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  Table of Contents    
CASE REPORT
Year : 2019  |  Volume : 36  |  Issue : 4  |  Page : 349-352  

Low-dose sirolimus in retroperitoneal lymphangioleiomyomas


1 Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
2 Division of Cardiovascular and Pulmonary Imaging, Department of Radiology, University of Iowa, Iowa City, IA, USA
3 Division of Pulmonary and Critical Care, Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA

Date of Web Publication28-Jun-2019

Correspondence Address:
Dr. Kamonpun Ussavarungsi
Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, C33 GH Iowa City, IA 52242
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/lungindia.lungindia_433_18

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   Abstract 


Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic lung destruction and abdominal tumors, including lymphangioleiomyomas, which frequently occur in the retroperitoneal region. Sirolimus therapy is currently recommended for LAM patients with abnormal or declining lung function with an adjusted dose to maintain a serum trough level of 5–15 ng/mL. We describe a significant reduction of retroperitoneal lymphangioleiomyomas after treatment with low-dose sirolimus therapy (serum trough level <5 ng/mL) in a patient with sporadic LAM.

Keywords: Low-dose sirolimus, lymphangioleimyomas, lymphangioleiomyomatosis


How to cite this article:
Ussavarungsi K, Laroia AT, Burger CD. Low-dose sirolimus in retroperitoneal lymphangioleiomyomas. Lung India 2019;36:349-52

How to cite this URL:
Ussavarungsi K, Laroia AT, Burger CD. Low-dose sirolimus in retroperitoneal lymphangioleiomyomas. Lung India [serial online] 2019 [cited 2019 Jul 22];36:349-52. Available from: http://www.lungindia.com/text.asp?2019/36/4/349/261709




   Introduction Top


Lymphangioleiomyomatosis (LAM) is a multisystem disorder that primarily affects women and is characterized by proliferation of abnormal smooth muscle-like cells with associated cystic lung destruction and abdominal tumors, such as renal angiomyolipoma and lymphangioleiomyomas.[1],[2]

The double-blind, randomized Multicenter International LAM Efficacy of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved quality of life and functional performance.[2] Sirolimus is now recommended for LAM patients with abnormal forced expiratory volume in 1 s (FEV1 <70%) predicted or declining lung function.[3] Sirolimus therapy was also reported to be associated with improvement or reduction in size of chylous effusions and lymphangioleiomyomas.[4] Optimal dose and duration are unsettled. Nonetheless, the sirolimus dose was adjusted during the MILES trial to maintain a serum trough between 5 and 15 ng/mL.[2] Conversely, Ando et al. reported the effectiveness of low-dose sirolimus (serum trough <5 ng/mL) for stabilizing lung function in 15 patients with sporadic LAM, but the effect of low-dose therapy on extrapulmonary LAM has not been explored.[5]

Clinical experience is important to report in rare disease states, particularly favorable outcomes with low-dose therapy. We describe a significant reduction of retroperitoneal lymphangioleiomyomas with low-dose sirolimus therapy (serum trough level <5 ng/mL) in a patient with sporadic LAM.


   Case Report Top


A 26-year-old woman with sporadic LAM was diagnosed when she presented with dyspnea on exertion and nonmassive hemoptysis with characteristic diffuse thin-walled cysts on chest computed tomography (CT) and elevated vascular endothelial growth factor-D (VEGF-D) level (4458 pg/mL). Abdominal and pelvic CT showed a large lobulated cystic and solid mass in the retroperitoneal region compatible with lymphangioleiomyoma [Figure 1]. The large multicystic lesion involving a large portion of retroperitoneum abutted the kidneys and encased both the descending aorta and inferior vena cava. No intra-abdominal adenopathy, ascites, or intrarenal lesion was identified. Pulmonary function test showed preserved FEV1/forced vital capacity (FVC) ratio with FEV1 4.11 L (112%) and FVC 5.04 (116%) but a reduced diffusing capacity of the lungs for carbon monoxide (DLCO) (59% predicted). Sirolimus was offered as a treatment option due to exertional dyspnea and hypoxemia in association with the reduced DLCO and the large, intra-abdominal disease burden. The patient tolerated sirolimus at 1 mg daily and remained on the same dose with the mean serum trough level at 2.98 ± 1.39 ng/mL. Her respiratory symptoms improved with stabilized FEV1 4.18 L (116%) and DLCO 56% after 14 months of sirolimus treatment. Repeat CT of chest, abdomen, and pelvis revealed stable pulmonary cystic lesions and nearly complete resolution of the retroperitoneal mass [Figure 1].
Figure 1: (a) Computed tomography chest demonstrating multiple small cystic lesions throughout the lungs. (b and c) Large multicystic retroperitoneal mass, measuring 26 cm × 14 cm × 8 cm, extending from the level of the superior mesenteric artery and renal arteries, encasing the aorta and inferior vena cava to bifurcation and further extending into the pelvis along the right external and internal iliac arteries. (d) Nearly complete resolution of retroperitoneal lymphangioleiomyomas after 14 months of sirolimus

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   Discussion Top


Lymphangioleiomyomas occur most often in the retroperitoneal region and have been observed more frequently in patients with sporadic LAM (29%) than in tuberous sclerosis complex patients with LAM (9%).[6] Extrapulmonary LAM cells form fascicles and papillary patterns that are commonly found in lymph nodes along lymphatic vessels.[7] Lymphangioleiomyoma-LAM cells have infiltrated the fatty capsule surrounding the mass.[8] In addition, chyle-filled cystic lesions resulted from the obstruction of lymphatic vasculature by proliferation of smooth muscle cells.[7],[8] Large lesions such as those seen in this case can encase and compress adjacent organs. Our patient also had a markedly high VEGF-D level, which has been shown to reflect lymphatic involvement and negatively correlate with pulmonary function in patients with LAM.[9] Historically, lymphangioleiomyomas were primarily managed with surgical resection but may recur after surgical removal. More recently, medical treatment with sirolimus has surfaced as beneficial due to its favorable effect on lymphangioleiomyoma size.[4],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19]

Nonetheless, the optimal sirolimus dose and serum level remain undetermined. A review of published case reports and series of LAM patients with abdominal lymphangioleiomyomas who received sirolimus therapy is summarized in [Table 1]. Most had dramatic reduction of mass with sirolimus trough level >5 ng/mL. In contrast, the effect of sirolimus also remained significant in several cases with serum trough level <5 ng/mL as was the case in our patient.[11],[12]
Table 1: Published cases of lymphangioleiomyomatosis with abdominal lymphangioleiomyomas treated with sirolimus

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Loss of beneficial effect occurred in the MILES trial; therefore, long-term treatment is generally required. Low-dose sirolimus has the potential to reduce adverse effects and may enhance the safety of long-term therapy. Multicenter Interventional LAM Early Disease (MILED) trial to determine the efficacy of low-dose sirolimus (fixed dose at 1 mg daily) for preventing progression of disease in patients with well-preserved lung function is underway (NCT03150914). Nonetheless, abdominal tumor size is not a primary outcome in MILED trail. Our report reinforces the role of medical therapy for lymphangioleiomyomas that can avoid unnecessary surgery. In addition, favorable responses of extrapulmonary LAM to low-dose sirolimus therapy that is well tolerated are important to report to contribute to the available literature on treatment of this rare disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, et al. The NHLBI lymphangioleiomyomatosis registry: Characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006;173:105-11.  Back to cited text no. 1
    
2.
McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595-606.  Back to cited text no. 2
    
3.
McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, et al. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: Lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med 2016;194:748-61.  Back to cited text no. 3
    
4.
Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 2011;154:797-805, W-292-3.  Back to cited text no. 4
    
5.
Ando K, Kurihara M, Kataoka H, Ueyama M, Togo S, Sato T, et al. Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respir Investig 2013;51:175-83.  Back to cited text no. 5
    
6.
Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Lymphangioleiomyomatosis: Abdominopelvic CT and US findings. Radiology 2000;216:147-53.  Back to cited text no. 6
    
7.
Glasgow CG, Taveira-DaSilva A, Pacheco-Rodriguez G, Steagall WK, Tsukada K, Cai X, et al. Involvement of lymphatics in lymphangioleiomyomatosis. Lymphat Res Biol 2009;7:221-8.  Back to cited text no. 7
    
8.
Matsui K, Tatsuguchi A, Valencia J, Yu Zx, Bechtle J, Beasley MB, et al. Extrapulmonary lymphangioleiomyomatosis (LAM): Clinicopathologic features in 22 cases. Hum Pathol 2000;31:1242-8.  Back to cited text no. 8
    
9.
Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest 2009;135:1293-300.  Back to cited text no. 9
    
10.
Radzikowska E, Blasinska-Przerwa K, Skronska P, Wiatr E, Switaj T, Skoczylas A, et al. Lymphangioma in patients with pulmonary lymphangioleiomyomatosis - Results of sirolimus treatment. J Cancer Sci Ther 2016;8:233-9.  Back to cited text no. 10
    
11.
Harari S, Elia D, Torre O, Bulgheroni E, Provasi E, Moss J. Sirolimus Therapy for Patients With Lymphangioleiomyomatosis Leads to Loss of Chylous Ascites and Circulating LAM Cells. Chest 2016;150:e29-32.  Back to cited text no. 11
    
12.
Ito T, Suno M, Sakamoto K, Yoshizaki Y, Yamamoto K, Nakanishi R, et al. Therapeutic Effect of Sirolimus for Lymphangioleiomyomatosis Remaining in the Abdominopelvic Region After Lung Transplantation: A Case Report. Transplant Proc 2016;48:271-4.  Back to cited text no. 12
    
13.
Cabeza Osorio L, Ruiz Cobos MA, Casanova Espinosa A. Resolution of Thoracic and Abdominal Lymphangioleiomyomas in a Patient With Lymphangioleiomyomatosis Treated With Sirolimus. Arch Bronconeumol 2016;52:329-30.  Back to cited text no. 13
    
14.
Freitas CS, Baldi BG, Araújo MS, Heiden GI, Kairalla RA, Carvalho CR, et al. Use of sirolimus in the treatment of lymphangioleiomyomatosis: Favorable responses in patients with different extrapulmonary manifestations. J Bras Pneumol 2015;41:275-80.  Back to cited text no. 14
    
15.
Hecimovic A, Jakopovic M, Pavlisa G, Jankovic M, Vukic-Dugac A, Redzepi G, et al. Successful treatment of pulmonary and lymphatic manifestations of lymphangioleiomyomatosis with sirolimus. Lymphology 2015;48:97-102.  Back to cited text no. 15
    
16.
Numata T, Araya J, Mikami J, Hara H, Harada T, Takahashi H, et al. A case of pulmonary lymphangioleiomyomatosis complicated with uterine and retroperitoneal tumors. Respir Med Case Rep 2015;15:71-6.  Back to cited text no. 16
    
17.
Rozenberg D, Thenganatt J. Dramatic response to sirolimus in lymphangioleiomyomatosis. Can Respir J 2013;20:413-4.  Back to cited text no. 17
    
18.
Chen F, Omasa M, Kondo N, Fujinaga T, Shoji T, Sakai H, et al. Sirolimus treatment for recurrent lymphangioleiomyomatosis after lung transplantation. Ann Thorac Surg 2009;87:e6-7.  Back to cited text no. 18
    
19.
Morton JM, McLean C, Booth SS, Snell GI, Whitford HM. Regression of pulmonary lymphangioleiomyomatosis (PLAM)-associated retroperitoneal angiomyolipoma post-lung transplantation with rapamycin treatment. J Heart Lung Transplant 2008;27:462-5.  Back to cited text no. 19
    


    Figures

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    Tables

  [Table 1]



 

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