Lymphangioleiomyomatosis

reviews Lymphangioleiomyomatosis* A Review Eugene]. Sullivan, MD, FCCP

(CHEST 1998; 114:1689-1703)

Key words: angiomyolipoma; interstitial lung disease; lymphangioleiomyomatosis; tuberous sclerosis complex Abbreviations: CXR = chest radiograph; DLCO = diffusing capacity for carbon monoxide; ER = estrogen receptor; HRCT = high-resolution CT; ILD = interstitial lung disease; LAM = lymphangioleiomyomatosis; PFT = pulmonary function test; PR = progesterone receptor; TLC = total lung capacity; TSC = tuberous sclerosis complex

Lymphangioleiomyomatosis (LAM) is a rare disease that affects women, primarily in their reproductive years. It is characterized by the nonneoplastic proliferation of atypical smooth muscle cells within the lung parenchyma and elsewhere, leading to progressive loss of lung function and, ultimately, death. The two most common presenting symptoms of LAM are dyspnea on exertion and pneumothorax. 1--3 Other common signs and symptoms include nonproductive cough, hemoptysis, chylous pleural effusion, and chylous ascites. 1- 4 There is no known familial tendency, although the pathologic findings in LAM are identical to those found when tuberous sclerosis complex (TSC), an autosomally inherited disorder, involves the lung. 5 The etiology of the disease and the efficacy of currently utilized treatments are unknown. The goal of this article is to review the current understanding of LAM.

HISTORICAL PERSPECTIVE

The 1966 article by Cornog and Enterline6 is the first significant collection of patients with what is *From the Cleveland Clinic Foundation, Department of Pulmonary and Critical Care Medicine, Cleveland, OH. Partial salary support (15%) provided by NIH grant No. 1 U01 HL58440-0l (Lymphangioleiomyomatosis Registry). Manuscript received January 22, 1998; revision accepted May 15, 1998. Correspondence to: Eugene ]. Sullivan, MD, FCCP, The Cleveland Clinic Foundation, Department of Pulrrwnary and Critical Care Medicine, A90, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: [email protected]

now known as LAM. In this article, the authors reported six cases of what they termed "lymphangiomyoma." In addition to their cases, the authors included 14 cases from the literature that they believed, based on histologic features, represented the same disease entity. These cases had been published under various terms, including lymphangioma, lymphangiomyoma, lymphangiopericytoma, leiomyomatosis, lymphangiomatous malformation, and intrathoracic angiomatous hyperplasia. All symptomatic cases presented with dyspnea and all but two had chylous pleural effusions. Although several cases were reported as "tumors," at least nine had documented cystic pulmonary parenchymal disease in addition to the mediastinal and/or retroperitoneal masses. In these early reports , investigators were unsure as to the possible malignant potential of the lesions. Although "diffuse infiltration of local soft tissues and the extensive involvement of lymphatics and lymph nodes" might suggest a malignant condition, Cornog and Enterline 6 pointed out that "the highly organized structure of the lesion, " the "absence of significant cellular atypia or mitotic activity," and the absence of distant metastases argued against malignancy. They suggested that lymphangiomyoma is better understood as a hamartomatous condition and that there was "little good evidence" that the lesion arises as a reaction after a primary rupture of the thoracic duct, as previously suggested by Laipply and Sherrick. 7 Instead, they theorized that "the pulmonary and mediastinal lesions are of multifocal origin in response to a single pathological stimulus, perhaps genetically determined, acting simultaneously on smooth muscle in both locations." 6 The authors also pointed out that the lymph node lesions seemed to be identical to those reported in some cases of TSC and that the pulmonary parenchymal lesions "resemble very closely, both grossly and microscopically" those in TSC .6 CHEST I 114 I 6 I DECEMBER, 1998

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THE RELATIONSHIP BETWEEN LAM AND TSC TSC is an autosomally inherited disorder characterized b y mental retardation, seizures, and facial angiofibromas. Twenty-five to 50% of patients with TSC have a family history of the disorder; the remaining cases are believed to be caused by either spontaneo us mutation or incomplete penetrance.8 TSC was first reported by von Recklinghausen in 1862.9 Later, in 1880, Bourneville termed it "tuberous sclerosis" in reference to th e potato-like CNS lesions that are found. 10 Pulmona1y parenchymal changes were associated vvith TSC as early as 1918 11 and 1939.12 The pathologic findings in the lung and lymph nodes are identical to those found in LAM . 13- 16 Pulmona1y symptoms are similar in isolated LAM and LAM associated with TSC: dyspnea, nonproductive cough, pneumothorax, hemoptysis,9 and chylothorax. 5·8 The incidence of pulmonary involvement in TSC seems to be low; estimates are < 0.1 to 2.3%. 5·1!·9 In 1971, Dwyer et al9 reviewed the literature and determined that women accounted for 84% of patients with TSC associated with pulmonary involvement. However, many of the cited cases involving men did not include histologic descriptions of the pulmonary lesions. Interestingly, of the two men d esc1ibed by Dwyer et al, 9 one did not undergo lung biopsy and the other, whose biopsy specimen was said to show "diHuse infiltration by vascular plain muscle," had underlying panhypopituitarism with "androgenic lack." Because more recent reports·5 •8·14- 17 documenting the nature of the pulmonary parenchymal lesions with biopsy or CT scan are all of women, it is likely that the pulmonary LAM pathology occurs only in a subset of women with TSC. Women vvith TSC who develop pulmona1y LAM were said by Dwyer etal9 to have "milder stigmata of the disease," based on their early review of the literature. Seizures and mental retardation maf·9 ·14 or may not5·8 ·9.J5.J 6 be present. For instance, Torres et al 18 described three women with TSC who had both pulmonary and extrapulmonary LAM . One had seizures and mental retardation, and one had seizures vvithout mental retardation. 1s In general, it seems that pulmonary involvement with TSC tends to be more common in women vvithout mental retardation. 9 The manifestations of TSC may not be consistent within families. For instance, Hauck et aP 6 described a family in which TSC appeared in five generations and in which pulmonary involve ment was found only in the most recent generation. IdentifYing underlying TSC in patients vvith pulmonary LAM is probably important for genetic counseling because normally intelligent women v.rith TSC may have "grossly retarded children with more complete forms of the 1690

disease."9 An example of such a case is provided by Lie et al 10 who describe a woman with pulmonary TSC and normal intelligence who had a son with TSC and mental retardation. In fact, the patient was not diagnosed as having TSC until after this son's birth. Although the pulmonary involvement tends to occur in adult life, 9 the mortality of patients with TSC-associated LAM does not seem to differ from patients with TSC alone .·5 Given that the symptoms, radiographic features, and histopathologic features of LAM are identical to those in patients with pulmona1y involvement of TSC, many investigators have suggested that LAM may be closely related to, or in fact be, a forme fruste ofTSC. 13·19 Anoth er argument in favor of an association is the fact that both LAM and TSC may be associated with the rare IGdney tumor angiomyolipoma.20 In fact , the distinction between the two diseases may be somewhat blurred in certain cases. For instance, renal angiomyolipomas are often considered to be an associated finding in women with LAM,21,22 but in some classiflcations, a patient with angiomyolipoma and pulmonary LAM meets the criteria for a diagnosis of TSC. 23 The nature of the possible relationship between LAM and TSC remains unclear. 5 ·24

CLINICAL FEATURES AND EPIDEMIOLOGY OF LAM LAM occurs exclusively in women. 1·25 An early repo1t of the histopathologic finding of LAM in a man 26 was later corrected. 25 In most case series, the mean age at disease onset is in the early 30s.2 - 4 The youngest patient described experienced dyspnea at age 9 years and was eventually diagnosed by lung biopsy specimen at age 11 years. 27 Several patients have been diagnosed as having LAM after menopause,2- 4·28-31 even as late as 75 years old. 26 Many of the patients diagnosed as having LAM after menopause were being treated with exogenous estrogens2·3·30·31 and in some cases, no speciflc mention is made of such medication;26 ·28 ·29 however, symptoms can develop after menopause in the absence of exogenous estrogens. 4 Because the first symptoms of the disease may occur before an abnormality is detectable by chest radiographs (CXRs) or pulmonary function tests, and because e venwhen such abnormalities exist, patients may be initially misdiagnosed, there is often a delay between the onset of symptoms and accurate diagnosis. In the series of Taylor et aP of 32 patients, the diagnosis of LAM was established an average of 44 months (range, 1 to 219 months) after the initial manifestations of the disease. In another smaller Reviews

series, the average duration of symptoms before diagnosis was 7.4 years (range, 1 to 27 years). 22 Initial misdiagnoses have included asthma, COPD, idiopathic pulmonmy fibrosis, or interstitial lung disease of unknown etiology, sarcoidosis , idiopathic pulmonary hemosiderosis, paraquat-induced lung disease, and tuberculosis. 3·32 ·33 Many of the case series do not describe the racial background of the patients. In the 1975 review of 28 cases by Corrin et al, 1 25 were white, 1was African-American, 1 was Filipino, and 1 was Chinese. The largest published collection of cases describes 46 patients from Japan, Korea, and Taiwan. 4 The most common presenting symptoms of LAM are dyspnea and pneumothorax. In the 1975 review by Corrin et aJl of 28 cases, breathlessness was the presenting symptom in 13 and pneumothorax in 6. In the 32 patients described by Taylor et al, 3 pneumothorax was the most common presenting symptom, followed by dyspnea. Rarely, bilateral spontaneous pneumothoraces have been reported as the presenting feature in LAM , with or without underlying TSC. 34 -3 7 Cough is also a fairly common presenting symptom, being present in 9 of 17 patients (53%) in one series32 and in 25 of 41 patients (61 %) in another series. 4 In addition to these common presenting symptoms, hemoptysis, chest pain, and chylous pleural effusion, if not present at presentation, often develop dming the course of the disease. 1·3·4 •32 Pneumothoraces are often recurrent and often occur in patients with normal CXRs. 3·38 ·39 Interrupted lymph flow may also result in several less-common manifestations such as chylous ascites,27,28,40-42 chyloptysis ,41.43 chyluria, 1 chylous pericardia! effusion/·30,31 and lower-extremity lymphedema.44 Chylous ascites may occur in the absence of pleural effusion 45 ·46 and can be the presenting symptom, even in the absence of apparent pulmonary parenchymal involvement. 47 Spontaneous pneumoretropharynx has also been reported in a patient with LAM who had previously undergone talc pleurodesis. 48 The physical examination may reveal crackles or rhonchi, which were present in 10 (22%) and 6 (14%) patients, respectively, in the recent series of 42 patients by Kitaichi et al. 4 The examination may also reveal evidence of pleural effusion or ascites. Clubbing is apparently uncommon, being reported in only 2 of 46 patients by Kitaichi et al,4 in 1 of 6 patients by Canington et al,49 and in rare case reports. 50 No specific laboratory abnormalities have been reported in patients with LAM. Lieberman et al51 found elevated angiotensin-converting enzyme levels in two of three patients tested. Most large series of patients vvith LAM do not include data on angiotensin-converting enzyme levels, but there are anecdotal reports of elevated levels in LAM pa-

tients. 52 •53 Finally, there is a single report of a patient with persistently elevated CA-125 levels. 45 Symptoms of LAM have been reported to develop54--57 or worsen 32 ·56 ·58 ·59 during pregnancy. In 1977, Carrington et al49 reported the case of a 23-year-old woman who experienced cough, chest pain, dyspnea, and hemoptysis during her first pregnancy. The CXR was normal at that time. These symptoms recurred dming her second pregnancy and, at age 28 years, during her fomth pregnancy, her dyspnea increased markedly. In another case,33 dyspnea developed during the fifth month of the patient's second pregnancy, resolved after delivery, and returned within 1 year to become slowly progressive. In yet another case, 60 a pregnant patient without a history of LAM experienced massive bilateral chylothorax that was related to mediastinal lymph node involvement with LAM. A chest CT scan showed no evidence of pulmonary parenchymal changes. Patients with pulmona1y involvement of TSC may also develop pulmonary symptoms during pregnancy.15·16 Hauck et al 16 described a woman with pulmonary involvement of TSC whose first pulmonary symptom was a pneumothorax during her first pregnancy. Thoracotomy was performed for pleurodesis, and the lungs showed gross surface cysts and nodules. The pregnancy was terminated. Three months later, a second pneumothorax developed during a second pregnancy. Dming this pregnancy, she experienced progressive dyspnea and deterioration in lung function. In their review of the literature in 1971, Dwyer et al 9 found two patients with "deterioration associated with the development of pneumothorax during pregnancy. " Finally, Kerr et al 21 reported the occurrence of acute hemorrhage from a renal angiomyolipoma during pregnancy. This patient was known to have angiomyolipoma in association with LAM, which was being treated with medroxyprogesterone. Despite this treatment, she became pregnant and, at 37 weeks' gestation, her right renal tumor hemorrhaged acutely. She underwent urgent cesarean section and subsequent arterial embolization of the tumor. Because of the anecdotal nature of these reports, it is not clear whether pregnancy caused the acute progression of LAM or whether the hemodynamic and ventilatory perturbations associated v.rith pregnancy simply brought out the symptoms of LAM that would otherwise not have been noticed until the disease progressed further. The administration of exogenous estrogens has also been anecdotally associated with new or progressive symptoms of LAM. In 1978, Kreisman et al 61 described a patient with undiagnosed interstitial lung disease who was placed on a regimen of exogenous estrogens after undergoing total hysterectomy CHEST I 114 I 6 I DECEMBER, 1998

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with bilateral salpingo-oophoredomy for benign utcline leiomyomata. vVithin 2 months, she was admitted to the hospital for cough, increasing dyspnea, and chest pain . She was found to have a n ew chylous pleural e ffusion , and subsequently died during the hospitalization. In 1987, Shen et alr;2 presented a similar case. This patient had undiagnosed underlying interstitial lung disease (ILD ) when she was placed on a regimen of cyclic estrogen and progesterone for osteoporosis. vVith the addition of these medications, her d sypnea progressed markedly. Discontinuing treatment with the hormonal medications and adding tamoxifen stabilized her symptoms . In addition to th ese cases, several of the few case reports of postmenopausal women with LAM have concerned women r eceiving hormone replacement thcrapy.:ucu J Also, several authors rep01t disease onset or worsening while patients are taking oral contraceptives. 40 A :>Ai Afl.rB 67 Despite these reports, \Vahedna et a]m> were unabl e to detect an association between the use of oral contraceptives and LAM in their case control study. Further, only 1 of th e 46 LAM patients desclibed by Kitaichi et a1 4 had used oral contraceptives before the onset of symptoms.

e ration of atypical smooth muscl e cells (LAM cells) (Figs 1 and 2). These smooth muscle cells are characterized b y elongated, closely packed, spindleto-oval-shaped c ells. LAM may involve any structure in the lung, including the pleura and the walls of the bronchioles, pulmomuy a1teries, venules, and small airspaces.l. 4 fl The most common complications of LAM-pneumothorax, chylous ple ural effusion , and hemoptysis-can be explained at least in part by the proliferation of these atypical smooth muscle cells around th e bronchioles, lymphatics, and venul es, respectively. 1 The bronchioles may be circumferentially narrowed b y the peribronchiolar proliferating tissue. Also, the proliferating tissue can protmde into the bronchiolar lumen. 72 The small ai1way obstruction is beli eved to cont1ibute to th e development of parenchymal cysts and pneumothorax. The walls of th e airspaces may be thickened focally or diffusely. Foci of hemosiderin-laden macrophages may be present in the airspaces and interstitium as re mnants of past hemorrhage. 72 Involvement of th e venules

CLINICAL FEATURES OF ASSOCIATED ANGIOMYOLIPOMAS Renal angiomyolipomas are rare hamcutomatous tumors of th e kidneys that arc composed of smooth muscle, blood vessels, and adipose tissue. They may occm in isolation or be p
FI G lJHE l. Gross specimen of lung tissue obtained at autopsy from a patient "~ th LAM who di ed b ecause of a t ension pneumothonL'(. Extensive cystic changes are evident.

Reviews

F'I GU HE 2. llistopatholoh'Y of LAM : Top: blood-filled ectatic spaces with interspersed spindle shaped .. LAM cells·· (arrow) (original magnifi cation , X 10; hematoxylin-eosin stain ) Ce11ter: hland spindk d nuclei (LAM ce lls) adjace nt to a pulnwmuy ve in (original magnification , X40; he matoxylin-eosin stain ) Botto111: LAM cells adj acent to inte rlobular se ptum demonstrating immunoreactivity to IIMB-4.'5 (hrown ).

may result in total oc:c:lusion of these vessels, 1 causing pulmonmy venous hyp ertension and resultant hemoptysis. Obstruction of lymphatic: channels may disrupt norm al l ymph flow and cause chylous pleural e ffu sions or c:hyloptysis. The pathogenesis of th e cystic destruction of the lun g parem:hyma in LAM is not known . The cysts

have been desc1ibed as a mixed proximal acinar and irregular emphyse ma. It has been suggested that the emphysema may develop because of airflow obstruction related to narrowing of the lumina of the bronchioles and small bronchi by th e prolife rating smooth mu sc:l e .l. 4 ~ However, in some biopsy specimens , emphyse matous airspaces are associated with more distal smooth muscle and normal-appearing bronc:hioles.4 B Fmther, using morphomet1ic analysis on the lungs of three patients (two with TSC and one with LAM ), Sobonya et aF'3 concluded that the emphysema contributes more to airflow limitation than does muscular prolife ration in the small airways. In these cases, it seemed as though the loss of alveolar support resulted in collapsed, tmtuous small ai1ways and that this lesion predominated over direct impingement of the ai1ways b y prolife rating smooth musc:l e cells. 7 '3 Fukuda et aF1 have postulated a diffe rent mechanism for the development of the emphysema-like lesion. They propose that these lesions are the result of the degradation of supportive elastic fibers, which is caused b y an imbalance between elastase and a 1-antih)'PSin. They raise the possibility that electron-dense granules in the cytoplasm of the prolife rating smooth muscle cells may contain some form of elastase and that th e release of this enzyme could be responsible for th e development of emphysema. Supporting the elastase hypothesis is a r ecent report by Hayashi et aF5 who suggest that enzymatic destruction of pulmomuy connective tissue components does occur and that it is an imbalance of matrix metalloproteinases and their inhibitors that is responsible for the cystic destruction of th e lung. The thoracic duct may be grossly e nlarged in LAM. These enlarged duds are divided into multiple microscopic channels by a "meshwork of smooth muscle fibers." ' E ven when the thoracic duct appears grossly normal , microscopic examination may show papillmy prolife ration of smooth muscle cells. 33 Lymph nodes, both in and outside of the chest (in the mediastinum , hilum , mesente1y, and retroperitoneum ), may also be involved. These involved nodes appear grossly spongy and resilie nt and microscopically show progressive replacement by prolife rating smooth muscl e c:ells.'3:3 As in the thoracic duct, smooth muscl e prolife ration causes the plexiform subdivision of the lymph channels.' Other associated abnormalities include renal angiomyolipomas 70 and abdominal or pelvic masses that may be cystic and histologically appear as cords of smooth muscl e cells and a network of lymphatic channels. Numerous authors have repmted the presence of estrogen r eceptors (ERs ) and progesterone receptors (PRs ) in LAM tissue.'3'3·3 ll·54 ·72 ·76 7 1-l Brentani et aF 2 found cytosolic receptors for estrogen, progesCHEST I 114 I 6 I DECEMBER, 1998

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terone, and glucocorticoids, but not androgen, in homogenized lung tissue obtained at autopsy in a patient with LAM. Because normal lung tissue does not display these receptors,77 their presence raises the possibility that these hormones affect LAM tissue. Likewise, Graham et aP3 found evidence of cytosolic receptors for both estrogen and progesterone in lung tissue from a patient with LAM. Further, using a nuclear-binding assay for these hormones, these investigators found specific nuclear binding of progesterone in LAM lung tissue. However, despite significant cytosolic estrogen binding, nuclear binding for this hormone was not found . The above reports document ERs and PRs in LAM tissue, but the methods used could not localize these receptors to the abnonnally proliferating cells. Subsequently, Berger et aF7 found ERs and PRs in the nuclei of the proliferating smooth muscle cells in a biopsy specimen from one patient and ERs only in another patient. That is, the receptors were localized to the abnormally proliferating cells. Likewise, Colley et aF 6 used immunohistochemisby to show that the nuclei of the proliferating smooth muscle cells stained darkly for PRs and more weakly for ERs. 76 Approximately 80% of the abnormal cells stained positive for ERs, and nearly all stained positive for PRs, whereas normal smooth muscle (bronchial and vascular) did not stain for either PRs or ERs. These authors examined several other organs and found similar staining patterns (PR positive, ER weakly positive) in normal myomehium and in leiomyomas, whereas colonic, bladder, and normal lung smooth muscle stained negative. Prostatic stroma showed scattered PR-positive nuclei. Other immunohistochemical studies of LAM cells have focused on HMB-45, a monoclonal antibody that recognizes antigens in the cytoplasm of melanoma cell lines and that more recently has been noted to bind to LAM cells. 79 Although the significance of HMB-45 positivity remains unclear in LAM, such staining has proved to be diagnostically useful. For example, proliferating LAM cells are HMB-45 positive, whereas normal lung tissue (particularly the normally present smooth muscle ) and a variety of other pulmonary lesions (including smooth muscle proliferation in fibrotic interstitial lung disease) are HMB-45 negative. 78 The proliferating LAM cells were not all HMB-45 positive, reflecting some degree of phenotypic heterogeneity. Because HMB-45 positive cells are detectable in transbronchial biopsy specimens in addition to open lung biopsies,78 Bonetti et aF8 suggest that HMB-45 may be a useful marker of LAM , particularly when only a transbronchial biopsy specimen is available. Guinee et al80 also suggest that in the proper clinicalradiographic setting, a transbronchial biopsy speci1694

men with immunohistochemical staining for HMB-45 can be sufficient to establish the diagnosis of LAM . In addition to lung tissue, HMB-45 reactivity has also been documented in retroperitoneal LAM 81·82 and in renal angiomyolipomas in patients without LAM or TSC,81- 84 including angiomyolipomas from men.s1·82 ·84 HMB-45 reactivity has also been seen in a clear-cell tumor of the lung from a patient with TSC,37 as well as in renal cell carcinoma in patients with TSC.s5 Reactivity is absent in normal kidneys and in several other tumors of the kidney, 83 as well as in a vvide variety of lesions involving smooth muscle proliferation , including leiomyoma of the uterus and stomach.s 1 Three other distinct pathologic findings have been noted in association with pulmonary LAM: (1) multifocal micronodular pneumocyte hyperplasia; (2) clear-cell tumors of the lung; and (3) noncaseating granulomas (Table 1). Corrin et al 1 discussed the finding of "peculiar acinar atypical adenomatoid proliferations of epithelium," in addition to the diagnostic features of LAM , in tv.ro patients with pulmona1y LAM . Although these patients were considered to have LAM , both had children who were described as "retarded," raising the possibility of TSC. This finding of focal type II pneumocyte hyperplasia has since been reported by others under various names, always in association with TSC.l 0 ·34 .36.37·86 Guinee et aP 4 have termed this lesion "multifocal micronodular pneumocyte hyperplasia." These lesions appear as multiple small nodules on CT scans of the chest34 ·36 and, in one case, they have been stable after 2 years' follow-up. 36 Unlike the LAM cells elsewhere in these lung biopsy specimens, the nodules stain negative for HMB-45, as well as for ERs and PRs. 34·36 They are believed to be distinct hamartomatous lesions.34,36 Clear-cell tumor of the lung (with HMB-45 reactivityP7 and noncaseating granulomas (parenchymal, hilar, and mediastinal)87 are two other l esions reported in association with pulmonary LAM. In the case of the clear-cell tumor, the patient also had TSC.37 Table !-Histopathologic Findings Associated With Pulmonary LAM* Findings Extrapulmonmy LAM (pelvic, retropetitoneal, or abdominal l ymph nodes or masses) Angiomyolipomas Clear-cell (sugar tumor) of th e lung Multifocal micronodular pneumocyte hypeqJiasia Noncaseatin g g ranulomas (a single case report) *These findings have been described in patients with pulmonaJ)' LAM. Some have been r eported thus far only in patients with underlying TSC. See text for references. Reviews

RADIOGRAPHIC FEATURES OF LAM The CXR in LAM classically shows a generalized, symmetric reticulonodular interstitial infiltrate, which is a nonspecific appearance that may be seen in many ILDs. In a recent collection of 46 patients by Kitaichi et al,4 bilateral reticulonodular infiltrates were seen on initial CXR in 39 (8.5%) . Unlike many of the ILDs, however, the lung volumes are either normal or increased in LAM. In addition to LAM , this unusual finding of increased interstitial markings and preserved lung volumes may also be seen in several other diseases, including chronic hypersensitivity pneumonitis, pulmonary histiocytosis X, sarcoidosis, and coexistent emphysema and idiopathic pulmonary fibrosis. As discussed elsewhere , patients with LAM may also experience spontaneous pneumothorax or chylothorax, which would be evident on CXR. Carrington et al 49 also described occasional waxing and waning parenchymal infiltrates, postulated to represent focal alveolar hemorrhage, as well as coarser reticulation, often with septal lines. This finding was said to be partially reversible and was attributed to lymphatic engorgement and interstitial edema. Finally, the CXR may also show evidence of hyperinflation. 1•4.HH As in many diseases, the CXR findings may v
FIGUHE 3. HRCT of the chest fi·om two patients with LAM. Top: in th is patient, the puhnonmy parenchyma appears normal with th e exception of a few tiny cysts. This contrasts with th e exte nsive cystic destruction seen on TIRCT from anoth e r patient (botto111 ). Both scans we re obtained soon after diagnosis.

diffuse cystic changes that account for the reticulation seen on CXH.. 89 ·9·5 The cysts are air filled, range in diameter from 2 to 60 mm , and have thin, re gular walls that range from barely perceptible to 4 mm in diameter.H9·94 Occasionally the cysts appear to have fus ed Y·5 They are usually round but may be polygonal or bizarrely shapeclH9 and usually appear scattered in a roughly symmetric pattern, without upper, lower, central, or peripheral predominance.H9,94 Aberl e e t al9·5 reported that although the disease was distributed throughout the chest, apical disease was less extensive, a finding not consistently reported by oth ers. HH. H 9 ,fl~ It appears that as the disease progresses, the cysts enlarge and become more numerous. HH.H 9·9 ·'> The parenchyma between the cysts appears normal. Although characteristic of LAM, cysts are not pathognomonic. For example, some patients with chronic histiocytosis X of the lung may have cysts whose appearance on CT is similar to those of LAM. However, these patients usually have a history of heavy cigarette smoking, and the cysts usually predominate in the upper lobes, with relative sparing of the lung bases, in contrast to the diffuse pattern of LAM. CHEST / 114 / 6 I DECEMBER, 1998

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In addition to cysts, HRCT scans of the chest may reveal other less common features of LAM. For instance, reticulation, although uncommon in LAM, may be seen at the margins of cysts where they abut the pleura, giving rise to a serrated-appearing lungpleural interfaceY·5 Also, one report described patchy, ill-deflned areas of increased attenuation in two of eight patients as "probably interstitial disease of uncertain significance."94 Finally, HRCT may reveal evidence of LAM-associated lymphadenopathf9·94 or LAM complications, such as pneumothoraces,8H·94 pleural effusions, 88 ·94 alveolar hemorrhage, or lymphatic stasis. Muller et al 88 described localized areas of airspace consolidation that they postulated may be related to areas of hemorrhage (as did Carrington et al49 : see CXR section above). 88 Lenoir et al8fl described one patient with chronic chyloptysis who, in addition to cystic changes, had areas of prominent polygonal septal lines and dependent alveolar opacities thought to be the result of lymphatic obstruction caused by the disease. Although radiographs and HRCT scans of the chest are the two most common imaging techniques for evaluating patients with LAM , numerous case reports have described features of various other imaging techniques. For instance, CT scans of the abdomen may reveal renal angiomyolipomas 21 -70 (Fig 4) and enlarged r etroperitoneal, para-aortic, or pelvic lymph nodes or masses 4 r1·94 Lymphangiograms may show abnormal filling and cystic changes within the lymph nodes . 1·47 ·92 ·94 ·96 In contrast to inflammatory ILDs, gallium scans have been r eported to be

FIGURE 4. Angiomyo lipoma: this CT scan of th e abdomen demonstratE's a .5-cm complex Fatty mass in the medi al aspect of the left kidn ey. Not the displacement of th e large bowel into th e right nephrectomy bed.

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normalJUJ?.HH Pulmonary blood flow has been abnormal on nuclear perfusion scans.5°,99 and, in one case, on a pulmonary angiogram that showed "stretched or attenuated vessels with slowed circulation of contrast rnaterial."·5°Finally, a recent case report describes features of low signal intensity that were surrounded by thin walls on spin-echo MRI of the lung. Inn

PULMONARY PHYSIOLOGY OF LAM The pulmonary physiologic features of patients with LAM are variable and include obstructive, restrictive, or mixed patterns. 3 ·4 The diffusing capacity for carbon monoxide (DLCO) is reduced in most patients.'3.4 Burger et al 101 assessed pulmonmy mechanics in eight patients with LAM to describe the pattern of abnormality and to clarify the cause of airflow obstruction. All eight patients had abnormal results of pulmonary function tests (PFTs ) and seven had decreased FEV/FVC ratios (mean, 61% of predicted). No patient had a significant bronchodilator response. Total lung capacity (TLC ) tended to be high: the mean was 114% of predicted, three patients had values above 120% of predicted, and none had values < 90% of predicted. The residual volume was markedly elevated, with a mean of 207% of predicted, and seven patients had values > 120% of predicted. Seven patients had decreased DLCO (mean, 57%) , seven had vvidened alveolar-arterial m.ygen difference, and none had hypercapnea. These findings should be interpreted with two cautions in mind: some patients were not included because the severity of their lung disease prohibited extensive testing, and all patients had undergone thoracotomy and four had also undergone pleurodesis, measures that might affect lung volumes. To measure the compliance characteristics of the lungs and to better understand the mechanisms involved in the airflow obstruction, Burger et aJl 01 also performed transpulmona1y pressure-volume curves and measures of dynamic compliance and pulmonary flow resistance . The pressure volume curves were shifted up and to the left in six of eight patients and static compliance was increased. However, dynamic compliance was decreased in association with excessive flow resistance. Addressing the issue of whether the observed obstruction to airflow was primarily the result of decreased elastic recoil or airway narrowing with obstruction, the authors noted that the degree of reduction in elastic recoil forces was less than the degree of reduction of expiratory flow. The maximum flow-static recoil curves, a plot of maximum flow determined at specific lung volumes vs the transpulmonary pressure at these same Reviews

lung volumes, were shifted down and to the right (Fig 5). Such a pattern is consistent with flow rates reduced primarily by airway obstruction (eg , asthma). The authors thus concluded that the reduced maximum expiratory flow in these patients was primarily the result of airway obstruction, rather than loss of elastic recoil. 1m Several attempts have been made to correlate radiologic findings with measures of lung function. Aberle et al 95 found no significant correlation between CXR severity scores and PFT parameters in eight patients with LAM .95 However, they did find that CT severity scores were correlated with the percentages of predicted FEY /FYC and DLCO . In 14 patients with LAM, Muller et al 88 also found no correlation between the CXR score and PFT measurements. Chest CT scores correlated well with DLco, but not with lung volume or airflow parameters.88 Lenoir et al8 D evaluated 11 patients (9 with LAM , 2with TSC) and found that both CXR and CT scores were correlated with FEY/FYC ratios and percent predicted of DLCOs. The CT score correlated better with DLCO than did the CXR score. Using a technique of quantitative CT scanning in 10 patients with LAM, Crausman et aJl 02 found correlations between total cyst area and various measures of pulmonary function and exercise performance. These measures include the following: FEY v FEY/

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FIGURE .5. Maximal flow (Vmax) determined at spe cified volumes on the flow-volume curve vs transpulmonary pressure (Pst) determined at the same volume points on the pressure-volume curves for eight patients (solid lines). The dashed lines indicate the normal range. Reprinted with permission from Burger et aJ. IOI

FYC, residual volume, DLCO, resting and maximal exertion alveolar-arterial oxygen gradient, dead space to tidal volume ratio, maximum oxygen consumption, and maximum workload. From the above, it appears that CT scans correlate better with pulmonary function abnormalities than do plain CXRs. Finally, in keeping with an earlier observation by Corrin et aF that radiographic evidence of increased lung volumes carried a poorer prognosis, Kitaichi et al 4 found that a reduced FEY /FYC ratio and an increased TLC were both associated with a poor prognosis.4

DIAGNOSIS, TREATMENT, AND PROGNOSIS OF LAM As mentioned above, many cases of LAM are initially misdiagnosed as more common diseases, such as asthma or COPD . Such a mistake is understandable because of the rarity of LAM and because of the frequent nonspecific nature of the symptoms and findings on plain radiographs. The diagnosis of LAM is often initially considered when a young woman presents with ILD, pneumothorax, or chylothorax. In other cases, the diagnosis is not suspected until the grossly abnormal appearance of the lung surface is seen by the thoracic surgeon at the time of pleurodesis performed for recurrent pneumothorax, or until a HRCT scan is obtained. The HRCT scan, when interpreted by an experienced chest radiologist, can be very helpful in suggesting the diagnosis. A d efinitive diagnosis of LAM usually requires a tissue biopsy and the judgment of an expetienced pulmonary pathologist. In most cases, a biopsy specimen is taken surgically from the lung to provide sufficient tissue for interpretation. Recent reports suggest that transbronchial lung biopsy specimens,so,so or even pleural fluid cytologic analysis, 103 may be sufficient in certain cases, although such diagnoses likely depend heavily on the expertise of the clinicians and pathologists involved. Because LAM may involve extraparenchymal sites, such as lymph nodes or abdominal or pelvic masses, a definitive diagnosis of LAM can occasionally be made from biopsy specimens from such sites. Although exceptions have been described, in most cases of extrapulmonary involvement of LAM , pulmonary parenchymal changes also exist. 6 It is unclear whether purely "extrapulmonary" LAM eventually progresses to involve the lung, although early case reports suggest that it can.7 In cases in which a biopsy cannot be performed, the diagnosis can be established vvith a fair degree of certainty when characteristic HRCT findings are seen along with renal angiomyolipoma. Because of the overlap beCHEST I 114 I 6 I DECEMBER, 1998

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tween LAM and TSC discussed previously, patients suspected of having LAM should be carefully screened for signs, symptoms, or family history that might suggest a diagnosis of TSC. The clinical course of patients with LAM is quite variable, and a full understanding of the natural history is hampered by the paucity of available studies and the small numbers of evaluable patients. In general, the disease is believed to be slowly progressive, leading eventually to respiratory failure and death, but the time to death varies among reports. In the report by Taylor et al,3 25 of 32 (78%) patients were alive 8.5 years after the onset of the disease. However, in the recent collection of 46 LAM patients from Japan, Korea, and Taiwan, only 10 of 26 patients (38%) were alive after 8.5 years. 4 In the earlier report by Corrin et al,I death occurred between 1 and 10 years after the onset of symptoms, yet one patient was alive after 17 years and another remained "virtually asymptomatic" with no radiographic evidence of progression after 9 years. Consensus regarding the most sensitive or relevant means of assessing disease severity or progression in patients \:v:ith LAM has not been established. Because no single test or measure is likely to capture all aspects of the disease manifestations, in practice a combination of subjective, radiographic, and physiologic parameters are usually used to monitor patients. Routine pulmonary function testing is a noninvasive and relatively inexpensive means of assessing lung function. Although interpretation of parameters of airflow obstruction and lung volumes must be undertaken with the knowledge that LAM may be associated vvith obstructive, restrictive, or mixed patterns of abnormality, 3·4 reduced FEV/ FVC ratio and increased TLC have both been associated with poor prognosis. 4 The DLco is reduced in most individuals with LAM 3.4 and may be a useful parameter to follow. Cardiopulmona1y exercise testing or other assessment of exercise capacity and gas exchange are also helpful. Because the CXR may be normal despite the presence of significant disease, and because the correlation between the CXR and measures of pulmonary physiology is poor, it is presumed that plain radiographs are insensitive means of assessment. HRCT scans correlate better with pulmonary physiology and exercise parameters and therefore likely provide a better understanding of overall disease severity. With these considerations in mind, a reasonable approach to following up patients with LAM might entail subjective evaluation, full PFT (spirometry, lung volumes, and DLco), and CXR at 6-month intervals with more expensive or invasive procedures such as exercise testing and/or HRCT scans at 12-month intervals. The wide variation in the rate of deterioration in 1698

patients vvith LAM may necessitate adjustments of these intervals for individual patients. Two issues that often arise in the care of LAM patients are the risks of pregnancy and the advisability of air travel. Both of these topics are ve1y difficult to deal with because inadequate data are available to support firm recommendations. Because of the reports of disease progression during pregnancy and because of the poor long-term prognosis for patients with LAM, most experts advise against initiating pregnancy. Further, while hormonal treatment of LAM may also have contraceptive effects, patients should be advised to utilize standard, effective contraceptive measures. Unplanned pregnancies present a particularly difficult dilemma. While termination of the pregnancy may avert potential pregnancy-related dete1ioration, the risk of such deterioration is uncertain. Clearly, the patient must participate fully in this very personal decision and it must be made clear that there are very little data on which to base the decision. Cabin pressure changes that commonly occur during air travel may increase the risk of pneumothorax in patients with cystic or bullous lung disease, including LAM. In a survey of patients with LAM administered by the LAM Foundation, 8 of 159 respondents reported a history of developing a pneumothorax during air travel (personal communication, Francis X. McCormack, MD, unpublished data). Although the absolute 1isk of pneumothorax is not known, air travel that is entirely discretionary should probably be avoided if another means of transpmtation is readily available. In patients with severe disease, a history of prior pneumothorax, or extensive subpleural cystic changes on HRCT scan, air travel should be more firmly discouraged. Because of the rarity of the disease and the variable clinical course, little is known regarding the efficacy of the various therapies for LAM. It seems apparent that corticosteroids and cytotoxic agents offer no benefit. 32 ·49 ·97·104 Given the occurrence of the disease in women of child-bearing years, reports of clinical worsening with exogenous estrogen,62 and the presence of ERs and PRs in the proliferating LAM cells, many clinicians have used hormonal manipulation therapeutically. There are numerous anecdotal reports of patients being treated with oophorectomy, 3.4.59·65·66·96·105 progesterone, 2- 4,27,31,53,54,57,59,106- uo tamoxifen or other antiestrogen agents, 3.4.30·55 ·58 ·104·111 · ll 2 luteinizing hormone releasing hormone agonists, 4,53,110,ll3,11.4 or radioablation of the ovaries. In many reports, various combinations of these treatments have been attempted. 2.21 ,33,40- 42,45,52,56,59,67, 73, 76,97,112,114,ll5 There is one repmt of the use of interferon alpha_Il2 Responses to such treatments have been variable, Reviews

and no definitive conclusions "Should be drawn from these reports. Based on an experience with 32 patients, Taylor et aP observed no therapeutic benefit from oophorectomy or antiestrogen therapy with tamoxifen. There was some evidence that progesterone was beneficial in at least some patients with LAM, and the investigators recommended its use in all symptomatic patients with LAM . Interestingly, combining their patients with those in the literature, they found no association between tissue ER or PR status and response to hormonal therapy. In 1989, Eliasson et al58 performed a meta-analysis of 30 previously reported cases and concluded that oophorectomy, progesterone, or both were the most effective treatments. It has been suggested that patients with chylous pleural effusions or chylous ascites are more likely to respond to treatment with medroxyprogesterone.3 Kitaichi et al4 observed that in several cases, treatments of various types had beneficial effects on the chylous fluid collections but not on the pulmonary parenchymal changes. The prevention of osteoporosis is very important for women who are being treated with any antiestrogen therapy. Whether the newer "tissue-specific" estrogens 116 will prove safe and effective in the prevention of osteoporosis in LAM patients treated with antiestrogen regimens is unknown. The interpretation of these treatment strategies is further clouded by reports of prolonged clinical courses in untreated patients. For instance, in one recent case report, a patient with LAM diagnosed from open-lung biopsy specimen after bilateral pneumothorax was given no treatment apart from surgical pleurodesis. 35 After 3 years of follow-up , the patient had experienced neither pneumothorax nor pulmonary symptoms. No information on serial pulmonary functions is provided in the report, but a follow-up HRCT scan showed only "a slight increase in cyst size."35 In addition to this case report, six of the patients in the Kitaichi et al4 series received no hormonal therapy. Of these six, four died with a "mean clinical duration" of 71.3 ± 25.4 months from the time of symptom onset.

OTHER TREATMENTS

In addition to hormonal medications intended to interrupt the proliferation of LAM cells, numerous reports describe various interventions aimed at preventing or treating the complications of LAM, such as pneumothorax and chylous pleural or peritoneal fluid collections. Drainage of chylous pleural fluid collections can be hazardous, lead to protein loss, and is not always necessary. Chemical6·32·38.99 or surgicaP9··55 ·73 pleurodesis has been performed with

vmiable success in preventing recurrent pneumothorax or pleural effusion. Although such procedures may make future lung transplantation more complicated, they are not a strict contraindication to subsequent transplantation and occasionally may be necessary to control symptoms. Early reports describe more aggressive measures aimed at decreasing the production of chylous pleural fluid, such as ligation7·32 or irradiation of the thoracic duct.6·7·26·117 Such procedures met with variable success and are no longer common in the treatment of LAM. Attempts at controlling chylous ascites with LaVeen shunts 40 .45 or fat-free diets supplemented vvith medium-chain triglycerides 40 ·45- 47 have also resulted in inconsistent benefit. More recently, patients with end-stage lung disease related to LAM have undergone lung transplantation. A recent report by Boehler et alll 8 describes the outcomes of 34 patients who underwent lung transplantation for end-stage LAM . Of the 34 patients, 18 were alive at a mean of 33 ± 20 months after transplantation, with an actuarial survival rate of 69% after 1 year and 58% after 2 years. Problems related to the underlying LAM included intraoperative hemorrhage secondary to extensive pleural adhesions, postoperative pneumothorax in the native lung, and postoperative chylothorax. Two reports document disease recurrence after single-lung transplantation.l 19·120 In neither case was graft function compromised by the recurrence. Interestingly, in both cases, the donor lungs were from men, and in one case, the proliferating immature smooth muscle cells in the transplanted lung were from the donor.l 19 This observation is intriguing because it raises the possibility of some type of circulating mitogen in the pathogenesis of the disease.

CURRENT DEVELOPMENTS

LAM is a devastating disease that strikes young women and carries a poor prognosis. Because it is rare, little is known regarding its pathogenesis and treatment, but several new avenues of research have recently emerged. First, to address the lack of understanding of the clinical features and natural history of LAM , a national registry of patients with LAM has recently been initiated. 121 Funded by the National Heart, Lung, and Blood Institute in cooperation with the Cleveland Clinic Foundation, the goals of the registry are as follows: (1) to characterize the clinical features of patients with LAM; (2) to examine the clinical features of patients referred for lung transplantation and assess the efficacy of this therapy for LAM; and (3) to collect and store CHEST I 114 I 6 I DECEMBER, 1998

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biological material, such as lung tissue and serum specimens, to facilitate studies into the molecular basis of LAM. Second, new insights are emerging into the cellular and molecular biology of LAM cells, including the significance of the HMB-45 reactivity and the presence of ERs and PRs. 122 Finally, our understanding of the genetic basis of TSC is rapidly advancing. Two genes responsible for TSC have been identified: TSCl on chromosome 9, and TSC2 on chromosome 16. Evidence suggests that these genes act as tumor suppressor genes. 123 Given the close association behveen LAM and TSC , such critical discoveri es regarding the nature of TSC are likely to be relevant to LAM as well. In fact , in a recent study by Smolarek et al, 124 loss of heterozygosity of the TSC2 gene was found in 54% of angiomyolipomas from patients with LAM. In addition, loss of heterozygosity of the TSC2 gene was also seen in four lymph nodes from a woman vvith retroperitoneal LAM . These findings support the concept of a common pathogenesis of LAM and TSC. l24 Perhaps, with improved understanding of the natural history as well as the genetic, molecular, and cellular biology of LAM , newtherapies will soon become available. ACKNOWLEDGMENTS: The author thanks doctors Elizabeth Petri Henske, Janet Maurer, Francis McCormack, and James Stoller for their support and thoughtful review of this manuscript, as well as Drs. Peter O'Donovan and Carol Farver for their help with the radiographic and pathologic images.

REFERENCES 1 Corrin B, Liebow AA, Friedm an PJ . Pulmonaty lymphangiomyomatosis: a review. Am J Pathol 1975; 79:348-367 2 Sieker 01-1, McCarty KS. Lymphangiomyomatosis: a respiratmy illness with an endocrinologic therapy. Trans Am Clin Climatol Assoc 1987; 99:57- 67 3 Taylor JR, Ryu J, Colby TV, et a! Lymphangioleiomyomatosis: clinical course in 32 pati ents. N Eng! J M ed 1990; 323: 1254 - 1260 4 Kitaichi M, Nishimura K, Itoh T-1, et !a. Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic fitctors. Am J Respir Crit Care Med 1995; 151:527-533 5 Castro M, Shepherd CW, Gomez MR, et al . Pulmonary tuberous sclerosis. Chest 1995; 107:189- 195 6 Cm·nog JL, Ente rline HT. Lymphangiomyoma, a beni gn lesion of chyliferous yl mphatics synonymous with lymphangiopericytoma. Cancer 1966; 19: 1909- 1930 7 Laipply TC, Shenick JC. Intrathoracic angiomyomatous hyperplasia associated 'vith chronic c hylothorax. Lab Invest 1958; 7:387- 400 8 Uzzo RG, Libby DM , Vaughan ED Jr, et al. Coexisting lymphangioleiomyomatosis and bilateral angiomyolipomas in a patient with tuberous sclerosis. J Urol1994; 151:16121615 9 Dwyer JM , Rickie JB , Garvan J. Pulmonary tuberous sclerosis: report of three patients and a review of the literature. Q J M ed1971; 40:ll5-125 1700

10 Lie JT, Miller RD, Williams DE . Cystic disease of the lungs in tuberous sclerosis: clinicopathologic correlation, including body plethysmographic lung function tests. Mayo Clin Proc 1980; 55:547- 553 ll Lutembacher R. Dysembryomes metatypique des reins: carcinose submiliaire aigue du poumon avec emphyseme generalise et double pneumothorax. Ann Med 1918; 5:435450 12 Berg G, Vejlens G. Maladie kystique du poumon et sclerose tubereuse du cerveau. Acta Paediatr (U ppsala) 1939; 26: 16-30 13 Valensi QJ. Pulmonary lymphangiomyoma, a probable forme fi·ust of tuberous sclerosis: acase report and survey of the literature. Am Rev Respir Dis 1973; 108:1411- 1415 14 Kaku T, Toyoshima S, Enjoji M. Tuberous sclerosis with pulmonary and lymph node involve men t: relationship to lymphangiomyomatosis. Acta Pathol Jpn 1983; 33:395-401 15 Capron F, Ameille J, Leclerc P, et a!. Pulmonaty lymphangioleiomyomatosis and Bourneville's tuberous sclerosis with pulmonary involve ment: the same disease? Cancer 1983; 52:851-855 16 Hauck RW, Konig G, Permanetter W, et al. Tuberous sclerosis with pulmonary involvement. Respiration 1990; 57:289 - 292 17 Peng SF, Chang YC, Su CT, et al . High-resolution computed tomography in pulmonaty lymphangio(leio)rnyomatosis and pulmonary tuberous sclerosis. J Formos Med Assoc 1996; 95:399-402 18 Torres VE, Bjornsson J, King BF, e t al. Extrapulrnonary lymphangioleiomyo matosis an d yl mphangiomatous cysts in tuberous sclerosis complex. Mayo Clin Proc 1995; 70:641648 19 Vadas G, Pare JAP, Thurlbeck WM. Pulmonary and lymph node myomatosis: review of the literature and report of a case. Can Med Assoc J 1967; 96:420- 424 20 Monteforte WJ, Kohnen PW. Angiomyolipomas in a case of lymphangiomyomatosis syndrome: relationships to tuberous sclerosis. Cancer 1974; 34:317- 321 21 K err LA, Blute ML, Ryu JH, et al. Renal angiomyolipoma in association \vith pulmonary lymphangioleiomyornatosis: forme fruste of tuberous sclerosis? Urology 1993; 41:440 444 22 Maziak DE, Kesten S, Rappaport DC, et al. Extrathoracic angiomyolipomas in lymphangioleiomyomatosis. Eur Respir J 1996; 9:402-405 23 Gomez MR. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic crite ria. Ann NY Acad Sci 1991; 615: 1- 7 24 Bonetti F , Chiodera P. Lymphangioleiomyomatosis and tuberous sclerosis: where is the border? [editorial]. Eur Respir J 1996; 9:399-401 25 Wolff M. Lymphangiomyoma: clinicopathologic study and ultrastructural confirmation of its histogenesis. Cancer 1973; 31:988-1007 26 Pachter MR, Lattes R. Mesenchymal tumors of the mediastinum: tumors of lymph vascular origin . Cancer 1963; 16:108- 117 27 Awai K, Fujikawa K, Sato T, et a!. Pulmonary lymphangiomyomatosis. Radiat Med 1990; 8:132- 135 28 Joliat G, Stalder I-1, Kapanci Y. Lymphangiomyomatosis: a clinico-anatomical entity. Cancer 1973; 31:455- 461 29 Sinclair W, 'vVright JL, Churg A. Lymphangioleiomyomatosis presenting in a postmenopausal woman . Thorax 1985; 40:475- 476 30 Baldi S, Papotti M, Valente ML, et !a. Pulmonary lyrnphangioleiomyomatosis in postmenopausal women: report of Reviews

two cases and review of the literature. Eur Respir J 1994; 7:1013-1016 31 Zanella A, Toppan P, Nitti D, et al. Pulmonary lymphangioleiomyomatosis: a case repmt in postmenopausal women treated with pleurodesis and progesterone ( medroxyprogesterone acetate). Tumori 1996; 82:96-98 32 Bush JK, McLean RL, Sieker HO. Diffuse lung disease due to !ymphangiomyoma. Am J M ed 1969; 46:645-654 33 Graham ML, Spe!sberg TC, Dines DE, e t a!. Pulmonary lymphangiomyomatosis: \vith particular reference to steroidreceptor assay studies and pathologic correlation. Mayo Clin Proc 1984; 59:3- ll 34 Guinee D , Singh R, Azumi N, etal. Multifocal micronodular pneumocyte hyperplasia: a distinctive pulmonary manifestation of tuberous sclerosis. Mod Pathol 1995; 8:902-906 35 Berkman N, Bloom A, Cohen P, eta!. Bilateral spontaneous pneumothorax as the presenting feature in lymphangioleiomyomatosis [see comments]. Respir Med 1995; 89:381383 36 Lantuejou! S, Ferretti G, Negoescu A, e t a!. Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis. Histopathology 1997; 30:570-575 37 Flieder DB , Travis WD. Clear cell 'sugar tumor' of the lung: association with lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperpl asia in a patient with tuberous sclerosis. Am J Surg Pathol 1997; 21:1242-1247 38 Kane PB, Lane BP, Cordice JvVV, et al. Ultrastructure of th e proliferating cells in pulmonary lymphangiomyomatosis. Arch Pathol Lab Med 1978; 102:618-622 39 Schiaffino E, Tavani E, Dellafiore L, et al. Pulmonary lymphangiomyomatosis: report of a case \vith immunohistochemical and ultrastructural findings. Appl Pathol 1989; 7:265- 272 40 Adamson D, Heinrichs WL, Raybin OM, et al. Successful treatment of pulmonary lymphangiomyo matosis with oophorectomy and progesterone. Am Rev Respir Dis 1985; 132: 916-921 41 Brock ET, Votto JJ. Lymph angioleiomyomatosis: treatment \vith hormonal manipulation. NY State J M ed 1986; 86:533536 42 van Milligen d e Wit AW, Meilof-Planteydt MN. Successful treatment of pulmonary lymphangioleiomyomatosis with oophorectomy and medroxyprogesterone-acetate: r eport of a case and brief review of the literature. Neth J Med 1990; 36:246 - 251 43 Stovin PGI, Lum LC, Flower CDR, et al. The lungs in lymphangiomyomatosis and in tuberous sclerosis. Thorax 1975; 30:497--509 44 Abe R, Kimura M, Airosaki A, et a!. Retroperitoneal lymphangiomyomatosis \vith lymphedema o fth e el gs. Lymphology 1980; 13:62-67 45 Kanbe A, Hajiro K, Adachi Y, et al. Lymphangiomyomatosis associated with chylous ascites and high serum CA-125 levels: a case report. Jpn J Med 1987; 26:237-242 46 Calvo E, Amarillas L, Mateos MA, e t al . Lymphangio!eiomyomatosis, chylous ascites, and diet. Dig Dis Sci 1996; 41:591-593 47 Calabrese PR, Frank HD, Taubin HL. Lymphangiomyomatosis with chylous ascites: treatment with dietary fat restriction and medium chain trig!ycerides. Cancer 1977; 40:895897 48 Crausman RS, Mellman D, Bloomfield EC, eta!. Pulmonary barotrauma as the cause of pneumoretropharynx in pulmonary !ymphangioleiomyomatosis. Am J Emerg Med 1996; 14:297-299 49 Carrington CB, Cugell OW, Gaensler EA, et al Lymphangioleiomyomatosis: physiologic pathologic radiologic

correlations. Am Rev Respir Dis 1977; 116:977- 995 50 Kawahara Y, Taniguchi T, Kadou T , et l.a Elevated pulmonary arterial pressure in pulmona1y lymphangiomyomatosis. Jpn J M ed 1989; 28:520--522 51 Lieberman J, Nosal A , Schlessner LA, et al. Serum angiotensin-converting enzyme for di agnosis and therapeutic evaluation of sarcoidosis. Am Rev Respir Dis 1979; 120:329335 52 El Allaf D, Borlee G, Hadjoudj H , et !a. Pulmonary lymphangiomyomatosis. Eur J Respir Dis 1984; 65:147-152 53 Rad ermecker M, Broux R, Corhay J-L, e t al . Failure of buserelin-induced m edical castration to control pulmonary lymphangiomyomatosis in hvo patients. Chest 1992; 101: 1724-1726 54 McCarty KS, Mossier JA, McLelland R, et al. Pulmonary lymphangiomyomatosis responsive to progesterone. N Engl J M ed 1980; 303:1461-1465 55 Hughes E, Hodder RV. Pulmonary lymphangiomyomatosis complicating pregnancy: acase repmt. J R eprod Med 1987; 32:553--557 56 Yockey CC, Riepe RE, Ryan K. Pulmonary lymphangioleiomyomatosis complicated by pregnancy. Kans Med 1986; 87:277- 278, 293 57 Sleiman C, Mal H, Jebrak G, et al. Pulmonary lymphangiomyomatosis treated b y single lung transplantation. Am Rev Respir Dis 1992; 145:964 -966 58 Eliasson AH, Phillips YY, Tenholder MF. Treatment of lymphangioleiomyomatosis: a meta-analysis. Chest 1989; 96:1352-1355 59 Urban T, Kuttenn F , Compel A, et la. Pulmonary lymphangiomyomatosis: follow-up and long-term outcome with antiestrogen therapy: a rep ort of eight cases. Chest 1992; 102:472- 476 60 Brunelli A, Catalini G, Fianchini A. Pregnancy exacerbating unsuspected mediastinal lymphangioleiomyomatosis and chylothorax. Int J Gynaecol Obstet 1996; 52:289-290 61 Kreisman H, Robitaille Y, Dionne GP, et al. Lymphangiomyomatosis syndrome with hyperparathyroidism: a case report. Cancer 1978; 42:364--372 62 Shen A, Iseman MD, Waldron JA, e t !a. Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens. Chest 1987; 91:782--785 63 Silverstein EF, Ellis K, Wolff M, et !a. Pulmonary lymphangiomyomatosis. AJR Am J Roentgenol 1974; 120:832850 64 Basset F , Soler P, Marsac J, et a!. Pulmonary lymphangiomyomatosis: three new cases studied with electron microscopy. Cancer 1976; 38:2357-2366 65 Kitzsteiner KA, Mallen RG. Pulmonary lymphangiomyo matosis: treatment with castration. Cancer 1980; 46:2248-2249 66 Banner AS , Carrington CB, Emory WB, et a!. Efficacy of oophorectomy in lym phangioleiomyomatosis and benign metastasizing leiomyoma. N Eng! J Med 1981; 305:204-209 67 Svendsen TL, Viskum K, Hansborg N, etal. Pulmonary lymphangioleiomyomatosis: a case of progesterone receptor positive lymphangioleiomyomatosis treated with medroxyprogesterone, oophorectomy and tamoxifen. Br J Dis Chest 1984; 78:264 - 271 68 Wahedna I, CooperS, Williams J, et a!. Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: a national case control study. Thorax 1994; 49:910-914 69 Blute ML, Malek RS, Segura .f\V. Angiomyolipoma: clinical metamorphosis and concepts for management. J Urol 1988; 139:20-24 70 Bernstein SM, Newell JD Jr, Adamczyk D, et a!. How common are renal angiomyolipomas in patients \vith pulinoCHEST I 114 I 6 I DECEMBER, 1998

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nary lymphangiomyomatosis? Am J Respir Crit Care Med 1995; 152:2138-2143 Conrad S, Wagner B, Hamper K, eta!. Nierenkarzinom und angiomyolipom bei lymphangiomyomatose [Kidney cancer and angiomyolipoma in lymphangiomyomatosis] (in German). Urologe A 1994; 33:76-79 Brentani MM , Carvalho CR, Saldiva PH, et a!. Steroid receptors in pulmonary lymphangiomyomatosis. Chest 1984; 85:96-99 Sobonya RE , Quan SF, Fleishman JS. Pulmonary lymphangioleiomyomatosis: quantitative analysis of lesions producing airflow limitation. Hum Pathol1985; 16:1122-1128 Fukuda Y, Kawamoto M, Yamamoto A, eta!. Role of elastic fiber degradation in emphysema-like lesions of pulmonary lymphangiomyomatosis [see comments]. Hum Pathol1990; 21:1252-1261 Hayashi T, Fleming MV, Stetler-Stevenson WG, e t al. Immunohistochemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pulmonary lymphangioleiomyomatosis (LAM). Hum Pathol 1997; 28: 1071-1078 Colley MH, Geppert E, Franklin WA. Immunohistochemical detection of steroid receptors in a case of pulmonary lymphangioleiomyomatosis. Am J Surg Pathol1989; 13:803807 Berger U, Khaghani A, Pomerance A, et al. Pulmonary lymphangioleiomyomatosis and steroid receptors: an immunocytochemical study. Am J Clin Pathol 1990; 93:609 - 614 Bonetti F, Chiodera PL, Pea M , eta!. Transbronchial biopsy in lymphangiomyomatosis of the lung: HMB45 for diagnosis [see comments]. Am J Surg Pathol 1993; 17:1092-1102 Bacchi CE, Bonetti F, Pea M, eta!. HMB-45, a eview. r Appl Immunohistochem 1996; 42:73-85 Guinee DG Jr, Feuerstein I, Koss MN , e t a!. Pulmonmy lymphangioleiomyomatosis: diagnosis based on results of trans bronchial biopsy and immunohistochemical studies and correlation with high-resolution computed tomography findings. Arch Pathol Lab Med 1994; 118:846-849 Chan JKC, Tsang WYW, Pau MY, et a!. Lymphangiomyomatosis and angiomyolipoma: closely related entities characterized by hamartomatous proliferation of HMB-45-positive smooth muscle. Histopathology 1993; 22:445-455 Hoon V, Thung SN, Kaneko M, eta!. HMB-45 reacth~ty in renal angiomyolipoma and lymphangioleiomyomatosis. Arch Pathol Lab !vied 1994; 118:732- 734 Pea M, Bonetti F, Zamboni G, et al. Melanocyte marker HMB-45 is regularly expressed in angiomyolip~ma of the kidney. Pathology 1991; 23:185-188 Abdulla M, Bui HX, delRosario AD, eta!. Renal angiomyolipoma: DNA content and immunohistochemical study of classic and multicentric variants. Arch Pathol. Lab !vied 1994; 118:735-739 Bjornsson J, Short MP, Kwiatkowski DJ, et a!. Tuberous sclerosis-associated renal cell carcinoma: clinical, pathological, and genetic features. 1996; 149:1201-1208 Popper HI-I , Juettner-Smolle Flvl, Pongratz MG. lvlicronodular hyperplasia of type II pneumocytes: a new lung lesion associated with tuberous sclerosis. Histopathology 1991; 18:347-354 Hum! JP, Borkgren MW, Henley LB, et al. Pulmonary lymphangioleiomyomatosis associated with pulmonary parenchymal, hilar, and mediastinal noncaseating granulomas [see comments]. Chest 1991; 100:1726-1728 Miiller NL, Chiles C, Kullnig P. Pulmona1y lymphangiomyomatosis: correlation of CT with radiographic and functional findings. Radiology 1990; 175:335--339 Lenoir S, Grenier P, Brauner MW, e t al. Pulmonary lym-

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phangiomyomatosis and tuberous sclerosis: comparison of radiographic and thin-section CT findings. Radiology 1990; 175:329-334 Anonymous. Case Records of the Massachusetts General Hospital (case 24-1988). N Engl J Med 1988; 318:1601-1610 Templeton PA, McLoud TC, Muller NL, et a!. Pulmonary lymphangioleiomyomatosis: CT and pathologic findings. J Comput Assist Tomogr 1989; 13:54--57 Merchant RN , Pearson MG, Rankin RN, eta!. Computerized tomography in the diagnosis of lymphangioleiomyomatosis. Am Rev Respir Dis 1985; 131:295-297 Anonymous. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises: case 18-1994: a 37-year-old woman with interstitial lung disease, renal masses, and a pre,~ous spontaneous pneumothorax [clinical conference] [see comments] [published erratum appears in N Eng! J Med 1995; 332:1455]. N Eng! J M ed 1994; 330:1300-1306 Sherrier RH, Chiles C, Roggli V. Pulmonary lymphangioleiomyomatosis: CT findings [see comments]. AJR Am J Roentgenol 1989; 153:937-940 Aberle DR, Hansell DM, Brown K, et a!. Lymphangiomyomatosis: CT, chest radiographic, and functional correlations. Radiology 1990; 176:381-387 Shuman RL, Engelman R, Kittle CF. Pulmonary lymphangiomyomatosis. Ann Thorac Surg 1979; 27:70-75 Rossi GA, Balbi B, Oddera S, et al. Response to treatment with an analog of the luteinizing-hormone-releasing hormone in a patient v~th pulmonary lymphangioleiomyomatosis. Am Rev Respir Dis 1991; 143:174-176 Callol L, Villegas Fernandez FR, Calderon Alvarez J, et a!. Pulmonary lymphangiomyomatosis and kidney angiomyolipomas [letter]. Respiration 1993; 60:311 Lieberman J, Agliozzo CM. Intrapleural nitrogen mustard for treating chylous effusion of pulmonary lymphangioleiomyomatosis. Cancer 1974; 33:150.5-1511 King MA. MR diagnosis of lymphangioleiomyomatosis: ~s­ ibility of pulmonary cysts on spin-echo images. Magn Reson Imaging, 1996; 14:361-363 Burger CD, Hyatt RE, Staats BA. Pulmonary mechanics in lymphangioleiomyomatosis. Am Rev Respir Dis 1991; 143: 1030-1033 Crausman RS, Jennings CA, Mortenson RL, et al. Lymphangioleiomyomatosis: the pathophysiology of diminished exercise capacity. Am J Respir Crit Care !vied 1996; 153: 1368-1376 Itami M, Tesbima S, Asakuma Y, et al. Pulmonary lymphangiomyomatosis diagnosed by effusion cytology: a case report. Acta Cytol 1997; 41:522--528 Tomasian A, Greenberg MS, Rumerman H. Tamoxifen for lymphangioleiomyomatosis [letter]. N Eng! J Med 1982; 306:745-746 Logan RF, Fawcett IW. Oophorectomy for pulmonary lymphangioleiomyomatosis: a case report. Br J Dis Chest 198.5; 79:98-100 Estenne M, de Francquen P, Wellens F, et a!. Combined heart-and-lung transplantation for lymphangioleiomyomatosis [letter]. Lancet 1984; 1:275 Wellens F, Estenne M, de Francquen P, et al. Combined heart-lung transplantation for terminal pulmonary lymphangioleiomyomatosis. J Thorac Cardiovasc Surg 1985; 89:872-876 Sawicka EH, Morris AJ. A report of two long-smvi\~ng cases of pulmonary lymphangioleiomyomatosis and th e response to progesterone therapy. Br J Dis Chest 1985; 79:400-406 Reviews

109 Lizotte PE, Whitlock WL, Prudhomme JC, et a!. Lymphangiomyomatosis. Chest 1990; 98:1044-1045 110 de la Fuente J, Paramo C, Roman F, et a!. Lymphangioleiomyomatosis: unsuccessful treatment with luteinizinghormone-releasing hormone analogues [letter]. Eur J Med 1993; 2:377--378 111 Clemm C, Jehn U, Wolf-Hornung B, et a!. Lymphangiomyomatosis: a report of three cases treated with tamoxifen. Klin Wochenschr 1987; 65:391-393 112 Klein M, Krieger 0 , Ruckser R, et a!. Treatment of lymphangioleiomyomatosis by ovariectomy, interferon alpha 2b and tamoxifen-a case report. Arch Gynecol Obstet 1992; 252:99-102 113 Eysvogel MMM, Page PS. Lymphangiomyomatosis. Chest 1990; 98:1045-1046 114 Desurmont S, Bauters C, Copin MC, et a!. Treatment of pulmonary lymphangioleiomyomatosis using a GnRH agonist (see comments). Rev Mal Respir 1996; 13:300--304 115 Luna CM, Gene R, Jolly EC, et al. Pulmonary lymphangiomyomatosis associated with tuberous sclerosis: treatment with tamoxifen and tetracycline-pleurodesis. Chest 1985; 88:473-475 116 Fuleihan GE-H. Tissue-specific estrogens-the promise for the future. N Eng! J Med 1997; 337:1686-1687 117 Enterline HT, Roberts B. Lymphangiopericytoma: case

118

119 120 121 122 123 124

report of a previously undescribed tumor type. Cancer 1955; 8:582--587 Boehler A, Speich R, Russi EW, et al. Lung transplantation for lymphangioleiomyomatosis. N Eng! J Med 1996; 335: 1275-1280 Nine JS, Yousem SA, Paradis IL, eta!. Lymphangioleiomyomatosis: recurrence after lung transplantation. J Heart Lung Transplant 1994; 13:714-719 O'Brien JD, Limn JH, Parosa JF, eta!. Lymphangiomyomatosis recurrence in the allograft after single-lung transplantation. Am J Respir Crit Care Med 1995; 151:2033-2036 Beck GJ, Sullivan EJ, Stoller JK, et al. Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med 1997; 155:670 Kalassian KG, Doyle R, Kao P, et al. Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med 1997; 155:1183-1186 The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell1993; 75:1305-1315 Smolarek TA, Wessner LL, McCormack FX, eta!. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women \vith lymphangiomyomatosis. Am J Hum Genet 1998; 62:810-815

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