels but not that of blood vessels [10], and it has been widely used to evaluate the lymphatic invasion of cancer [1,4,11]. One of the earliest known events in lymphangiogenesis is expression of the homeobox transcription factor Prox1, and VEGFR-3, which is the high-affinity ligand of VEGF-C [17,18]. Immunohistochemically, VEGFR-3 and Prox1 have been reported to be highly expressed in lymphangiomas, but VEGFR-3 is less specific than D2-40 and Prox1 [18]. In the present case, CD31 and CD34 were diffusely positive in the cells lining the lesion and the pulmonary blood vessels; in contrast, D2-40 and Prox1 were only positive in the cells lining the lesion and the slit-like spaces and normal lymphatics in the bronchovascular bundles and pleura. These findings are consistent with the lesion being derived from lymphatic vessels. The roles of various vascular endothelial growth factors have been recently actively investigated, especially in the area of tumor lymphangiogenesis [20]. However, only few studies have reported their role in lymphangioma cases [9,18]. Itakura et al. reported that VEGF-C was immunohistochemically detected in 32% of 108 cases of lymphangiomatous lesions, and VEGFR-3 was detected in 70% of the same lesions [9]. Only weak immunostaining of VEGFR-3 and negative staining of VEGF-A, VEGF-C, and VEGFR-1 may favor the malformative nature of this case compared to neoplastic lesions. But further study is necessary to clarify the role of these growth factors and pathogenesis of pulmonary lymphangioma cases. Disorders of the pulmonary lymphatic system are rare and occur in a variety of non-neoplastic and neoplastic settings, and congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders [6,16]. Classification of these disorders is challenging. Faul et al. classified pulmonary lymphatic disorders into lymphangiomas, lymphangiectasis, lymphangiomatosis, lymphatic
dysplasia syndrome, and other intrathoracic lymphatic disorders, such as lymphangioleiomyomatosis (LAM) and lymphangiosarcoma [6]. Primary pulmonary lymphangiectasis occur in neonate babies, sporadically or with autosomal recessive inheritance, and the lesions are usually diffuse and fatal [6,16]. Secondary lymphangiectasis can arise from thoracic-duct obstruction, thoracic masses, and total anomalous pulmonary venous return. Pathologically, pulmonary lymphangiectasis shows diffuse dilated lymphatics in the perihilar tissue, subpleural regions and in the interstitium [16,28]. Such perihilar and subpleural lymphangiectasis was not observed in the present case. Moreover, the present patient had no other anomalies or significant family history. Pulmonary lymphangiomatosis can pathologically resemble a lymphangioma, but differs in that it shows proliferation of complex anastomosing lymphatic spaces involving both lungs [6,28]. Occasionally it displays concomitant fascicles of smooth muscle. Chest radiographs demonstrate increased interstitial markings and pleural effusions [6]. A search of the international literature found only 15 cases of solitary pulmonary lymphangioma in addition to the present case (Table 1) [5,7,8,13–15,21–27,30,32]. On analysis of the complete series, including the present case, patient age ranged from 2 days to 59 years (median 21 years, 44% were younger than 10 years). The female to male ratio was 3–5. Nearly half of the patients were asymptomatic, and the rest had a variety of symptoms such as cough, dyspnea, hemoptysis, fever, pain, and pneumothorax. The lesions were randomly distributed without any propensity for the right or left lung. The maximum diameter ranged from 1.5 to 18 cm (median 3.5 cm); average size was 5.1 cm (median 5.8 cm) in those under 10 years and 4.2 cm (median 1.8 cm) in those aged 10 years and older. In the neonatal cases reported by Milovic et al. and Lee et
854
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
Fig. 4. Immunohistochemical findings. (a) The cells lining the inner surface of the cystic lesion are positive for D2-40. (b) Immunostaining for D2-40 is helpful in discerning the extent of the lesion in the lung tissue (arrows). (c) Prox1 is also positive in the nuclei of endothelial cells of the lesion. (d) VEGFR-3 shows very weak staining in the lining endothelial cells (arrows).
al., the lesions were described as occupying the entire lobe; however, the precise size was not given. Younger patients tended to have lesions that occupied more of the lung. Extrapulmonary cystic lymphangiomas most commonly affect children. They are more common in some congenital disorders including Turner syndrome, hydrops fetalis, Down syndrome and fetal alcohol syndrome. However, none of the pulmonary cystic lymphangiomas in the literature showed any association with congenital disorders. The differential diagnoses of intrapulmonary lymphangioma include lobar or interstitial emphysema, bronchogenic cyst, CPAM, and alveolar adenoma. The localized form of interstitial emphysema cases predominantly occurs in infants receiving mechanical ventilation [12]. Microscopically, the cystic wall consists of connective tissues with occasional giant cell reaction and no apparent
lining. The present case did not have a history of mechanical ventilation or respiratory distress. Moreover, giant cells were seen only focally and most of the cystic wall had a lymphatic endothelial lining. Foreign-body-type giant cells are often referred to as the histological hallmark of interstitial emphysema. However, it is noteworthy that those giant cells can also be seen in a case of pulmonary lymphangioma, the finding not having been mentioned in the reported cases of pulmonary lymphangioma. In summary, solitary intrapulmonary lymphangioma is a rare, benign and localized lesion. D2-40 and Prox1 were shown to be useful in differentiating it from other conditions and in determining the extent of the lesion. In neonatal or infant patients, lesions tend to occupy more of the lung. Microscopically, they can be accompanied by focal giant cell reaction.
855
Acknowledgment
Air and serous fluid Air and serous fluid Air and serous fluid Air Bloody fluid Bloody fluid Serous and xanthochromic fluid Serous fluida Serous fluida ND Gelatinous secretion ND Bloody fluid Air and blood clot Serous fluid Blood clot
This work was supported in part by the Grant-in-Aid for Scientific Research (C) (No.20590586) from Japan Society for the Promotion of Science. References
m, months; M, male; F, female; LLL, left lower lobe; RUL, right upper lobe; RLL, right lower lobe; RML, right middle lobe; CPAM, congenital pulmonary airway malformation; ND, not described. a Findings from histopathological observation.
Cystic Cystic Cystic Cystic Cavernous Cavernous Cavernous Cavernous Cavernous Cavernous and cystic Cystic and cavernous Cavernous Cystic Cystic Cystic Cystic Lobectomy Bilobectomy Lobectomy Pneumonectomy Pneumonectomy Lobectomy Lobectomy Partial resection Partial resection ND Cystectomy Partial resection Partial resection Pneumonectomy Partial resection Partial resection Congenital tension cysts CPAM Bronchogenic cyst CPAM No definitive diagnosis Malignant tumors or malformations Hamartomatous lesion ND ND ND Bronchogenic cyst Non-small cell cancer Bronchogenic cyst ND Benign cystic tumor Benign cystic lesion Entire lobe Entire lobe 5.5 3.5 8 9.5 6.5 2 1.8 ND 18 1.8 1.6 ND 1.5 3 LLL RUL RLL LLL RLL LLL RML RUL LLL RLL R hilar RUL RLL R hilar RLL UL Respiratory distress Dyspnea Cough Pneumothorax Fever, Cough Hemoptysis None None Cough None Pain, dyspnea None None Hemoptysis, cough None None 0 2m 2m 6m 5 9 10 21 39 41 49 51 53 54 57 59 Milovic [21] Lee [14] Present case Kim [13] Drut [5] Nakajima [23] Hamada [7] Takemura [27] Stephens [25] Shaffer [24] Limmer [15] Wilson [30] Nagayasu [22] Holden [8] Takahara [26] Yamagishi [32]
M F M M F F M M M F M M F M M F
Symptoms Sex Age (year) References
Table 1 Clinicopathological features of pulmonary lymphangiomas.
Location
Size (cm)
Preoperative diagnosis
Treatment
Type
Contents
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
[1] J. Afonso, L.L. Santos, T. Amaro, F. Lobo, A. Longatto-Filho, The aggressiveness of urothelial carcinoma depends to a large extent on lymphovascular invasion – the prognostic contribution of related molecular markers, Histopathology 55 (2009) 514–524. [2] A. Beham, Lymphangioma, in: C.D.M. Fletcher, K.K. Unni, F. Mertens (Eds.), Pathology and Genetics Tumours of Soft Tissue and Bone, IARC Press, Lyon, 2002, pp. 162–163. [3] A.H. Bill Jr., D.S. Sumner, A unified concept of lymphangioma and cystic hygroma, Surg. Gynecol. Obstet. 120 (1965) 79–86. [4] P. Birner, M. Schindl, A. Obermair, G. Breitenecker, H. Kowalski, G. Oberhuber, Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer, Int. J. Cancer 95 (2001) 29–33. [5] R. Drut, H.H. Mosca, Intrapulmonary cystic lymphangioma, Pediatr. Pulmonol. 22 (1996) 204–206. [6] J.L. Faul, G.J. Berry, T.V. Colby, S.J. Ruoss, M.B. Walter, G.D. Rosen, T.A. Raffin, Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome, Am. J. Respir. Crit. Care Med. 161 (2000) 1037–1046. [7] K.Y. Hamada, Y. Ishii, M. Nakaya, N. Sawabata, K. Fukuda, H. Suzuki, Solitary lymphangioma of the lung, Histopathology 27 (1995) 482–483. [8] W.E. Holden, J.F. Morris, R. Antonovic, T.H. Gill, S. Kessler, Adult intrapulmonary and mediastinal lymphangioma causing haemoptysis, Thorax 42 (1987) 635–636. [9] E. Itakura, H. Yamamoto, Y. Oda, M. Furue, M. Tsuneyoshi, VEGF-C and VEGFR-3 in a series of lymphangiomas: is superficial lymphangioma a true lymphangioma? Virchows Arch. 454 (2009) 317–325. [10] H.J. Kahn, D. Bailey, A. Marks, Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas, Mod. Pathol. 15 (2002) 434–440. [11] H.J. Kahn, A. Marks, A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors, Lab. Invest. 82 (2002) 1255–1257. [12] A.L. Katzenstein, Katzenstein and Askin’s Surgical Pathology of Non-neoplastic Lung Disease, Saunders Elsevier, Philadelphia, 2006, p. 400. [13] W.S. Kim, K.S. Lee, I. Kim, K.M. Yeon, C.J. Kim, J.G. Chi, J.G.M.C. Han, Cystic intrapulmonary lymphangioma: HRCT findings, Pediatr. Radiol. 25 (1995) 206–207. [14] C.H. Lee, Y.D. Kim, K.I. Kim, Y.T. Lim, K.M. Lee, K.U. Choi, J.S. Lee, M.Y. Sol, Intrapulmonary cystic lymphangioma in a 2-month-old infant, J. Korean Med. Sci. 19 (2004) 458–461. [15] S. Limmer, M. Krokowski, P. Kujath, Pulmonary lymphangioma, Ann. Thorac. Surg. 85 (2008) 336–339. [16] C.J. Lockwood, A.S. Nadel, M.E. King, D.J. Roberts, Case records of the Massachusetts General Hospital. Case 16-2009. A 32-year-old pregnant woman with an abnormal fetal ultrasound study, N. Engl. J. Med. 360 (2009) 2225–2235. [17] T. Mäkinen, C. Norrmen, T.V. Petrova, Molecular mechanisms of lymphatic vascular development, Cell. Mol. Life Sci. 64 (2007) 1915–1929. [18] C.C. Mankey, J.B. McHugh, D.G. Thomas, D.R. Lucas, Can lymphangiosarcoma be resurrected? A clinicopathological and immunohistochemical study of lymphatic differentiation in 49 angiosarcomas, Histopathology 56 (2010) 364–371. [19] A. Marks, D.R. Sutherland, D. Bailey, J. Iglesias, J. Law, M. Lei, H. Yeger, D. Banerjee, R. Baumal, Characterization and distribution of an oncofetal antigen (M2A antigen) expressed on testicular germ cell tumours, Br. J. Cancer 80 (1999) 569–578. [20] M. Matsuura, M. Onimaru, Y. Yonemitsu, H. Suzuki, T. Nakano, H. Ishibashi, K. Shirasuna, K. Sueishi, Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells, Am. J. Pathol. 175 (2009) 1709–1721. [21] I. Milovic, D. Oluic, Lymphangioma of the lung associated with respiratory distress in a neonate, Pediatr. Radiol. 22 (1992) 156. [22] T. Nagayasu, T. Hayashi, K. Ashizawa, M. Muraoka, T. Tagawa, S. Akamine, T. Oka, A case of solitary pulmonary lymphangioma, J. Clin. Pathol. 56 (2003) 396–398. [23] J. Nakajima, A. Goto, S. Takamoto, T. Murakawa, T. Fukami, M. Kusakabe, Invasive lymphangioma of the lung manifesting as a large pulmonary mass with hemoptysis: report of a case, Surg. Today 37 (2007) 418–422. [24] K. Shaffer, M.L. Rosado-de-Christenson, E.F. Patz Jr., S. Young, C.F. Farver, Thoracic lymphangioma in adults: CT and MR imaging features, Am. J. Roentgenol. 162 (1994) 283–289. [25] F.G. Stephens, S.M. Roberts, M.W. Wolcott, Peripheral lymphangioma of the lung, J. Thorac. Surg. 36 (1958) 182–184. [26] T. Takahara, Y. Morisaki, T. Torigoe, S. Sano, E. Nakamura, K. Fujino, H. Yoshida, Y. Ishii, H. Hidaka, Intrapulmonary cystic lymphangioma: report of a case, Surg. Today 28 (1998) 1310–1312. [27] T. Takemura, M. Watanabe, K. Takagi, S. Tanaka, S. Aida, Thoracoscopic resection of a solitary pulmonary lymphangioma: report of a case, Surg. Today 25 (1995) 651–653. [28] W.D. Travis, T.V. Colby, M.N. Koss, M.L. Rosado-de-Christenson, N.L. Muller, T.E. King, Congenital anomalies and pediatric disorders: vascular anomalies, in:
856
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
W.D. Travis, T.V. Colby, M.N. Koss, M.L. Rosado-de-Christenson, N.L. Muller, T.E. King (Eds.), Non-neoplastic Disorder of the Lower Respiratory Tract, American Registry of Pathology and the Armed Forces Institute of Pathology, Washington, DC, 2002, pp. 501–507. [29] W.L. Watson, W.B. McCarthy, Blood and lymph vessel tumors. A report of 1056 cases, Surg. Gynecol. Obstet. 71 (1940) 569–588. [30] C. Wilson, F.B. Askin, R.F. Heitmiller, Solitary pulmonary lymphangioma, Ann. Thorac. Surg. 71 (2001) 1337–1338.
[31] C.C. Wright, D.M. Cohen, R.K. Vegunta, J.T. Davis, D.R. King, Intrathoracic cystic hygroma: a report of three cases, J. Pediatr. Surg. 31 (1996) 1430– 1432. [32] S. Yamagishi, K. Koizumi, T. Hirata, K. Hirai, J. Kurita, K. Shimizu, Experience of thoracoscopic extirpation of intrapulmonary lymphangioma, Jpn. J. Thorac. Cardiovasc. Surg. 53 (2005) 313–316.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Solitary intrapulmonary cystic lymphangioma in an infant: A case report with literature review Hiroshi Minato a,∗ , Sachiko Kaji a,1 , Eriko Kinoshita a , Nozomu Kurose a , Takayuki Nojima a , Miyuki Kohno b , Kunio Konuma b,2 , Hiromichi Ikawa b a b
Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Japan Department of Pediatric Surgery, Kanazawa Medical University, Japan
a r t i c l e
i n f o
Article history: Received 26 May 2010 Received in revised form 5 September 2010 Accepted 9 September 2010 Keywords: Lymphangioma Lung Cyst Giant cells Immunohistochemistry
a b s t r a c t Lymphangioma rarely presents as a solitary pulmonary lesion. We encountered a case of solitary cystic lymphangioma and present its clinicopathologic and immunohistochemical findings. A 2-month-old boy was referred to the hospital after developing a persistent cough. Chest X-ray showed a large cyst in the right lung. Under the preoperative diagnosis of bronchogenic cyst, he underwent right lower lobectomy at the age of 11 months. The resected specimen contained a 5.5-cm septate cystic lesion. Microscopically, the lesion consisted of a large cystic space and interconnected slit-like spaces surrounding bronchovascular islands. The cyst was lined by a monolayer of flat cells with focal multinucleated giant cells. Immunohistochemically, the cells lining the cystic lesion were positive for D2-40, Prox1, CD34, and CD31, and weakly positive for VEGFR-3, but were negative for AE1/3, HMB45, VEGF-A, VFGF-C, VEGFR-1. Differential diagnoses included lobar or interstitial emphysema, bronchogenic cyst, congenital pulmonary airway malformation and alveolar adenoma. D2-40 and Prox1 were useful in differentiation and in determining the extent of the lesion. A review of the literature found only 15 cases of solitary pulmonary lymphangioma. In younger patients, the lesions tend to occupy more of the lung. Focal giant cell reaction has not been described in the reported papers. © 2010 Elsevier GmbH. All rights reserved.
Introduction Lymphangiomas are much less common than hemangiomas and comprise <5% of all vascular tumors [2,3,29]. It is generally believed that most are developmental anomalies rather than true neoplasms. Lymphangiomas can affect any site in the body, but 75% occur in the head and neck, followed by 20% in the axilla. Less than 1% of lymphangiomas are mediastinal [31], and pulmonary lesions are even less common. Primary pulmonary lymphatic disorders or neoplasms are rare and are often difficult to diagnose and classify [6]. The abnormal lymphatic vessels may be cavernous or cystic. Only 15 solitary pulmonary lesions have been reported in the English literature to our knowledge [5,7,8,13–15,21–27,30,32]. We encountered an infant with large solitary cystic lymphangioma and present the clinico-
∗ Corresponding author at: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 9200293, Japan. Tel.: +81 76 218 8017; fax: +81 76 218 8440. E-mail address: [email protected] (H. Minato). 1 She is now in the Department of Pathology, Toho University Sakura Medical Center, Japan. 2 He is now in the Department of Pediatric Surgery, Fuji Heavy Industries Health Insurance Corporation Ota General Hospital, Gunma, Japan. 0344-0338/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.prp.2010.09.004
pathological and immunohistochemical findings. The differential diagnoses are also discussed.
Clinical summary A 2-month-old boy was referred to our hospital because of a persistent cough. Chest X-ray had shown a large cyst in the right lung. He had been born at full-term by a normal delivery, and no skeletal or cardiovascular anomaly was apparent at birth. On admission, chest X-ray revealed a large cyst in the middle to upper field of the right lung (Fig. 1a). No clear air-fluid level was seen. Computed tomography (CT) (Fig. 1b) and magnetic resonance imaging (MRI) studies (Fig. 1c) showed a septate cystic lesion occupying the right lung. The mediastinum had shifted to the left. No other intraor extrapulmonary cystic lesions were found. A Tc-99m macroaggregated albumin (MAA) pulmonary perfusion study revealed that right-to-left pulmonary blood flow ratio was 44.2–55.8%, which suggested a decrease in the right lung blood flow resulting from compression by the cystic lesion. Under a preoperative diagnosis of bronchogenic cyst or congenital pulmonary airway malformation (CPAM), the patient underwent right lower lobectomy at the age of 11 months. The postoperative course was uneventful, and the patient has remained well and free of recurrence for 47 months.
852
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
Fig. 1. (a) Chest X-ray shows a large cystic lesion in the right middle field of the lung. No air-fluid level is apparent. (b) CT reveals a few septa within the large cystic lesion in the lung parenchyma. (c) MRI reveals that the lesion compressed the right lung with shift of the mediastinum to the left.
Pathological findings The resected specimen contained a septate cystic lesion measuring 5.5 × 5.5 × 4.5 cm (Fig. 2). The cyst contained a small amount of serous fluid, and the inner surface was smooth. Microscopically, the lesion was composed of large cystic spaces compressing the lung parenchyma and bronchovascular bundles (Fig. 3a). The compressed lung tissue comprised the wall of the cyst and contained many slit-like spaces interconnected with the cystic lumen. These slit-like spaces occasionally surrounded bronchovascular islands (Fig. 3b). The inner surface of the cyst was lined
with a monolayer of flat cells, the nuclei of which were bland and elongated without mitosis (Fig. 3c). Occasionally, erosion of the surface was observed with focal proliferation of fibromuscular tissue and multinucleated giant cells (Fig. 3d). Hemosiderin-laden alveolar macrophages were distributed in the cyst wall. No significant mature smooth muscle proliferation or lymphoid follicles were seen. Immunohistochemically, the cells lining the cystic lesion were diffusely positive for D2-40 (Signet, MA, USA), Prox1 (abcam, Tokyo) (Fig. 4), CD34 (Nichirei, Tokyo, Japan), and CD31 (DAKO, Grostrup, Denmark), but they were negative for cytokeratin AE1/AE3 (DAKO), HMB45 (DAKO), estrogen receptor (ER) (DAKO), and progesterone receptor (PgR) (DAKO). Ki-67(MIB-1) (DAKO) labeling index was <1%. Based on the morphological findings and the results of immunohistochemical studies, a diagnosis of intrapulmonary cystic lymphangioma was made. As for the markers of vascular endothelial growth factors, VEGFR-3 (FLT-4) (Santa Cruz, CA, USA) was very weakly positive (Fig. 4), while VEGF-A (Santa Cruz), VEGF-C (IBL, Gunma, Japan), and VEGFR-1 (FLT-1) (Santa Cruz) were negative for the lining endothelial cells. Discussion
Fig. 2. Cut surface of the right lower lobe shows a large cystic lesion, measuring 5.5 × 5.5 × 4.5 cm, with septa and a few vessels. The lesion contained little serous fluid.
We have presented the clinicopathological and immunohistochemical findings of a solitary cystic lymphangioma of the lung. The patient had a large cystic lesion with a lining of flat endothelial cells. The cystic lumen interconnected with slit-like spaces in the lung parenchyma. The interstitial, perivascular, and peribronchial distributions of the spaces were consistent with the localization of lymphatic vessels. The cyst and slit-like spaces did not contain erythrocytes. The cells lining the lesion were immunohistochemically positive for endothelial markers: D2-40, Prox1, CD31, and CD34, but negative for cytokeratin AE1/AE3. D2-40 is a monoclonal antibody to podoplanin which is a 40-kDa O-linked sialoglycoprotein detected on a variety of tissues including fetal testis and testicular germ cell tumors [19]. D2-40 is a highly reliable lymphatic endothelial marker used in tissues that
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
853
Fig. 3. Microscopical feature of the lesion (HE staining). (a) The cyst wall is composed of the compressed lung parenchyma. (b) The cystic spaces are interconnected with peribronchial and perivascular slit-like spaces. (c) The inner surface of the cysts are lined by a monolayer of flat endothelial cells (arrows). (d) Multinucleated giant cells are seen focally in the cyst wall.
are fixed with formalin and embedded in paraffin [10]. In normal vessels, D2-40 stains the endothelium of lymphatic channels but not that of blood vessels [10], and it has been widely used to evaluate the lymphatic invasion of cancer [1,4,11]. One of the earliest known events in lymphangiogenesis is expression of the homeobox transcription factor Prox1, and VEGFR-3, which is the high-affinity ligand of VEGF-C [17,18]. Immunohistochemically, VEGFR-3 and Prox1 have been reported to be highly expressed in lymphangiomas, but VEGFR-3 is less specific than D2-40 and Prox1 [18]. In the present case, CD31 and CD34 were diffusely positive in the cells lining the lesion and the pulmonary blood vessels; in contrast, D2-40 and Prox1 were only positive in the cells lining the lesion and the slit-like spaces and normal lymphatics in the bronchovascular bundles and pleura. These findings are consistent with the lesion being derived from lymphatic vessels. The roles of various vascular endothelial growth factors have been recently actively investigated, especially in the area of tumor lymphangiogenesis [20]. However, only few studies have reported their role in lymphangioma cases [9,18]. Itakura et al. reported that VEGF-C was immunohistochemically detected in 32% of 108 cases of lymphangiomatous lesions, and VEGFR-3 was detected in 70% of the same lesions [9]. Only weak immunostaining of VEGFR-3 and negative staining of VEGF-A, VEGF-C, and VEGFR-1 may favor the malformative nature of this case compared to neoplastic lesions. But further study is necessary to clarify the role of these growth factors and pathogenesis of pulmonary lymphangioma cases. Disorders of the pulmonary lymphatic system are rare and occur in a variety of non-neoplastic and neoplastic settings, and congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders [6,16]. Classification of these disorders is challenging. Faul et al. classified pulmonary lymphatic disorders into lymphangiomas, lymphangiectasis, lymphangiomatosis, lymphatic
dysplasia syndrome, and other intrathoracic lymphatic disorders, such as lymphangioleiomyomatosis (LAM) and lymphangiosarcoma [6]. Primary pulmonary lymphangiectasis occur in neonate babies, sporadically or with autosomal recessive inheritance, and the lesions are usually diffuse and fatal [6,16]. Secondary lymphangiectasis can arise from thoracic-duct obstruction, thoracic masses, and total anomalous pulmonary venous return. Pathologically, pulmonary lymphangiectasis shows diffuse dilated lymphatics in the perihilar tissue, subpleural regions and in the interstitium [16,28]. Such perihilar and subpleural lymphangiectasis was not observed in the present case. Moreover, the present patient had no other anomalies or significant family history. Pulmonary lymphangiomatosis can pathologically resemble a lymphangioma, but differs in that it shows proliferation of complex anastomosing lymphatic spaces involving both lungs [6,28]. Occasionally it displays concomitant fascicles of smooth muscle. Chest radiographs demonstrate increased interstitial markings and pleural effusions [6]. A search of the international literature found only 15 cases of solitary pulmonary lymphangioma in addition to the present case (Table 1) [5,7,8,13–15,21–27,30,32]. On analysis of the complete series, including the present case, patient age ranged from 2 days to 59 years (median 21 years, 44% were younger than 10 years). The female to male ratio was 3–5. Nearly half of the patients were asymptomatic, and the rest had a variety of symptoms such as cough, dyspnea, hemoptysis, fever, pain, and pneumothorax. The lesions were randomly distributed without any propensity for the right or left lung. The maximum diameter ranged from 1.5 to 18 cm (median 3.5 cm); average size was 5.1 cm (median 5.8 cm) in those under 10 years and 4.2 cm (median 1.8 cm) in those aged 10 years and older. In the neonatal cases reported by Milovic et al. and Lee et
854
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
Fig. 4. Immunohistochemical findings. (a) The cells lining the inner surface of the cystic lesion are positive for D2-40. (b) Immunostaining for D2-40 is helpful in discerning the extent of the lesion in the lung tissue (arrows). (c) Prox1 is also positive in the nuclei of endothelial cells of the lesion. (d) VEGFR-3 shows very weak staining in the lining endothelial cells (arrows).
al., the lesions were described as occupying the entire lobe; however, the precise size was not given. Younger patients tended to have lesions that occupied more of the lung. Extrapulmonary cystic lymphangiomas most commonly affect children. They are more common in some congenital disorders including Turner syndrome, hydrops fetalis, Down syndrome and fetal alcohol syndrome. However, none of the pulmonary cystic lymphangiomas in the literature showed any association with congenital disorders. The differential diagnoses of intrapulmonary lymphangioma include lobar or interstitial emphysema, bronchogenic cyst, CPAM, and alveolar adenoma. The localized form of interstitial emphysema cases predominantly occurs in infants receiving mechanical ventilation [12]. Microscopically, the cystic wall consists of connective tissues with occasional giant cell reaction and no apparent
lining. The present case did not have a history of mechanical ventilation or respiratory distress. Moreover, giant cells were seen only focally and most of the cystic wall had a lymphatic endothelial lining. Foreign-body-type giant cells are often referred to as the histological hallmark of interstitial emphysema. However, it is noteworthy that those giant cells can also be seen in a case of pulmonary lymphangioma, the finding not having been mentioned in the reported cases of pulmonary lymphangioma. In summary, solitary intrapulmonary lymphangioma is a rare, benign and localized lesion. D2-40 and Prox1 were shown to be useful in differentiating it from other conditions and in determining the extent of the lesion. In neonatal or infant patients, lesions tend to occupy more of the lung. Microscopically, they can be accompanied by focal giant cell reaction.
855
Acknowledgment
Air and serous fluid Air and serous fluid Air and serous fluid Air Bloody fluid Bloody fluid Serous and xanthochromic fluid Serous fluida Serous fluida ND Gelatinous secretion ND Bloody fluid Air and blood clot Serous fluid Blood clot
This work was supported in part by the Grant-in-Aid for Scientific Research (C) (No.20590586) from Japan Society for the Promotion of Science. References
m, months; M, male; F, female; LLL, left lower lobe; RUL, right upper lobe; RLL, right lower lobe; RML, right middle lobe; CPAM, congenital pulmonary airway malformation; ND, not described. a Findings from histopathological observation.
Cystic Cystic Cystic Cystic Cavernous Cavernous Cavernous Cavernous Cavernous Cavernous and cystic Cystic and cavernous Cavernous Cystic Cystic Cystic Cystic Lobectomy Bilobectomy Lobectomy Pneumonectomy Pneumonectomy Lobectomy Lobectomy Partial resection Partial resection ND Cystectomy Partial resection Partial resection Pneumonectomy Partial resection Partial resection Congenital tension cysts CPAM Bronchogenic cyst CPAM No definitive diagnosis Malignant tumors or malformations Hamartomatous lesion ND ND ND Bronchogenic cyst Non-small cell cancer Bronchogenic cyst ND Benign cystic tumor Benign cystic lesion Entire lobe Entire lobe 5.5 3.5 8 9.5 6.5 2 1.8 ND 18 1.8 1.6 ND 1.5 3 LLL RUL RLL LLL RLL LLL RML RUL LLL RLL R hilar RUL RLL R hilar RLL UL Respiratory distress Dyspnea Cough Pneumothorax Fever, Cough Hemoptysis None None Cough None Pain, dyspnea None None Hemoptysis, cough None None 0 2m 2m 6m 5 9 10 21 39 41 49 51 53 54 57 59 Milovic [21] Lee [14] Present case Kim [13] Drut [5] Nakajima [23] Hamada [7] Takemura [27] Stephens [25] Shaffer [24] Limmer [15] Wilson [30] Nagayasu [22] Holden [8] Takahara [26] Yamagishi [32]
M F M M F F M M M F M M F M M F
Symptoms Sex Age (year) References
Table 1 Clinicopathological features of pulmonary lymphangiomas.
Location
Size (cm)
Preoperative diagnosis
Treatment
Type
Contents
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
[1] J. Afonso, L.L. Santos, T. Amaro, F. Lobo, A. Longatto-Filho, The aggressiveness of urothelial carcinoma depends to a large extent on lymphovascular invasion – the prognostic contribution of related molecular markers, Histopathology 55 (2009) 514–524. [2] A. Beham, Lymphangioma, in: C.D.M. Fletcher, K.K. Unni, F. Mertens (Eds.), Pathology and Genetics Tumours of Soft Tissue and Bone, IARC Press, Lyon, 2002, pp. 162–163. [3] A.H. Bill Jr., D.S. Sumner, A unified concept of lymphangioma and cystic hygroma, Surg. Gynecol. Obstet. 120 (1965) 79–86. [4] P. Birner, M. Schindl, A. Obermair, G. Breitenecker, H. Kowalski, G. Oberhuber, Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer, Int. J. Cancer 95 (2001) 29–33. [5] R. Drut, H.H. Mosca, Intrapulmonary cystic lymphangioma, Pediatr. Pulmonol. 22 (1996) 204–206. [6] J.L. Faul, G.J. Berry, T.V. Colby, S.J. Ruoss, M.B. Walter, G.D. Rosen, T.A. Raffin, Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome, Am. J. Respir. Crit. Care Med. 161 (2000) 1037–1046. [7] K.Y. Hamada, Y. Ishii, M. Nakaya, N. Sawabata, K. Fukuda, H. Suzuki, Solitary lymphangioma of the lung, Histopathology 27 (1995) 482–483. [8] W.E. Holden, J.F. Morris, R. Antonovic, T.H. Gill, S. Kessler, Adult intrapulmonary and mediastinal lymphangioma causing haemoptysis, Thorax 42 (1987) 635–636. [9] E. Itakura, H. Yamamoto, Y. Oda, M. Furue, M. Tsuneyoshi, VEGF-C and VEGFR-3 in a series of lymphangiomas: is superficial lymphangioma a true lymphangioma? Virchows Arch. 454 (2009) 317–325. [10] H.J. Kahn, D. Bailey, A. Marks, Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas, Mod. Pathol. 15 (2002) 434–440. [11] H.J. Kahn, A. Marks, A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors, Lab. Invest. 82 (2002) 1255–1257. [12] A.L. Katzenstein, Katzenstein and Askin’s Surgical Pathology of Non-neoplastic Lung Disease, Saunders Elsevier, Philadelphia, 2006, p. 400. [13] W.S. Kim, K.S. Lee, I. Kim, K.M. Yeon, C.J. Kim, J.G. Chi, J.G.M.C. Han, Cystic intrapulmonary lymphangioma: HRCT findings, Pediatr. Radiol. 25 (1995) 206–207. [14] C.H. Lee, Y.D. Kim, K.I. Kim, Y.T. Lim, K.M. Lee, K.U. Choi, J.S. Lee, M.Y. Sol, Intrapulmonary cystic lymphangioma in a 2-month-old infant, J. Korean Med. Sci. 19 (2004) 458–461. [15] S. Limmer, M. Krokowski, P. Kujath, Pulmonary lymphangioma, Ann. Thorac. Surg. 85 (2008) 336–339. [16] C.J. Lockwood, A.S. Nadel, M.E. King, D.J. Roberts, Case records of the Massachusetts General Hospital. Case 16-2009. A 32-year-old pregnant woman with an abnormal fetal ultrasound study, N. Engl. J. Med. 360 (2009) 2225–2235. [17] T. Mäkinen, C. Norrmen, T.V. Petrova, Molecular mechanisms of lymphatic vascular development, Cell. Mol. Life Sci. 64 (2007) 1915–1929. [18] C.C. Mankey, J.B. McHugh, D.G. Thomas, D.R. Lucas, Can lymphangiosarcoma be resurrected? A clinicopathological and immunohistochemical study of lymphatic differentiation in 49 angiosarcomas, Histopathology 56 (2010) 364–371. [19] A. Marks, D.R. Sutherland, D. Bailey, J. Iglesias, J. Law, M. Lei, H. Yeger, D. Banerjee, R. Baumal, Characterization and distribution of an oncofetal antigen (M2A antigen) expressed on testicular germ cell tumours, Br. J. Cancer 80 (1999) 569–578. [20] M. Matsuura, M. Onimaru, Y. Yonemitsu, H. Suzuki, T. Nakano, H. Ishibashi, K. Shirasuna, K. Sueishi, Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells, Am. J. Pathol. 175 (2009) 1709–1721. [21] I. Milovic, D. Oluic, Lymphangioma of the lung associated with respiratory distress in a neonate, Pediatr. Radiol. 22 (1992) 156. [22] T. Nagayasu, T. Hayashi, K. Ashizawa, M. Muraoka, T. Tagawa, S. Akamine, T. Oka, A case of solitary pulmonary lymphangioma, J. Clin. Pathol. 56 (2003) 396–398. [23] J. Nakajima, A. Goto, S. Takamoto, T. Murakawa, T. Fukami, M. Kusakabe, Invasive lymphangioma of the lung manifesting as a large pulmonary mass with hemoptysis: report of a case, Surg. Today 37 (2007) 418–422. [24] K. Shaffer, M.L. Rosado-de-Christenson, E.F. Patz Jr., S. Young, C.F. Farver, Thoracic lymphangioma in adults: CT and MR imaging features, Am. J. Roentgenol. 162 (1994) 283–289. [25] F.G. Stephens, S.M. Roberts, M.W. Wolcott, Peripheral lymphangioma of the lung, J. Thorac. Surg. 36 (1958) 182–184. [26] T. Takahara, Y. Morisaki, T. Torigoe, S. Sano, E. Nakamura, K. Fujino, H. Yoshida, Y. Ishii, H. Hidaka, Intrapulmonary cystic lymphangioma: report of a case, Surg. Today 28 (1998) 1310–1312. [27] T. Takemura, M. Watanabe, K. Takagi, S. Tanaka, S. Aida, Thoracoscopic resection of a solitary pulmonary lymphangioma: report of a case, Surg. Today 25 (1995) 651–653. [28] W.D. Travis, T.V. Colby, M.N. Koss, M.L. Rosado-de-Christenson, N.L. Muller, T.E. King, Congenital anomalies and pediatric disorders: vascular anomalies, in:
856
H. Minato et al. / Pathology – Research and Practice 206 (2010) 851–856
W.D. Travis, T.V. Colby, M.N. Koss, M.L. Rosado-de-Christenson, N.L. Muller, T.E. King (Eds.), Non-neoplastic Disorder of the Lower Respiratory Tract, American Registry of Pathology and the Armed Forces Institute of Pathology, Washington, DC, 2002, pp. 501–507. [29] W.L. Watson, W.B. McCarthy, Blood and lymph vessel tumors. A report of 1056 cases, Surg. Gynecol. Obstet. 71 (1940) 569–588. [30] C. Wilson, F.B. Askin, R.F. Heitmiller, Solitary pulmonary lymphangioma, Ann. Thorac. Surg. 71 (2001) 1337–1338.
[31] C.C. Wright, D.M. Cohen, R.K. Vegunta, J.T. Davis, D.R. King, Intrathoracic cystic hygroma: a report of three cases, J. Pediatr. Surg. 31 (1996) 1430– 1432. [32] S. Yamagishi, K. Koizumi, T. Hirata, K. Hirai, J. Kurita, K. Shimizu, Experience of thoracoscopic extirpation of intrapulmonary lymphangioma, Jpn. J. Thorac. Cardiovasc. Surg. 53 (2005) 313–316.