Clin Chest Med 27 (2006) 355 – 368 Pleural Disease in Lymphangioleiomyomatosis Khalid F. Almoosa, MDa,T, Francis X. McCormack, MDa, Steven A. Sahn, MDb a Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, 6004 MSB, PO Box 670564, Cincinnati, OH 45267-0564, USA b Division of Pulmonary and Critical Care Medicine, Department of Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, SC, USA Lymphangioleiomyomatosis (LAM) is a rare lung sentinel event that leads the clinician to consider the disease of unknown etiology that is characterized by diagnosis of LAM. Because pleural complications are the proliferation and infiltration of the pulmonary important for the recognition of LAM and constitute interstitium with atypical smooth muscle cells [1 – 3]. unique challenges for clinical management, this The first case description was published in 1919 in article presents an overview of pleural complications a child with tuberous sclerosis complex (TSC) who in LAM. There is a paucity of data on this topic, and presented with bilateral spontaneous pneumothorax most of this article is based on published case series . TSC is an inherited neurocutaneous disorder with and survey reports. variable penetrance characterized by the development of multiorgan hamartomas, cognitive impairment, and seizures [5 – 9]. In 1966, Cornog and Enterline  Pneumothorax attempted to bring order to the LAM literature by clarifying the nomenclature and describing charac- Pneumothorax is defined as the abnormal pres- teristic histologic features in a group of patients. ence of air in the pleural cavity. Pneumothorax can Whether LAM is associated with TSC or not, it oc- occur traumatically by the introduction of ambient curs almost exclusively in women of reproductive age air after penetration of the chest wall and pleura or and leads to the development of numerous pulmonary spontaneously. Spontaneous pneumothorax can occur parenchymal cysts (Figs. 1 and 2). The pathologic in patients without clinically apparent underlying findings of TSC-LAM are similar to those found in lung disease (primary spontaneous pneumothorax) sporadic LAM and include profuse smooth muscle or in patients with pulmonary disorders (secondary infiltration of all lung structures—airways, blood spontaneous pneumothorax). Secondary spontaneous vessels, lymphatics, and interstitium [7,9]. In either pneumothorax can occur with virtually any pulmo- TSC-LAM or sporadic LAM, progressive respiratory nary disease, but is more common in specific ob- insufficiency and pleural complications, specifically structive, interstitial, and infectious lung diseases, pneumothorax and chylothorax, are the clinical hall- such as chronic obstructive pulmonary disease, cystic marks. Because most of the initial episodes of pneu- fibrosis, Langerhans’ cell histiocytosis, and Pneumo- mothorax or chylothorax occur before the diagnosis cystis jiroveci pneumonia [11 – 16]. of LAM is established, their occurrence is often the Incidence, recurrence, and clinical presentation T Corresponding author. The incidence of pneumothorax in LAM is one of E-mail address: email@example.com (K.F. Almoosa). the highest among diseases associated with secondary 0272-5231/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ccm.2006.01.005 chestmed.theclinics.com 356 almoosa et al Fig. 1. Chest CT scan of a patient with LAM shows characteristic bilateral cysts of various sizes. spontaneous pneumothorax (range 39 – 76%) (Table 1). was 66% (260 patients). Of the 193 patients who re- Pneumothorax frequently is the presenting event that sponded to a secondary questionnaire specifically leads to the diagnosis of LAM in affected patients inquiring into the details of their pneumothoraces, [17 – 19]. Chu et al  reported that pneumothorax most (80%) had developed at least one pneumothorax was the presenting event leading to the diagnosis of before their diagnosis of LAM was established LAM in 15 (63%) of 24 patients with a pneumo- (Fig. 3). These patients averaged 2.6 pneumothoraces thorax. Corrin et al  reported that 6 (21%) of before diagnosis. 28 patients had pneumothorax as a presenting mani- One of the most remarkable characteristics of pneu- festation of LAM. Oh et al  reported that 10 mothorax in LAM is the rate of recurrence (Table 1). (48%) of 21 patients they evaluated had a pneumo- Most case series report that most LAM patients thorax at presentation; 7 of these 10 patients had developed a recurrent pneumothorax [22 – 24]. Urban recurrent pneumothoraces before the diagnosis of et al  reported a recurrence rate of 68% among LAM was established. Rarely, bilateral spontaneous 69 patients, whereas Taylor et al  reported a pneumothoraces have been reported to be the pre- recurrence in 81% of 32 patients. Not all studies senting feature of LAM [20,21]. In a large retro- discriminated between ipsilateral and contralateral spective study of pneumothorax using the database of recurrence, however. In the LAM Foundation study the LAM Foundation, Almoosa et al  reported , recurrence occurred in 140 (73%) of 193 patients that the prevalence of pneumothorax among who developed at least one pneumothorax. These 395 LAM patients during the course of their disease recurrences were ipsilateral (71%) and contralateral Fig. 2. Gross (A) (From McCormack FX, Sullivan EJ. Lymphangioleiomyomatosis. In: Mason RJ, Murray JF, Courtney V, et al, editors. Murray and Nadel’s textbook of respiratory medicine. Fourth Edition. Philadelphia: Harcourt Health Sciences Group; 2005. p. 1706; with permission.) and microscopic (B) appearance of LAM lungs. Multiple cysts throughout both lungs are characteristic of LAM. pleural disease in lymphangioleiomyomatosis 357 Table 1 Prevalence, recurrence rate, and pleurodesis for Pneumothorax during course of lymphangioleiomyomatosis Incidence Recurrence No. patients who Author [reference] No. patients of PTX (%) of PTX (%) had pleurodesis (%) Corrin et al  28 12 (43) n/a NA Taylor et al  32 17 (53) 26 (81) NA Kitaichi et al  46 18 (39) NA NA Chu et al  35 24 (69) NA 19 (54) Oh et al  21 13 (76) NA 7 (33) Urban et al  69 32 (46) 47 (68) 40 (58) Johnson and Tattersfield  50 30 (60) 23 (46) NA Ryu et al  230 128 (56) NA NA Almoosa et al  193 NA 140 (73) 154 Abbreviations: NA, not available; PTX, pneumothorax. (74%), occurring an average of 21.7 and 30 months endometriosis [26 – 28]. A high-resolution CT scan after the initial pneumothorax, respectively. Com- that reveals normal lung parenchyma suggests cata- pared with the incidence of recurrence of pneumo- menial pneumothorax, whereas the presence of cysts thorax in other diseases, LAM has the highest rate suggests LAM. (Table 2), although the absolute number of pneumo- The most common presenting symptoms of pneu- thoraces in this patient group is small because of the mothorax are dyspnea and chest pain. In the LAM rarity of the disease. Consistent with the conclusions Foundation study , most pneumothorax occurred of the Delphi consensus conference on pneumothorax at rest or with minimal activity (81%). Less com- management, early aggressive intervention is sug- monly, pneumothorax occurred during exertion, such gested to avoid the morbidity and risk of subsequent as lifting or during exercise. Four patients developed pneumothoraces in patients with compromised lung a pneumothorax during pulmonary function testing, function, although firm evidence to support this ap- where most described feeling a ‘‘pop’’ in the chest. proach is lacking . Cough and hemoptysis also may occur in association An important alternative diagnosis that must be with pneumothorax in a few cases. considered for recurrent pneumothorax in nonsmok- Bilateral simultaneous pneumothorax is an acute ing women of childbearing age is catamenial pneu- and potentially fatal situation that occurs rarely in mothorax, a spontaneous pneumothorax that occurs patients with underlying lung disease. A few case during or within 24 to 48 hours of menstruation and series have described bilateral simultaneous pneu- is usually, but not always, associated with thoracic mothorax, and most have occurred in patients with Fig. 3. Age at onset of initial pneumothorax compared with diagnosis of LAM. Most women developed their first pneumo- thorax before a diagnosis of LAM was established. (From Almoosa KF, Ryu JH, Mendez J, et al. Management of pneumo- thorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129:1277; with permission.) 358 almoosa et al Table 2 Pathophysiology Prevalence and recurrence rates of secondary spontane- ous pneumothorax The cardinal pathologic feature of LAM is the Prevalence Recurrence proliferation of immature smooth muscle cells along PSP 4.3 – 12/100,000 16 – 52% the peribronchial, perivascular, and perilymphatic CF (>18 years old) 16 – 20% 50 – 78% structures [18,32,33]. Compression and obstruction LCH 10 – 28% 25 – 50% of these conduits result in the development of airflow COPD 26/100,000 39 – 47% obstruction and pneumothorax, hemoptysis and alve- LAM 64 – 66% 62 – 76% olar hemorrhage, and chyloptysis and chylothorax, Abbreviations: CF, cystic fibrosis; COPD, chronic obstruc- respectively. There is little or no associated inflam- tive pulmonary disease; LCH, Langerhan’s cell histiocyto- mation or fibrosis in LAM. Although it is known sis; PSP, Pneumocystis jiroveci pneumonia. that smooth muscle cells can infiltrate the pleura, a systematic pathologic study of pleural involvement in LAM has not been reported . Some investigators have suggested that bronchial chronic obstructive pulmonary disease, pulmonary or obstruction by overgrowth of LAM cells is respon- pleural metastases, Hodgkin’s disease, tuberculosis, sible for the obstructive pattern and air trapping Langerhans’ cell histiocytosis, undefined interstitial (Fig. 4) [2,18,32,33]. It has been postulated that this lung disease, cystic fibrosis, and LAM [29 – 31]. De- process ultimately leads to the formation of diffuse, spite the rarity of LAM, it is routinely mentioned in bilateral, thin-walled pulmonary cysts, ranging in size case reports discussing bilateral simultaneous pneu- from a few millimeters to a few centimeters in diame- mothorax [20,29]. The LAM Foundation study ter, which are the pathologic and radiographic hall- identified 8 (4%) of 193 patients who developed bi- mark of LAM [18,33]. Biopsy specimens also have lateral simultaneous pneumothorax during the course revealed the presence of a mixed proximal acinar and of their disease, with several patients experiencing irregular emphysematous pattern, however, which recurrent bilateral simultaneous pneumothorax . may be present in areas associated with less affected bronchioles. This finding has led to other theories for the pathogenesis of airflow obstruction, such as the Fig. 5. Lung of LAM patient showing multiple cysts, some of which abut the pleura (arrow). (From Almoosa KF, Ryu JH, Mendez J, et al. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129:1277; Fig. 4. Pathogenesis of pneumothorax in LAM. with permission.) pleural disease in lymphangioleiomyomatosis 359 destruction of supportive fibers by matrix degrading between lung tissue and airspace. CT more clearly enzymes resulting in an emphysematous pattern and defines the pneumothorax and may show the classic cyst formation [35,36]. Notwithstanding their origin, findings of LAM pathology in the unaffected lung these cysts often involve the pleural surface (Fig. 5), [17,24,37]. These findings include reticulonodular and a pneumothorax can occur from their direct shadows, cysts or bullae, and hyperinflation. Inci- rupture into the pleural space or through alveolar wall dental small pneumothoraces occasionally are dis- disruption that allows air to enter the lung interstitium covered on CT scans performed for other purposes and mediastinum and eventually cause rupture of the (see Fig. 6B). Pleurodesis complicates the diagnosis mediastinal pleura (Fig. 6). and management of pneumothorax in LAM patients. Patients may present with persistent chest pain, short- Radiologic features ness of breath, or subcutaneous emphysema in the absence of a radiographically apparent pneumothorax The patient’s history first suggests the diagnosis of on chest radiograph. CT may show a small loculated pneumothorax in LAM, and the diagnosis most com- pneumothorax in these instances. monly is confirmed by a standard chest radiograph [17,19,37] showing the classic visceral pleural line Treatment that runs parallel to the inner thoracic wall . In some cases, the cystic changes in LAM are appar- All LAM patients should be counseled on the ent on a chest radiograph only when partial collapse symptoms associated with pneumothorax and given secondary to pneumothorax enhances the contrast explicit instructions to seek medical care when a Fig. 6. Chest radiograph (A) and CT scan (B) show pneumothorax in two patients with LAM. The pneumothorax on chest CT scan was discovered incidentally. 360 almoosa et al pneumothorax is suspected. The American College of patients treated conservatively (20 of 30, 66%) com- Chest Physicians Delphi Consensus Statement pub- pared with the surgical intervention group (3 of 17, lished in 2001 offers recommendations on the optimal 18%). Although the reason for the poor treatment approach to the management of spontaneous pneu- response for LAM compared with other lung diseases mothorax [23,25]. It states that for small or large is unclear, it is possible that the dramatic profusion of secondary spontaneous pneumothoraces, whether sta- blebs on the lung surface could limit the apposition of ble or unstable, chest tube thoracostomy and hospitali- the visceral and parietal pleurae after mechanical zation are recommended. For recurrence prevention, abrasion or chemical sclerosant instillation and lead most members of the panel suggested a pleurodesis to incomplete fusion. intervention because of the potential lethality of re- One of the major conclusions of the LAM Foun- current pneumothoraces in patients with compro- dation study was that current experience with pneu- mised lung function. The preferred intervention for mothorax in LAM supports an early interventional the lung diseases studied in that report was surgical procedure—chemical pleurodesis or surgery—after because it was associated with a lower recurrence rate the first pneumothorax. This recommendation was compared with the instillation of a sclerosant . made because of the high incidence of pneumothorax The authors evaluated failure rates for chemical and recurrence and associated morbidity, including a surgical pleurodesis in LAM . lifelong average of 1 month in the hospital for pneu- Nonsurgical treatment options for pneumothorax mothorax management in LAM patients who develop can be divided into lung expansion therapy (ie, con- an initial pneumothorax (Fig. 7). Most initial pneu- servative, including observation, simple aspiration, mothoraces in LAM patients occur before the and tube thoracostomy) and interventional therapy diagnosis of LAM, however [21,22,24,37]. Patients (ie, chemical pleurodesis). Surgical options include often experience several pneumothoraces before a mechanical pleurodesis, talc poudrage at thoraco- diagnosis is established and an intervention is per- scopy and thoracotomy, and partial or complete formed. The paucity of data and published literature pleurectomy. For secondary spontaneous pneumo- on this issue is a major impediment to the develop- thorax in general, surgical interventions have been ment of recommendations with a high degree of associated with lower recurrence rates than non- clinical confidence. surgical techniques [39,40]. Limited data address this Patient perspectives on interventions for pneumo- issue in LAM. Only two studies reported success thorax in LAM also have been addressed. In a study rates of different interventions for pneumothorax. The by Young et al , 314 patients registered with the LAM Foundation study  reported lower failure LAM Foundation were given a questionnaire inquir- rates with chemical pleurodesis (27%) and surgery ing into their perspectives regarding different treat- (32%) compared with conservative interventions ment options. Although 41% believed that a previous (66%). Johnson and Tattersfield  reported that pneumothorax contributed to the decline in their lung approximately half (23 of 47, 49%) of the patients function, and one third made lifestyle modifications treated had a recurrence, with most occurring in to prevent pneumothorax, only 12% worried about Fig. 7. Recurrence of pneumothorax (PTX) in LAM. Most LAM patients developed multiple pneumothoraces during their lifetime. (From Sullivan EJ. Lymphangioleiomyomatosis: a review. Chest 1998;114:1689 – 703; with permission.) pleural disease in lymphangioleiomyomatosis 361 developing a pneumothorax. Although most patients were judged to be of moderate severity in 8 and agreed that pleurodesis helps prevent pneumothorax severe in 10 cases. In addition, 13 (72%) of 18 cases recurrence, only 25% thought it was appropriate for of pleural adhesions were believed to be secondary to the first pneumothorax, and only 60% believed it was the underlying disease because they occurred in pa- appropriate for a recurrence. This finding may be re- tients who had not had previous pleural interventions, lated to concerns of extensive and inadequately whereas the remaining 5 (28%) were due to prior treated pain associated with chest tube thoracostomy pleurectomy. Moderate-to-severe hemorrhage oc- that were reported by the subjects. This study suggests curred in four patients, leading to intraoperative that views between physicians and patients differ death in one patient and repeat thoracotomy in two regarding the optimal therapy for pneumothorax in patients. Overall, post-transplantation survival in this LAM, and that patients favor a more conservative cohort of LAM patients was similar to other chronic approach initially. It remains to be determined whether lung disease populations. The authors concluded optimal pain management may change these views. that although perioperative complications do occur in LAM patients who had pleural procedures, lung Effect of treatment on lung transplantation transplantation remains an important option that improves long-term outcomes. Interventional approaches for pneumothorax in A study by Pechet et al  retrospectively LAM may affect candidacy and outcomes of lung evaluated seven single and seven bilateral lung trans- transplantation. As obstructive lung disease prog- plant recipients for LAM. All 14 patients had mul- resses in this population of young, otherwise healthy tiple previous pleurodeses for pleural complications women, lung transplantation frequently is considered. of LAM, and 6 patients had at least one thoracotomy It is well accepted that prior chemical or surgical for pleurectomy or bullectomy. Extensive pleural ad- pleurodesis increases the risk of perioperative bleed- hesions were present in 10 (71%) of 14 patients, and ing in any lung transplant recipient [42,43]. LAM 7 (50%) experienced blood loss greater than 1000 mL patients are prone to pleural complications and often intraoperatively. There were no perioperative deaths. present for consideration for lung transplantation after The authors concluded that although perioperative unilateral or bilateral pleurodesis. It is especially im- morbidity is common in LAM patients undergoing lung portant to understand the consequences of pleural transplantation, early and late survival is comparable interventions in LAM patients to minimize the impact to that of lung transplant patients for other diseases. of pleural manangement decisions on eligibility for In the LAM Foundation study , 85 registered lung transplantation. LAM Foundation patients who received a lung Few studies have evaluated specifically the out- transplant were sent a questionnaire focused on the comes of lung transplantation in LAM patients who impact of pleural symphysis on complications arising have had a pleural symphysis procedure (Table 3). in the perioperative period. Data from 80 recipients Boehler et al  conducted a retrospective survey of of 81 transplants (1 patient had a re-transplant) were 34 LAM patients who underwent lung transplantation evaluated. In 45 (56%) of 80 patients, chemical or at 16 centers in the United States and Europe. Of pa- surgical pleurodesis had been performed before the tients, 27 received single-lung transplants, 6 received transplant for a pneumothorax or a chylothorax. In bilateral transplants, and 1 received a heart-lung 12 (27%) of 45 patients, the side of previous pleural transplant. Of 34 patients, 13 (38%) had previous procedure influenced the side of the lung transplant. pleurectomy or pleurodesis. Also, 18 (53%) of Fourteen (18%) of 80 patients reported pleural-related 34 patients had extensive pleural adhesions, which bleeding complications perioperatively, 13 (93%) of Table 3 Lung transplantation, pleurodesis, and perioperative bleeding in lymphangioleiomyomatosis No. patients No. patients with No. patients with with previous adhesions seen perioperative Author [reference] No. patients transplanted pleurodesis (%) during surgery bleeding Pechet et al  14 (7 single, 7 bilateral) 14 (100) 10 7 Boehler et al  34 (27 single, 6 bilateral, 13 (38) 18 4 1 heart-lung) Almoosa et al  81 (38 single, 43 bilateral) 45 (56) NA 14 Abbreviation: NA, not available. 362 almoosa et al whom had previous pleural procedures. Half (7 of 14) risk of flight on the development of pneumothorax of these complications required a return to surgery, in LAM can be reached. and most occurred in patients with previous bilateral Pregnancy may contribute to an increased risk of pleural procedures. The average length of stay in pleural complications in LAM. Several investigators the group with prior pleural procedures tended to be have speculated that the elevated hormonal levels greater than the group without prior procedures associated with pregnancy may accelerate the pro- (33.5 ± 5.4 days versus 26.4 ± 6.2 days), although gression of LAM. The changes in lung volumes and the different was not statistically significant. There pressures that occur with pregnancy may increase the were no perioperative deaths. These results indicate risk of pleural complications. No published reports that although perioperative complications, bleeding in specifically describe the prevalence of pneumothorax particular, are common in patients with prior pleural in pregnant LAM patients. A few subjects reported interventions, they are generally manageable. in two separate LAM cases series developed a pneu- An ongoing study is evaluating the bias of mothorax during pregnancy, however. Johnson and transplant centers regarding candidacy for transplant Tattersfield  reported that 7 (14%) of 50 LAM in LAM patients who have had previous pleurodesis patients studied were pregnant, 3 (43%) of whom (Chris Lyons, personal communication, 2005). Of developed a pneumothorax during pregnancy. In the 52 centers evaluated, 22 responded, of which 40% 21 patients evaluated by Oh et al , all 3 patients considered previous bilateral pleurodesis with talc or who were pregnant developed a pneumothorax dur- pleurectomy a contraindication to transplant. Para- ing pregnancy. In view of this paucity of data, the doxically, most centers (55%) agreed that talc was the LAM Foundation conducted a survey among regis- preferred agent for pleurodesis for pneumothorax tered patients inquiring into the incidence and man- recurrence. In the LAM Foundation study, 43% of agement of pneumothorax during pregnancy (Janet patients had bilateral pleurodesis before transplant Maurer, MD, MBA, personal communication, 2005). . This study suggests considerable controversy Of the 239 registered women who had at least one exists regarding the optimal management for pleural pregnancy, 53 (22%) reported complications associ- disease in LAM. ated with their pregnancy and received a second ques- tionnaire. Among the 41 respondents, there were a Specific situations of pneumothorax total of 80 pregnancies. Twenty-one patients had a in lymphangioleiomyomatosis total of 122 pneumothoraces that complicated 49 pregnancies. Of these patients, 16 (76%) experi- The risk of developing a pneumothorax in LAM enced their initial pneumothorax during pregnancy, patients may be increased further during certain ac- and in 7 it led to the diagnosis of LAM. Ten (48%) tivities or specific situations. Air travel poses a po- of 21 patients eventually required surgical manage- tential risk for patients with underlying lung disease. ment of pneumothorax, and 13 (62%) pregnancies The decrease in partial pressure of oxygen that ac- were delivered by cesarean section because of pneu- companies the fall in cabin pressure during commer- mothorax. Twenty (95%) patients reported that cial flights results in several physiologic responses, the occurrence of pneumothorax discouraged them including hyperventilation, pulmonary vasoconstric- from future pregnancies, and 30 (73%) of 41 be- tion, and an altered ventilation-perfusion ratio, which lieved that pregnancy accelerated their pulmonary may place increased demand on the respiratory sys- deterioration. These data suggest that pneumothorax tem [46,47]. Patients with chronic obstructive pulmo- is common in pregnant LAM patients and may nary disease may experience hypoxemia during air influence the mode of delivery and decisions about travel [47,48], and pneumothorax during flight has future pregnancies. In addition, most patients been reported in patients with underlying lung disease thought that pregnancy accelerated the deterioration [49 – 52]. There are no data, however, on the in- of their pulmonary function. cidence or risk of pneumothorax in LAM patients during flight. Data collected through the LAM Foundation on the incidence of pneumothorax dur- Chylothorax ing commercial flight reported a total of 8 (2%) cases of pneumothorax among 395 registered patients (Eu- Chylothorax is defined as the accumulation of gene Sullivan, MD, personal communication, 2005). chyle in the pleural space . It results from dis- Without knowing the number of flights, the distances ruption or obstruction of the thoracic duct or its traveled, or the altitudes reached during all trips taken tributaries in the thorax by tumor, trauma, or surgery, by these patients, no firm conclusions regarding the leading to leakage of chyle into the thoracic cavity pleural disease in lymphangioleiomyomatosis 363 Fig. 8. Chest radiograph (A) and CT scan (B) (From McCormack FX, Sullivan EJ. Lymphangioleiomyomatosis. In: Mason RJ, Murray JF, Courtney V, et al, editors. Murray and Nadel’s textbook of respiratory medicine. Fourth Edition. Philadelphia: Harcourt Health Sciences Group; 2005. p. 1708; with permission.) shows chylothoraces in two LAM patients. [53,54]. Chylothorax also may complicate medical chylothoraces are unilateral with no side preference, disorders, such as superior vena cava syndrome, lym- and most are large enough to require intervention phatic disorders such as lymphangiomatosis, and [58,64,65,68 – 70]. Reports often describe the occur- yellow nail syndrome [53,55 – 57]. Chylothorax is rence of a pneumothorax or a chylothorax complicat- a well-recognized complication of LAM (Fig. 8) ing LAM, but these two complications rarely seem [17 – 19,22 – 24,37,58 – 67]. to occur simultaneously. Abdominal involvement in patients with chylothorax also may be present, mani- Prevalence and clinical presentation festing as chylous ascites and lymphadenopathy [66,71 – 73]. The clinical presentation of chylothorax Table 4 summarizes the prevalence of chylotho- almost invariably includes progressive dyspnea, but rax in LAM patients based on published reports. this may be a manifestation of the underlying lung Chylothorax is a less common pleural complication disease and the pleural effusion. Chest pain, cough, of LAM than pneumothorax, with a prevalence of and chyloptysis also may occur. In a retrospective about 20% to 30% among all reported cases. Most review of 79 LAM patients, Ryu et al  identified 8 (10%) who developed a chylothorax. The average Table 4 age at presentation of chylothorax in these LAM Prevalence of chylothorax during course of lymphangio- patients was 41.1 years compared with the average leiomyomatosis age for diagnosis of LAM of 34 years. The occur- No. Prevalence of rence of chylothorax in these patients did not cor- Author [reference] patients chylothorax (%) relate with the extent of lung involvement. Corrin et al  28 11 (39) Pathophysiology and diagnosis Taylor et al  32 9 (28) Kitaichi et al  46 3 (7) Chu et al  35 8 (23) Chylothorax in LAM most likely results from Oh et al  21 0 obstruction of lymphatic vessels by infiltration of Urban et al  69 20 (29) smooth muscle cells. Lymphangiography has shown Johnson and Tattersfield  50 11 (22) that obstruction occurs at several different levels, Ryu et al  79 8 (10) causing chyle leakage to occur on the surface of the Ryu et al  230 48 (21) lung, pleura, and mediastinum [18,70,74]. A histo- logic section of the thoracic duct in a LAM patient Total 590 118 (20) typically reveals a grossly enlarged duct containing 364 almoosa et al proliferating smooth muscle cells . Evidence depletion with persistent drainage, careful monitor- suggests that lymphangiogenesis plays a role in dis- ing of the patient’s weight, serum prealbumin and ease progression. Kumasaka et al  used immu- albumin, total protein, absolute lymphocyte count, nohistochemistry to identify VEGFR-3, a vascular and electrolyte levels is essential [54,84]. The nutri- endothelial growth factor (VEGF) receptor and tional approach to chylothorax involves substitution specific marker for lymphatic endothelial cells, and of long-chain dietary fat with medium-chain tri- VEGF-C, a lymphatic-specific VEGF, in specimens glycerides, which do not become incorporated into obtained from autopsy and surgical cases. They con- chylomicrons. Dietary supplements can be oral or cluded that lymphatics were extremely abundant in intravenous. Hyperalimentation with medium-chain pulmonary and extrapulmonary LAM, and lymphan- triglyceride supplementation can shorten the duration giogenesis was abundant in vascular walls and inter- of the chylous effusion [22,70,85], although variable stitium surrounding the area where LAM cells were degrees of success have been reported in adults . proliferating. In addition, a significant correlation was Similarly, total parenteral nutrition has been used to noted between the degree of lymphangiogenesis in replete nutrients and decrease chyle formation in LAM or VEGF-C expression on LAM cells and the persistently draining effusions and is generally LAM histologic score, which represents the histo- more effective than dietary modification . Im- logic severity of pulmonary LAM, a prognostic in- provements in the formulation and delivery of to- dicator. Chylothorax also may develop through tal parenteral nutrition have improved the safety and transdiaphragmatic flow of chylous ascites. Thoracic reliability of this mode of supplementation, although and abdominal lymphadenopathy may be present  it remains costly . and reveal proliferating smooth muscle cells . Nonoperative drainage may be useful initially to Globular collections of HMB 45 – positive cells can improve symptoms, but many patients eventually be found in the pleural fluid [77,78]. In a subsequent require a chemical or surgical pleurodesis procedure study, Kumasaka et al  further showed that these [22,69]. This intervention seems to be more success- clusters of LAM cells are enveloped by VEGF- ful at preventing recurrences of chylothorax than positive lymphatic endothelial cells, and that the drainage alone [10,70,89 – 91]. In the series by Ryu shedding of these structures into the lymphatic cir- et al , four of five patients with recurrent culation may play a central role in the dissemination chylothorax were treated successfully with pleuro- of LAM lesions. desis. Thoracic duct ligation [10,70,92,93] and the The diagnosis of chylothorax should be enter- placement of a LeVeen shunt  have been at- tained when a LAM patient presents with a pleural tempted, with variable success. effusion on a chest radiograph. Although most pleural Hormonal therapy has been used to treat LAM effusions in LAM are chylothoraces [2,17,70,80], lung disease with mixed results [94 – 97]. Some stud- diagnostic thoracentesis should be performed to con- ies have reported that medroxyprogesterone therapy firm the diagnosis. A triglyceride level greater than has been useful in treating chylothorax that compli- 110 mg/dL makes the diagnosis highly likely, and the cates LAM [23,37,69]. Taylor et al  found that presence of chylomicrons on lipoprotein electropho- most patients whose LAM improved with medroxy- resis is confirmatory if the triglyceride concentra- progesterone therapy had chylothorax or chylous tion is less than 110 mg/dL. Radionuclide or contrast ascites present. The authors postulated that the pres- lymphangiography may be used to locate the site of ence of chylothorax seemed to be a marker for clini- thoracic duct obstruction [81,82]. cal response and might reflect a reversible element in the LAM-affected lung. Octreotide, a long-acting Treatment somatostatin analogue, also has been reported to be effective in treating persistent chylothorax in several Management of chylothorax in LAM is no differ- case reports [98 – 102]. Octreotide reduces the thora- ent than for other diseases [53,54,83]. Although the cic duct flow and triglyceride levels and may be par- treatment of the underlying cause may help in treating ticularly effective when combined with a reduction in chylothorax in other diseases, it is problematic in oral intake. LAM because there is no effective therapy for LAM. Management is based on clinical experience and an- ecdotal reports. Nonoperative management, consist- Summary ing of aspiration or thoracostomy tube drainage, often is done initially to re-expand the lung and improve LAM is a rare, gender-restricted interstitial lung symptoms. Because there is a high risk of nutritional disease that causes significant morbidity and mortal- pleural disease in lymphangioleiomyomatosis 365 ity. Pneumothorax or chylothorax occurs during the  Mitchell-Heggs PF. Spontaneous pneumothorax in course of illness in most patients. The incidence of cystic fibrosis. Thorax 1970;25:256 – 7. secondary spontaneous pneumothorax in LAM is  Penketh AR, Knight RK, Hodson ME, Batten JC. Management of pneumothorax in adults with cystic among the highest of all chronic lung diseases and fibrosis. Thorax 1982;37:850 – 3. may result in considerable morbidity. The effect of  Sahn SA, Heffner JE. Spontaneous pneumothorax. pneumothorax and chylothorax on disease pro- N Engl J Med 2000;342:868 – 74. gression and prognosis is unknown, however. 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