Seminars in Pediatric Surgery 23 (2014) 186–190
Contents lists available at ScienceDirect
Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg
Complex lymphatic anomalies Cameron C. Trenor III, MD, MMSca,n, Gulraiz Chaudry, MBChBb a
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 300 Longwood Ave, Boston, Massachusetts 02115 Division of Interventional Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115
b
a r t i c l e in f o
Keywords: Gorham–Stout disease Generalized lymphatic anomaly Kaposiform lymphangiomatosis
abstract Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham–Stout disease have been segregated with distinctive bone lesions and peri-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies. & 2014 Elsevier Inc. All rights reserved.
Introduction The lymphatic system initially develops as blind-ending sacs, which coalesce to form a delicate plexus of vessels. These peripheral lymphatics then drain into the central lymphatic channels, including the cisterna chyli. Chyle is a mixture of lymph and chylomicrons absorbed from the intestine and conducted centrally via lacteals. Mesenteric chyle then mixes with clear lymph from the pelvis and lower extremities. The central conducting channels eventually drain into the venous system via the thoracic duct. Lymphatic dysfunction and hypertension lead to expansion of the interstitial spaces with lymphatic fluid, also known as lymphedema. Obstruction or anomalies of the lymphatic system can result in leakage, manifesting as pleural effusions and ascites. The fluid may be clear lymph or chylous depending on the site of obstruction, leakage, and reflux. Chyle accumulation in or leakage
n
Corresponding author. E-mail address: [email protected] (C.C. Trenor III).
http://dx.doi.org/10.1053/j.sempedsurg.2014.07.006 1055-8586/& 2014 Elsevier Inc. All rights reserved.
from caudal structures such as the vagina, scrotum, urinary tract, and lower extremities may also be seen as a result of chylous reflux.1 Pleural effusions with clear lymph may be seen secondary to disruption of intrathoracic lymphatic channels draining the upper extremities, head and neck, upper torso, and lungs, while chylous effusions imply leakage from the thoracic duct. Similarly, nonchylous ascites implies a non-intestinal lesion or disruption of the central lymphatic channels below the level of the cisterna chyli. Chylous ascites is usually the result of an intestinal or retroperitoneal lesion, but it may also be seen in leaks from other locations as a result of chylous reflux.2
Diagnostic investigations and clinical patterns Whether chylous or not, the fluid collections are usually anechoic by ultrasonography, although mild internal echoes and fluid levels may be seen in chylous effusions and ascites. It is similarly difficult to differentiate between simple and chylous fluid
C.C. Trenor III, G. Chaudry / Seminars in Pediatric Surgery 23 (2014) 186–190
187
Fig. 1. A 3-year-old boy with CCLA presenting with chylous ascites. Axial T2 fatsaturated MRI sequence. Perivascular high-signal soft tissue is seen in the posterior mediastinum. Heterogeneous signal abnormality is also noted in the spleen.
on CT, although lower attenuation and fluid–fluid levels suggest the presence of chyle.3 The diagnosis can be confirmed by aspiration. A high lymphocyte count will be seen in both, while milky white fluid with a high triglyceride level is consistent with chyle. Sonography of the affected soft tissues may demonstrate enlarged hypoechoic compressible channels with absent blood flow on color Doppler. Dynamic assessment of flow and valve function in the terminal thoracic duct can be assessed with the use of a high-resolution transducer.4 Retrograde flow in the terminal portion is suggestive of dysmotility. On MRI, perivascular highsignal tissue surrounding the iliac vessels or aorta on fluidweighted sequences is suggestive of underlying dysfunction of the lymphatic channels with reflux into the perivascular lymphatics (Figure 1). Definitive diagnosis of anatomic and functional abnormalities can be established by contrast lymphangiography.5 Pedal lymphangiography with cut-down and cannulation of a lymphatic channel in the foot requires significant time and technical expertise, especially in small children. However, direct sonographic-guided intranodal injection of contrast offers a less invasive and time-consuming alternative.6 A lymphatic-specific MRI contrast agent has been successfully used in animals and may offer non-invasive visualization of the anatomy and function of the lymphatic system in the near future.7 The lymphangiogram may identify delayed or non-opacification of the cephalad channels, chylous reflux, a focal leak, or abnormalities of the terminal portion of the thoracic duct (Figure 2). There is inconsistency in the literature regarding diagnosis based on lymphatic involvement of bone. Diffuse osteopenia of regional bones, often adjacent to lymphedema or engorged perivascular lymphatics, commonly represents lymphatic reflux into the marrow cavity. This can be confirmed with lymphangiography. Effusions and ascites can also accompany lymphatic diseases of bone, specifically generalized lymphatic anomaly (GLA) and Gorham–Stout disease (GSD).8 These two conditions have recently been differentiated on the basis of imaging findings.9 Gorham– Stout Disease (GSD) is characterized by progressive osteolysis with loss of cortical bone. The mechanism of this is poorly understood. Current hypotheses include bone loss secondary to proliferation of thin-walled sinusoidal lymphatic channels or osteoclastic dissolution of cortical bone, perhaps driven by adjacent soft tissue lymphatic disease that then expands into the space left after osteolysis. Osseous involvement is also seen in GLA, but as part of generalized anomaly with persistence of dilated lymphatics10
Fig. 2. A 15-year-old boy with CCLA and recurrent pericardial effusions. Intranodal lymphangiogram. Stagnant flow is seen in the patulous superior portion of the thoracic duct. Direct puncture of the terminal portion demonstrates marked dilation with no spontaneous emptying.
and a distinct pattern of bony involvement. The cortical resorption and progressive osteolysis seen in GSD is a key differentiating factor (Figure 3A). Although the number of bones involved and the size of the lesions in GLA can increase over time, there are often years of stability, and the cortex is usually preserved (Figure 4). The distribution of osseous changes also appears to be different; contiguous involvement across joints is seen in GSD, whereas GLA is usually characterized by involvement of a greater number of bones, which are often non-contiguous or remote. Lesions in the appendicular skeleton are also much more commonly seen in GLA. In the study by Lala et al.,9 the most common sites affected were the ribs in both groups, followed by the cranium, cervical spine, and clavicle in GSD and the thoracic spine, humerus, and scapula in GLA. GLA bone lesions are lytic and round, sometimes described as “punched out.” Histology is challenging to interpret in these disorders but can confirm an imaging diagnosis and rule out nonvascular bone diseases such as Langerhans cell histiocytosis, multiple myeloma, or aneurysmal bone cysts. Lymphatic rib lesions are often tempting to biopsy; however, we advise against rib biopsy, as we are aware of several patients who developed refractory, pleural effusions after rib biopsy. Extension of the proliferating sinusoidal channels into the soft tissues often results in an infiltrative mass in GSD, which is high signal on fluid-weighted sequences and enhances intensely on administration of gadolinium (Figure 3B and C).9 Chylothorax is commonly seen in both conditions, attributed to disruption of the thoracic duct or pleural lymphatics by adjacent osteolysis.11 Reflecting the systemic nature of the disease, visceral organ involvement, specifically splenic or hepatic cysts, and macrocystic LM are more common in GLA. The osseous changes can be readily visualized with plain radiography or CT, but bone marrow changes and soft tissue involvement are best assessed with MRI.9
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Fig. 3. A 28-year-old female with Gorham–Stout disease. (A) CT sagittal reformat. Multiple erosive changes in the occiput, clivus, and the cervical spine. (B) Sagittal T2 fatsaturated (FS) MRI sequence. High signal is seen in the clivus and C 1–5 vertebral and the surrounding soft tissue. (C) Post-gadolinium T1 FS MRI. Enhancement is seen in the areas of osseous and soft tissue abnormalities.
The imaging appearances of KLA overlap with that of GLA, with multiple non-contiguous lytic osseous lesions sparing the cortex.12 The vertebral bodies are the most common sites of bony involvement. Chylothorax and splenic cysts are also seen. However, there appears to be much more extensive thoracic involvement in KLA. Mediastinal disease is nearly universal on imaging, with soft tissue that is hyperintense on fluid-weighted MRI sequences and hypodense on CT extending to the hila (Figure 5A). Thickening along the bronchovascular bundle and interlobular septal thickening are also seen in the majority, which is uncommon in GLA12,13 (Figure 5B). The histology of KLA has diagnostic spindle-shaped lymphatic endothelium, similar to that seen in kaposiform hemangioendothelioma (KHE), and extravascular hemorrhage is common. The origin of KLA is unknown. The multiple overlapping imaging characteristics with GLA have led to a hypothesis that KLA may arise from GLA. Central conducting lymphatic anomalies (CCLA) have been poorly characterized in the literature. Enlargement of lymphatic
channels (lymphangiectasia), dysmotility, or distal obstruction results in inadequate clearing of lymph, with resultant stasis and reflux. Depending on the site of the anomaly, this may manifest as chylothorax, pulmonary lymphangiectasia, chylous ascites, protein-losing enteropathy, cutaneous vesicles, or superficial chylous leaks.1 Osseous changes can also be seen in CCLA, demonstrating focal areas of hyperlucency due to dilated intraosseous channels or a more permeative appearance. Laboratory studies in patients with complex lymphatic anomalies may support a diagnosis but are not specific enough to be diagnostic. An increased number or severity of abnormalities may correlate with extent of involvement, concurrent infection, or raise concerns for KLA. D-dimer elevation is common in lymphatic anomalies, while prolongation of prothrombin or partial thromboplastin times and low fibrinogen are rarely present. Mild thrombocytopenia ( 4100,000/μl) can occur with extensive involvement of abnormal lymphatic tissue. While the mechanism of thrombocytopenia is unproven, perhaps platelets are entrapped by
Fig. 4. A 8-year-old female with GLA. (A) Axial CT. Multiple lucent lesions seen in the vertebral body and left posterior rib, with preservation of the surrounding cortex. Note is also made of large left pleural effusion. (B) Sagittal inversion recovery. High signal is seen in the T9–L1 vertebra. Loss of height of the T9 and T10 vertebral bodies is noted. There is no surrounding soft tissue abnormality.
C.C. Trenor III, G. Chaudry / Seminars in Pediatric Surgery 23 (2014) 186–190
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Fig. 6. Intra-operative photograph. Thoracic duct to external jugular vein anastomosis (courtesy of Amir Taghinia, MD). (Color version of figure is available online.)
Fig. 5. A 14-year-old girl with KLA. (A) Contrast-enhanced CT of chest. Low-density soft tissue is seen in the mediastinum. (B) Axial HASTE FS MRI. High-signal soft tissue is seen extending along the bronchovascular bundles.
abnormal lymphatic endothelium as occurs in Kasabach–Merritt phenomenon associated with kaposiform hemangioendothelioma. Moderate thrombocytopenia (50–100,000/μl) may suggest infection or more aggressive disease, such as KLA. Lymphopenia may occur with more extensive disease and does not predict lymphopenic infections such as Pneumocystis jirovecii. Hypogammaglobulinemia, hypoalbuminemia, and electrolyte abnormalities correlate with leaky lymphatics.
Treatment Treatment of complex lymphatic anomalies varies by mechanism of lymphatic dysfunction and location of active complications. Unfortunately, for the majority of children with engorged lymphatics, dysmotility, and reflux, interventional and surgical treatments are largely palliative. Procedures such as pleurodesis or sclerotherapy are primarily aimed at providing symptomatic relief and local control. For symptoms related to reflux of lymphatic fluid, diversion of fluid by embolization or surgical resection can improve symptoms, although recurrence or redirection of lymphatic fluid is inevitable. For pleural effusions or ascites, treatment is usually directed toward the underlying cause, although some patients with chronic lymphatic leaks require serial paracentesis/ thoracentesis and may benefit from pleurodesis. Shunting of ascites into the venous circulation (e.g., Denver shunt) is also temporizing and generally not recommended as the shunt clogs and can lead to bacteremia/septicemia. Cutaneous lymphatic leakage can be treated successfully, at least temporarily, with sclerotherapy or CO2 laser ablation, improving localized pain and recurrent infections. When lymphangiography demonstrates thoracic duct dysfunction and failure to empty into the venous circulation, there may be a role for surgical resection of the terminal thoracic duct and micro-anastomosis to a valved vein (e.g., the external jugular vein; Figure 6). We have performed this procedure for several patients at our center but have not yet
reported long-term results. Focal leaks identified on lymphangiography can potentially be treated by direct puncture of the cisterna chyli with subsequent embolization of the thoracic duct.14 For pulmonary disease, aggressive bronchodilation, corticosteroid, and maneuvers to improve pulmonary clearance can ameliorate symptoms and facilitate recovery. Systemic medical therapy for lymphatic anomalies is rapidly evolving. Sildenafil response was reported in an isolated case report of macrocystic lymphatic malformation,15 leading to off-label use16 and a pilot study.17 Due to the variable natural history of lymphatic malformations, including spontaneous shrinkage of macrocysts, the efficacy of sildenafil is currently unclear. After the success of propranolol for treatment of infantile hemangioma, widespread use has grown to include lymphatic anomalies. Propranolol use has reportedly improved pleural effusions, mucosal lymphatic leak, and lymphatic malformations in a small number of case reports,18–22 although propranolol resistance is also reported.23,24 Durable effects remain in doubt. Sirolimus, an mTOR inhibitor, has been reported to improve pleural effusions and mediastinal mass size25,26 and is currently under study in a phase 2 clinical trial (NCT00975819) with results expected in 2014. The future of therapies for lymphatic anomalies will evolve through results of clinical studies and a better understanding of combinations of multiple medications and medical and procedural treatment protocols.
Outcomes and prognosis While natural history studies are lacking in these conditions, some patterns of outcomes and prognosis are emerging from clinical experience. Uncorrected, chronic lymphedema leads to dermal hypertrophy, cutaneous leak, and chronic infection. In severe cases of chronic lymphedema, chronic ulceration and angiosarcoma (Stewart–Treves syndrome)27 development are reported. Patients with lytic bone disease, as in GLA, may present with pathologic fractures. Osteolysis in Gorham–Stout disease leads to fracture and skeletal instability, as well as spinal cord compromise and CSF leak in cases with vertebral disease. Splenic cysts are generally not associated with complications, even with moderate splenomegaly. Pulmonary involvement leads to recurrent pneumonia and scarring, with both restrictive and obstructive pulmonary diseases. KLA is an aggressive disease with episodic worsening with infection and/or hemorrhage followed by periods of incomplete recovery, usually involving the lungs, pleura, pericardium, and mediastinum. Cardiopulmonary failure and infection are common causes of morbidity and mortality in patients with
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lymphatic anomalies. The five-year survival after presentation with KLA is only 51%.13 Natural history studies and disease- or complication-specific clinical trials are urgently needed. References 1. Fishman SJ. Slow-flow vascular malformations. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Mulliken & Young's Vascular Anomalies Hemangiomas and Malformations. New York, United States of America: Oxford University Press; 2013. 2. Fishman SJ. Truncal, visceral and genital vascular malformations. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Mulliken & Young's Vascular Anomalies: Hemangiomas and Malformations. New York, United States of America: Oxford University Press; 2013. 3. Hibbeln JF, Wehmueller MD, Wilbur AC. Chylous ascites: CT and ultrasound appearance. Abdom Imaging. 1995;20(2):138–140. 4. Seeger M, Bewig B, Gunther R, et al. Terminal part of thoracic duct: highresolution US imaging. Radiology. 2009;252(3):897–904. 5. Fishman SJ, Burrows PE, Upton J, Hendren WH. Life-threatening anomalies of the thoracic duct: anatomic delineation dictates management. J Pediatr Surg. 2001;36(8):1269–1272. 6. Rajebi MR, Chaudry G, Padua HM, et al. Intranodal lymphangiography: feasibility and preliminary experience in children. J Vasc Interv Radiol. 2011;22(9):1300–1305. 7. Sena LM, Fishman SJ, Jenkins KJ, et al. Magnetic resonance lymphangiography with a nano-sized gadolinium-labeled dendrimer in small and large animal models. Nanomed. 2010;5(8):1183–1191. 8. Chen W, Adams D, Patel M, Gupta A, Dasgupta R. Generalized lymphatic malformation with chylothorax: long-term management of a highly morbid condition in a pediatric patient. J Pediatr Surg. 2013;48(3):e9–e12. 9. Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham–Stout disease and generalized lymphatic anomaly—clinical, radiologic, and histologic differentiation. Skeletal Radiol. 2013;42(7):917–924. 10. Enzinger FM. Tumors of lymphatic vessels. In: Weiss SW, Goldblum JR, Enzinger FM, editors. Enzinger and Weiss' Soft Tissue Tumors. Philadelphia, PA: Mosby Elsevier; 2008. p. 1258. 11. Chavanis N, Chaffanjon P, Frey G, Vottero G, Brichon PY. Chylothorax complicating Gorham's disease. Ann Thorac Surg. 2001;72(3):937–939. 12. Croteau SE, Kozakewich HP, Perez-Atayde AR, et al. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. J Pediatr. 2014;164(2): 383–388.
13. Safi F, Gupta A, Adams D, Anandan V, McCormack FX, Assaly R. Kaposiform lymphangiomatosis, a newly characterized vascular anomaly presenting with hemoptysis in an adult woman. Ann Am Thorac Soc. 2014;11(1):92–95. 14. Nadolski G, Itkin M. Thoracic duct embolization for the management of chylothoraces. Curr Opin Pulm Med. 2013;19(4):380–386. 15. Swetman GL, Berk DR, Vasanawala SS, et al. Sildenafil for severe lymphatic malformations. N Engl J Med. 2012;366(4):384–386. 16. Singh P, Singh P, Mundy D. Giant neonatal thoraco-abdominal lymphatic malformations treated with sildenafil: a case report and review of the literature. J Neonatal Perinat Med. 2013;6(1):89–92. 17. Danial C, Tichy AL, Tariq U, et al. An open-label study to evaluate sildenafil for the treatment of lymphatic malformations. J Am Acad Dermatol. 2014;70 (6):1050–1057. 18. Ozeki M, Fukao T, Kondo N. Propranolol for intractable diffuse lymphangiomatosis. N Engl J Med. 2011;364(14):1380–1382. 19. Leboulanger N, Garel C, Borde IT, Garabedian EN, Denoyeue F. Propranolol therapy for hemorrhagic lymphangioma of the tongue. Arch Otolaryngol Head Neck Surg. 2011;137(8):813–815. 20. Ozeki M, Kanda K, Kawamoto N, et al. Propranolol as an alternative treatment option for pediatric lymphatic malformation. Tohoku J Exp Med. 2013;229 (1):61–66. 21. Nir V, Guralnik L, Livnat G, et al. Propranolol as a treatment option in Gorham– Stout syndrome: a case report. Pediatr Pulmonol. 2014;49(4):417–419. 22. Poralla C, Specht S, Born M, Müller A, Bartmann P. Treatment of congenital generalized lymphangiectasia with propranolol in a preterm infant. Pediatrics. 2014;133(2):e439–e442. 23. Maruani A, Brown S, Lorette G, Pondaven-Letourmy S, Herbreteau D, Eisenbaum A. Lack of effect of propranolol in the treatment of lymphangioma in two children. Pediatr Dermatol. 2013;30(3):383–385. 24. Akyuz C, Atas E, Varan A. Treatment of a tongue lymphangioma with sirolimus after failure of surgical resection and propranolol. Pediatr Blood Cancer. 2014;61 (5):931–932. 25. Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the treatment of complicated vascular anomalies in children. Pediatr Blood Cancer. 2011;57 (6):1018–1024. 26. Reinglas J, Ramphal R, Bromwich M. The successful management of diffuse lymphangiomatosis using sirolimus: a case report. Laryngoscope. 2011;121 (9):1851–1854. 27. Sharma A, Schwartz RA. Stewart–Treves syndrome: pathogenesis and management. J Am Acad Dermatol. 2012;67(6):1342–1348.
Contents lists available at ScienceDirect
Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg
Complex lymphatic anomalies Cameron C. Trenor III, MD, MMSca,n, Gulraiz Chaudry, MBChBb a
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 300 Longwood Ave, Boston, Massachusetts 02115 Division of Interventional Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115
b
a r t i c l e in f o
Keywords: Gorham–Stout disease Generalized lymphatic anomaly Kaposiform lymphangiomatosis
abstract Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham–Stout disease have been segregated with distinctive bone lesions and peri-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies. & 2014 Elsevier Inc. All rights reserved.
Introduction The lymphatic system initially develops as blind-ending sacs, which coalesce to form a delicate plexus of vessels. These peripheral lymphatics then drain into the central lymphatic channels, including the cisterna chyli. Chyle is a mixture of lymph and chylomicrons absorbed from the intestine and conducted centrally via lacteals. Mesenteric chyle then mixes with clear lymph from the pelvis and lower extremities. The central conducting channels eventually drain into the venous system via the thoracic duct. Lymphatic dysfunction and hypertension lead to expansion of the interstitial spaces with lymphatic fluid, also known as lymphedema. Obstruction or anomalies of the lymphatic system can result in leakage, manifesting as pleural effusions and ascites. The fluid may be clear lymph or chylous depending on the site of obstruction, leakage, and reflux. Chyle accumulation in or leakage
n
Corresponding author. E-mail address: [email protected] (C.C. Trenor III).
http://dx.doi.org/10.1053/j.sempedsurg.2014.07.006 1055-8586/& 2014 Elsevier Inc. All rights reserved.
from caudal structures such as the vagina, scrotum, urinary tract, and lower extremities may also be seen as a result of chylous reflux.1 Pleural effusions with clear lymph may be seen secondary to disruption of intrathoracic lymphatic channels draining the upper extremities, head and neck, upper torso, and lungs, while chylous effusions imply leakage from the thoracic duct. Similarly, nonchylous ascites implies a non-intestinal lesion or disruption of the central lymphatic channels below the level of the cisterna chyli. Chylous ascites is usually the result of an intestinal or retroperitoneal lesion, but it may also be seen in leaks from other locations as a result of chylous reflux.2
Diagnostic investigations and clinical patterns Whether chylous or not, the fluid collections are usually anechoic by ultrasonography, although mild internal echoes and fluid levels may be seen in chylous effusions and ascites. It is similarly difficult to differentiate between simple and chylous fluid
C.C. Trenor III, G. Chaudry / Seminars in Pediatric Surgery 23 (2014) 186–190
187
Fig. 1. A 3-year-old boy with CCLA presenting with chylous ascites. Axial T2 fatsaturated MRI sequence. Perivascular high-signal soft tissue is seen in the posterior mediastinum. Heterogeneous signal abnormality is also noted in the spleen.
on CT, although lower attenuation and fluid–fluid levels suggest the presence of chyle.3 The diagnosis can be confirmed by aspiration. A high lymphocyte count will be seen in both, while milky white fluid with a high triglyceride level is consistent with chyle. Sonography of the affected soft tissues may demonstrate enlarged hypoechoic compressible channels with absent blood flow on color Doppler. Dynamic assessment of flow and valve function in the terminal thoracic duct can be assessed with the use of a high-resolution transducer.4 Retrograde flow in the terminal portion is suggestive of dysmotility. On MRI, perivascular highsignal tissue surrounding the iliac vessels or aorta on fluidweighted sequences is suggestive of underlying dysfunction of the lymphatic channels with reflux into the perivascular lymphatics (Figure 1). Definitive diagnosis of anatomic and functional abnormalities can be established by contrast lymphangiography.5 Pedal lymphangiography with cut-down and cannulation of a lymphatic channel in the foot requires significant time and technical expertise, especially in small children. However, direct sonographic-guided intranodal injection of contrast offers a less invasive and time-consuming alternative.6 A lymphatic-specific MRI contrast agent has been successfully used in animals and may offer non-invasive visualization of the anatomy and function of the lymphatic system in the near future.7 The lymphangiogram may identify delayed or non-opacification of the cephalad channels, chylous reflux, a focal leak, or abnormalities of the terminal portion of the thoracic duct (Figure 2). There is inconsistency in the literature regarding diagnosis based on lymphatic involvement of bone. Diffuse osteopenia of regional bones, often adjacent to lymphedema or engorged perivascular lymphatics, commonly represents lymphatic reflux into the marrow cavity. This can be confirmed with lymphangiography. Effusions and ascites can also accompany lymphatic diseases of bone, specifically generalized lymphatic anomaly (GLA) and Gorham–Stout disease (GSD).8 These two conditions have recently been differentiated on the basis of imaging findings.9 Gorham– Stout Disease (GSD) is characterized by progressive osteolysis with loss of cortical bone. The mechanism of this is poorly understood. Current hypotheses include bone loss secondary to proliferation of thin-walled sinusoidal lymphatic channels or osteoclastic dissolution of cortical bone, perhaps driven by adjacent soft tissue lymphatic disease that then expands into the space left after osteolysis. Osseous involvement is also seen in GLA, but as part of generalized anomaly with persistence of dilated lymphatics10
Fig. 2. A 15-year-old boy with CCLA and recurrent pericardial effusions. Intranodal lymphangiogram. Stagnant flow is seen in the patulous superior portion of the thoracic duct. Direct puncture of the terminal portion demonstrates marked dilation with no spontaneous emptying.
and a distinct pattern of bony involvement. The cortical resorption and progressive osteolysis seen in GSD is a key differentiating factor (Figure 3A). Although the number of bones involved and the size of the lesions in GLA can increase over time, there are often years of stability, and the cortex is usually preserved (Figure 4). The distribution of osseous changes also appears to be different; contiguous involvement across joints is seen in GSD, whereas GLA is usually characterized by involvement of a greater number of bones, which are often non-contiguous or remote. Lesions in the appendicular skeleton are also much more commonly seen in GLA. In the study by Lala et al.,9 the most common sites affected were the ribs in both groups, followed by the cranium, cervical spine, and clavicle in GSD and the thoracic spine, humerus, and scapula in GLA. GLA bone lesions are lytic and round, sometimes described as “punched out.” Histology is challenging to interpret in these disorders but can confirm an imaging diagnosis and rule out nonvascular bone diseases such as Langerhans cell histiocytosis, multiple myeloma, or aneurysmal bone cysts. Lymphatic rib lesions are often tempting to biopsy; however, we advise against rib biopsy, as we are aware of several patients who developed refractory, pleural effusions after rib biopsy. Extension of the proliferating sinusoidal channels into the soft tissues often results in an infiltrative mass in GSD, which is high signal on fluid-weighted sequences and enhances intensely on administration of gadolinium (Figure 3B and C).9 Chylothorax is commonly seen in both conditions, attributed to disruption of the thoracic duct or pleural lymphatics by adjacent osteolysis.11 Reflecting the systemic nature of the disease, visceral organ involvement, specifically splenic or hepatic cysts, and macrocystic LM are more common in GLA. The osseous changes can be readily visualized with plain radiography or CT, but bone marrow changes and soft tissue involvement are best assessed with MRI.9
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Fig. 3. A 28-year-old female with Gorham–Stout disease. (A) CT sagittal reformat. Multiple erosive changes in the occiput, clivus, and the cervical spine. (B) Sagittal T2 fatsaturated (FS) MRI sequence. High signal is seen in the clivus and C 1–5 vertebral and the surrounding soft tissue. (C) Post-gadolinium T1 FS MRI. Enhancement is seen in the areas of osseous and soft tissue abnormalities.
The imaging appearances of KLA overlap with that of GLA, with multiple non-contiguous lytic osseous lesions sparing the cortex.12 The vertebral bodies are the most common sites of bony involvement. Chylothorax and splenic cysts are also seen. However, there appears to be much more extensive thoracic involvement in KLA. Mediastinal disease is nearly universal on imaging, with soft tissue that is hyperintense on fluid-weighted MRI sequences and hypodense on CT extending to the hila (Figure 5A). Thickening along the bronchovascular bundle and interlobular septal thickening are also seen in the majority, which is uncommon in GLA12,13 (Figure 5B). The histology of KLA has diagnostic spindle-shaped lymphatic endothelium, similar to that seen in kaposiform hemangioendothelioma (KHE), and extravascular hemorrhage is common. The origin of KLA is unknown. The multiple overlapping imaging characteristics with GLA have led to a hypothesis that KLA may arise from GLA. Central conducting lymphatic anomalies (CCLA) have been poorly characterized in the literature. Enlargement of lymphatic
channels (lymphangiectasia), dysmotility, or distal obstruction results in inadequate clearing of lymph, with resultant stasis and reflux. Depending on the site of the anomaly, this may manifest as chylothorax, pulmonary lymphangiectasia, chylous ascites, protein-losing enteropathy, cutaneous vesicles, or superficial chylous leaks.1 Osseous changes can also be seen in CCLA, demonstrating focal areas of hyperlucency due to dilated intraosseous channels or a more permeative appearance. Laboratory studies in patients with complex lymphatic anomalies may support a diagnosis but are not specific enough to be diagnostic. An increased number or severity of abnormalities may correlate with extent of involvement, concurrent infection, or raise concerns for KLA. D-dimer elevation is common in lymphatic anomalies, while prolongation of prothrombin or partial thromboplastin times and low fibrinogen are rarely present. Mild thrombocytopenia ( 4100,000/μl) can occur with extensive involvement of abnormal lymphatic tissue. While the mechanism of thrombocytopenia is unproven, perhaps platelets are entrapped by
Fig. 4. A 8-year-old female with GLA. (A) Axial CT. Multiple lucent lesions seen in the vertebral body and left posterior rib, with preservation of the surrounding cortex. Note is also made of large left pleural effusion. (B) Sagittal inversion recovery. High signal is seen in the T9–L1 vertebra. Loss of height of the T9 and T10 vertebral bodies is noted. There is no surrounding soft tissue abnormality.
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Fig. 6. Intra-operative photograph. Thoracic duct to external jugular vein anastomosis (courtesy of Amir Taghinia, MD). (Color version of figure is available online.)
Fig. 5. A 14-year-old girl with KLA. (A) Contrast-enhanced CT of chest. Low-density soft tissue is seen in the mediastinum. (B) Axial HASTE FS MRI. High-signal soft tissue is seen extending along the bronchovascular bundles.
abnormal lymphatic endothelium as occurs in Kasabach–Merritt phenomenon associated with kaposiform hemangioendothelioma. Moderate thrombocytopenia (50–100,000/μl) may suggest infection or more aggressive disease, such as KLA. Lymphopenia may occur with more extensive disease and does not predict lymphopenic infections such as Pneumocystis jirovecii. Hypogammaglobulinemia, hypoalbuminemia, and electrolyte abnormalities correlate with leaky lymphatics.
Treatment Treatment of complex lymphatic anomalies varies by mechanism of lymphatic dysfunction and location of active complications. Unfortunately, for the majority of children with engorged lymphatics, dysmotility, and reflux, interventional and surgical treatments are largely palliative. Procedures such as pleurodesis or sclerotherapy are primarily aimed at providing symptomatic relief and local control. For symptoms related to reflux of lymphatic fluid, diversion of fluid by embolization or surgical resection can improve symptoms, although recurrence or redirection of lymphatic fluid is inevitable. For pleural effusions or ascites, treatment is usually directed toward the underlying cause, although some patients with chronic lymphatic leaks require serial paracentesis/ thoracentesis and may benefit from pleurodesis. Shunting of ascites into the venous circulation (e.g., Denver shunt) is also temporizing and generally not recommended as the shunt clogs and can lead to bacteremia/septicemia. Cutaneous lymphatic leakage can be treated successfully, at least temporarily, with sclerotherapy or CO2 laser ablation, improving localized pain and recurrent infections. When lymphangiography demonstrates thoracic duct dysfunction and failure to empty into the venous circulation, there may be a role for surgical resection of the terminal thoracic duct and micro-anastomosis to a valved vein (e.g., the external jugular vein; Figure 6). We have performed this procedure for several patients at our center but have not yet
reported long-term results. Focal leaks identified on lymphangiography can potentially be treated by direct puncture of the cisterna chyli with subsequent embolization of the thoracic duct.14 For pulmonary disease, aggressive bronchodilation, corticosteroid, and maneuvers to improve pulmonary clearance can ameliorate symptoms and facilitate recovery. Systemic medical therapy for lymphatic anomalies is rapidly evolving. Sildenafil response was reported in an isolated case report of macrocystic lymphatic malformation,15 leading to off-label use16 and a pilot study.17 Due to the variable natural history of lymphatic malformations, including spontaneous shrinkage of macrocysts, the efficacy of sildenafil is currently unclear. After the success of propranolol for treatment of infantile hemangioma, widespread use has grown to include lymphatic anomalies. Propranolol use has reportedly improved pleural effusions, mucosal lymphatic leak, and lymphatic malformations in a small number of case reports,18–22 although propranolol resistance is also reported.23,24 Durable effects remain in doubt. Sirolimus, an mTOR inhibitor, has been reported to improve pleural effusions and mediastinal mass size25,26 and is currently under study in a phase 2 clinical trial (NCT00975819) with results expected in 2014. The future of therapies for lymphatic anomalies will evolve through results of clinical studies and a better understanding of combinations of multiple medications and medical and procedural treatment protocols.
Outcomes and prognosis While natural history studies are lacking in these conditions, some patterns of outcomes and prognosis are emerging from clinical experience. Uncorrected, chronic lymphedema leads to dermal hypertrophy, cutaneous leak, and chronic infection. In severe cases of chronic lymphedema, chronic ulceration and angiosarcoma (Stewart–Treves syndrome)27 development are reported. Patients with lytic bone disease, as in GLA, may present with pathologic fractures. Osteolysis in Gorham–Stout disease leads to fracture and skeletal instability, as well as spinal cord compromise and CSF leak in cases with vertebral disease. Splenic cysts are generally not associated with complications, even with moderate splenomegaly. Pulmonary involvement leads to recurrent pneumonia and scarring, with both restrictive and obstructive pulmonary diseases. KLA is an aggressive disease with episodic worsening with infection and/or hemorrhage followed by periods of incomplete recovery, usually involving the lungs, pleura, pericardium, and mediastinum. Cardiopulmonary failure and infection are common causes of morbidity and mortality in patients with
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lymphatic anomalies. The five-year survival after presentation with KLA is only 51%.13 Natural history studies and disease- or complication-specific clinical trials are urgently needed. References 1. Fishman SJ. Slow-flow vascular malformations. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Mulliken & Young's Vascular Anomalies Hemangiomas and Malformations. New York, United States of America: Oxford University Press; 2013. 2. Fishman SJ. Truncal, visceral and genital vascular malformations. In: Mulliken JB, Burrows PE, Fishman SJ, editors. Mulliken & Young's Vascular Anomalies: Hemangiomas and Malformations. New York, United States of America: Oxford University Press; 2013. 3. Hibbeln JF, Wehmueller MD, Wilbur AC. Chylous ascites: CT and ultrasound appearance. Abdom Imaging. 1995;20(2):138–140. 4. Seeger M, Bewig B, Gunther R, et al. Terminal part of thoracic duct: highresolution US imaging. Radiology. 2009;252(3):897–904. 5. Fishman SJ, Burrows PE, Upton J, Hendren WH. Life-threatening anomalies of the thoracic duct: anatomic delineation dictates management. J Pediatr Surg. 2001;36(8):1269–1272. 6. Rajebi MR, Chaudry G, Padua HM, et al. Intranodal lymphangiography: feasibility and preliminary experience in children. J Vasc Interv Radiol. 2011;22(9):1300–1305. 7. Sena LM, Fishman SJ, Jenkins KJ, et al. Magnetic resonance lymphangiography with a nano-sized gadolinium-labeled dendrimer in small and large animal models. Nanomed. 2010;5(8):1183–1191. 8. Chen W, Adams D, Patel M, Gupta A, Dasgupta R. Generalized lymphatic malformation with chylothorax: long-term management of a highly morbid condition in a pediatric patient. J Pediatr Surg. 2013;48(3):e9–e12. 9. Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham–Stout disease and generalized lymphatic anomaly—clinical, radiologic, and histologic differentiation. Skeletal Radiol. 2013;42(7):917–924. 10. Enzinger FM. Tumors of lymphatic vessels. In: Weiss SW, Goldblum JR, Enzinger FM, editors. Enzinger and Weiss' Soft Tissue Tumors. Philadelphia, PA: Mosby Elsevier; 2008. p. 1258. 11. Chavanis N, Chaffanjon P, Frey G, Vottero G, Brichon PY. Chylothorax complicating Gorham's disease. Ann Thorac Surg. 2001;72(3):937–939. 12. Croteau SE, Kozakewich HP, Perez-Atayde AR, et al. Kaposiform lymphangiomatosis: a distinct aggressive lymphatic anomaly. J Pediatr. 2014;164(2): 383–388.
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