Clinical-Pathological Conference

Wien Klin Wochenschr (2021) 133:65–72https://doi.org/10.1007/s00508-020-01753-3

Clinical-Pathological Conference Series from theMedical University of Graz

Case No 170: A 33-year-old psychologist with severe dyspnea andright-sided chylothorax

Philipp K. Bauer · Martin Flicker · Elisabeth Fabian · Holger Flick · Luka Brcic · Bernadette Liegl-Atzwanger ·Michael Janisch · Michael Fuchsjäger · Horst Olschewski · Guenter J. Krejs

Published online: 29 October 2020© The Author(s) 2020

Keywords Cystic lung disease ·Lymphangioleiomyomatosis · VEGF-D · Sirolimus

Presentation of case

Dr. H. Flick: A 33-year-old psychologist complainedof palpitations and the feeling of tightness in herchest, dyspnea on exertion (and sometimes evendyspnea at rest) since 1 week ago. She has been

P. K. Bauer, MDDivision of Infectious Diseases and Tropical Medicine,Department of Internal Medicine I, Medical University ofVienna, Vienna, Austria

M. Flicker, MDDepartment of Internal Medicine, State HospitalHochsteiermark, Leoben, Austria

E. Fabian, MD, PhD, MSc, BScDivision of Gastroenterology and Hepatology, Departmentof Internal Medicine III, Medical University of Vienna,Vienna, Austria

H. Flick, MD · H. Olschewski, MDDivision of Pulmonology, Department of Internal Medicine,Medical University of Graz, Graz, Austria

L. Brcic, MD, PhD · B. Liegl-Atzwanger, MDDiagnostic and Research Institute of Pathology, MedicalUniversity of Graz, Graz, Austria

M. Janisch, MD · M. Fuchsjäger, MDDivision of General Radiology, Department of Radiology,Medical University of Graz, Graz, Austria

G. J. Krejs, MD, AGAF, MWGO (�)Division of Gastroenterology and Hepatology, Departmentof Internal Medicine, Medical University of Graz,Auenbruggerplatz 15, 8036 Graz, Austriaguenter.krejs@medunigraz.at

taking hormonal therapy (progesterone/lynestrenol)because of endometriosis for the last 2 years. Her pul-monologist referred her to the emergency room (ER)of Graz University Medical Center because of rapidlyprogressive dyspnea and suspected pulmonary em-bolism. A mass had been detected in the retroperi-toneum and biopsied in a hospital in another state2 months prior to admission. Results of the biopsywere not available. Physical examination on admis-sion was unremarkable except for complete dullnessover the right lung on percussion. Blood pressure was120/80mmHg, heart rate (HR) 138 beats per minute(bpm), temperature 36.0 °C, oxygen saturation at am-bient air 95%. Electrocardiogram showed sinus tachy-cardia (HR 117bpm), S1Q3 type, and P waves and PQinterval were unremarkable. Transthoracic echocar-diography revealed normal aortic, mitral and tricuspidvalves. The pulmonic valve was not assessable, tri-cuspid annular plane systolic excursion was reducedat 0.8cm. When moving the sonography sensor tothe abdomen, no ascites was seen. Laboratory tests:leukocytes 15.36× 10^9/L (normal: 4.4–11.3× 10^9/L),hemoglobin 16.8g/dL (normal: 12–15.3g/dL), hema-tocrit 50.3% (normal: 35–45%), gamma-glutamyltransferase 63U/L (normal: <38U/L), C-reactive pro-tein (CRP) 7.5mg/L (normal: <5.0mg/dL), D-dimer2.18mg/L (normal: <0.5mg/L).

X-ray and computed tomography (CT) of the chestrevealed a massive pleural effusion on the right side.Immediate paracentesis in the ER yielded 1 L ofa white turbid effusion. Detailed analysis see Table 1.

A diagnostic test was performed and specific treat-ment was initiated.

Dr. M. Fuchsjäger: The patient’s chest X-ray showedsubtotal opacity of the right lung with merely a resid-

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Fig. 1 Chest X-ray (in expiration) with subtotal opacity of theright lung andmerely residual ventilation of the right upper lobe(arrow) as well as a mediastinal shift to the left

ual ventilation of the right upper lobe and a mediasti-nal shift to the left (Fig. 1). Subsequent CT of the chestshowed a massive right pleural effusion with subtotalatelectasis of the right lung and a marked mediasti-nal shift to the left. Multiple small lung cysts witha diameter of up to 6mm as well as extensive groundglass opacities were seen in the left lung. There wasno evidence of pulmonary embolism or enlargementof lymph nodes (Fig. 2).

Differential diagnosis

Dr. M. Flicker: The patient under discussion is a 33-year-old woman who complained of progressive dys-pnea, palpitations and chest tightness. Laboratorydata revealed increased markers of inflammation andelevated D-dimer. Chest X-ray showed a large pleuraleffusion on the right; CT scan ruled out pulmonary

Table 2 Tests indicatedbased on the appearance ofthe pleural effusion [1]

Appearance of fluid Test indicated Interpretation

Cloudy or turbidTurbid supernatant

CentrifugationTriglyceride levels

Turbid supernatant→ high lipid levels>110mg/dL→ chylothorax>50mg/dL but ≤110mg/dL→ obtain lipoprotein analysisPresence of chylomicrons→ chylothorax≤50mg/dL and cholesterol >250mg/dL→ pseudochylothorax

Bloody Hematocrit <1%→ non-significant1–20%→ cancer, pulmonary embolism, trauma>50% of peripheral hematocrit: hemothorax

Putrid odor Stain and culture Infection

Table 1 Laboratory analysis of the patient’s milky pleuraleffusion

Parameter Patient data Common results in chy-lothorax

Leukocytes Total (per µL) 7377 >400

Lymphocytes(%)

76 >50

Total protein (g/dL) 4.6 2–4

Lactate dehydrogenase (U/L) 185 70–200

Glucose (mg/dL) 96 80–130

Cholesterol (mg/dL) 143 <200

Triglycerides (mg/dL) 3959 >110a (diagnostic criteria)

pH 7.37 7.35–7.50aOr presence of chylomicrons

embolism but revealed an opacity and multiple cystsin the left lung. The absence of ascites strongly sug-gests a problem of pulmonary or pleural etiology. Lab-oratory analysis of the milky pleural fluid revealeda right-sided chylothorax (i.e. accumulation of chylewithin the pleural space). According to the appear-ance of a pleural effusion, different tests are indi-cated (Table 2) [1]. Chyle is described classically ashaving a white, milky or opalescent appearance [2].A chylous effusion has a high concentration of triglyc-erides (>110mg/dL), lymphocytes and immunoglob-ulins (Table 1) [3, 4]. If triglyceride levels are below50mg/dL, it is not a chylothorax. If a conclusive diag-nosis cannot be made, lipoprotein analysis should beperformed. The presence of chylomicrons establishesthe diagnosis of a chylothorax [1]. Chylous pleural ef-fusion or chylothorax occurs when flow in the thoracicduct, which carries fat after being absorbed in the in-testine up to the superior vena cava, is compromised.It develops from disruption or obstruction of the tho-racic duct or its tributaries with leakage of chyle fromthe ductal system into the pleural space. Chylothoraxhas various causes and is usually attributable to one offour etiologies [5]: (1) malignancy, (2) trauma (includ-ing surgery), (3) miscellaneous disorders and (4) idio-pathic. Malignancy is the most common cause of chy-lothorax with lymphoma accounting for 37–75%, andbronchogenic carcinoma being the second most com-mon reason [5, 6]. The proximity of the thoracic ductto the esophagus, aorta and spine, along with its vari-able anatomy, makes it particularly vulnerable duringsurgical procedures performed near these anatomi-

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Fig. 2 CT of the chest.Axial (a) and coronal (b) im-ages (soft tissue windowsetting); massive right pleu-ral effusion (asterisk), at-electasis of the right mid-dle and lower lung lobes(arrowheads) as well asa marked mediastinal shiftto the left (arrows). Axialimage (c; lung window set-ting); multiple small lungcysts (diameter up to 6mm;arrows) as well as exten-sive ground glass opacities(arrowheads)

cal structures. Postoperative chylothorax has beendescribed after nearly every known thoracic surgeryas well as after neck surgery [7], but in rare casesmay also occur after partial hepatectomy [8] (Table 3).Moreover, a wide variety of diseases, such as sarcoido-sis, tuberous sclerosis, different infections or variouslymphatic disorders have been associated with chy-lous pleural effusion (Table 3) [9]. Although the ma-jority of causes for chylothorax listed in Table 3 can beexcluded as a diagnosis in the discussed patient be-cause of a negative history or lacking clinical features,it should be kept in mind that the patient had been di-agnosed with a mass in the retroperitoneum 2monthsbefore admission. However, since (1) laboratory data

Table 3 Etiologies of chylothorax [5–9]

Malignancy Lymphoma, chronic lymphocytic leukemiaLung cancerMetastatic disease

Traumatic Surgery for congenital heart disease, cardiovascular surgery (e.g. aortic procedures, coronary artery bypass graft surgery, valve replacement),esophagectomy, resection for lung cancer, lung transplantation, resection of mediastinal mass (e.g. neuronal tumor, thymoma, neuroblas-toma, cystic hygroma, ganglioneuroma, metastatic tonsillar carcinoma), mediastinoscopy and lymphadenectomy, spinal surgery, central lineplacement, pacemaker implantation (via subclavian vein), embolization procedure for pulmonary arteriovenous malformation, partial hepatec-tomy, blunt chest trauma and other external injury

Miscellaneousdisorders

Sarcoidosis, tuberous sclerosis, pulmonary lymphangioleiomyomatosis, congestive heart failure, Kaposi sarcoma, radiation therapy of themediastinum,(Granulomatous) Infections: tuberculosis, histoplasmosis, filariasisSubclavian venous thrombosisCongenital or acquired lymphatic disorders: Gorham’s disease, Milroy disease, congenital lymphatic hypoplasiaVarious lymphatic diseases: lymphangiomatosis, yellow nail syndrome, lymphangioma, thoracic duct cystSecondary to chylous ascites (due to e.g. alcoholic or cryptogenic cirrhosis, hepatitis C infection, primary biliary cholangitis, primary scleros-ing cholangitis, cholangiocarcinoma, pancreatic carcinoma)

Idiopathic Congenital (neonatal)Cases with no clear cause

did not suggest lymphoma or leukemia, (2) there wereno signs or symptoms indicating another malignancy(such as bronchogenic cancer) and (3) the describedmass was anatomically not located in the proximity ofthe thoracic duct and, therefore, cannot be responsi-ble for the development of the chylothorax, a malig-nancy seems very unlikely as the underlying cause ofthe chylous pleural effusion in this patient. Indeed,in this case the described mass is probably related tothe patient’s endometriosis. Although the discussedpatient had an increased level of D-dimer, and sub-clavian venous thrombosis could basically lead to chy-lous pleural effusion, this diagnosis can also be ruled

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out because no thrombosis of the chest vessels wasfound on the CT scan.

Besides chylothorax, the finding of multiple lungcysts is also a key clinical feature in this patient, andvarious differential diagnoses should be included.Lung cysts may be congenital or occur due to Langer-hans histiocytosis, rare genetic disorders, such as theBirt-Hogg-Dube ́ syndrome or various interstitial lungdiseases [10]. Moreover, lymphangioleiomyomato-sis (LAM), a multisystemic disorder characterized bythe proliferation of smooth muscle cells resulting incystic lung disease [11], should be considered in thispatient. This disease is a rare progressive disorderwith a prevalence of about 2.6 patients per 1,000,000population [12]. It typically affects women of child-bearing age with an estimated prevalence of 5 per1,000,000 women [13]. Two forms of LAM presentclinically—the sporadic LAM and tuberous sclerosiscomplex-associated LAM [14]. Pulmonary manifesta-tions include multiple thin-walled cysts in the lungsand a high frequency and recurrence rate of pneu-mothorax (66%) and chylothorax (25%). As the dis-ease progresses it leads to narrowing and obstructionof the airways and presents similarly to obstructivelung disease. It results in alveolar damage and thedevelopment of cystic disease of the lungs and thelymphatic system [11]. LAM patients lose about 90mLof their forced expiratory volume in 1s (FEV1) annu-ally. Diffusing capacity for carbon monoxide (DLCO)is another measurement for disease progression andmay be reduced even if FEV1 is normal. Both FEV1and DLCO are related to disease progression [15]. Ex-trapulmonary features include angiomyolipomas andlymphangioleiomyomas in 20% of affected patients[16]. Vascular endothelial growth factor-D (VEGF-D)is a biomarker of LAM and reflects disease severity[17]. Clinical observations found that the menstrualcycle influences symptoms and occurrence of pneu-mothorax. The decline in lung function slows aftermenopause and accelerates with exogenous estrogenuse and pregnancy [18, 19]. Numerous studies havedetermined the role of estrogen and progesterone inthe pathogenesis of LAM [20]. LAM lesions furthershare characteristics with uterine leiomyomas withboth containing abnormal immature smooth muscle-like cells and expression of estrogen and progesteronereceptors [21]. Concluding from animal models, theuterus may be the origin of LAM [22, 23]. Since LAMis caused by TSC2 or TSC1 mutations that result inoveractivation of the mechanistic target of rapamycinpathway (mTOR), sirolimus (an mTOR inhibitor) hasbeen approved for the treatment of LAM in manycountries [14]. The effectiveness of sirolimus includesimprovement of lung function, exercise capacity, oxy-gen level, quality of life and a decrease in VEGF-Dlevels [24].

In summary, the following four key findings stronglysuggest the diagnosis of LAM in this patient: (1) hor-mone therapy for endometriosis for 2 years, (2) a mass

in the retroperitoneum, (3) chylothorax and (4) mul-tiple cysts in the lungs.

In order to establish the final diagnosis, serum lev-els of VEGF-D should be measured and the biopsy re-sults of the retroperitoneal mass should be obtained.

An elevated D-dimer is not associated with LAM.In this patient, pulmonary embolism was excludedby a CT scan; nevertheless, elevated D-dimer levelsmay result from a thrombosis localized elsewhere inthe body (e.g. deep venous thrombosis in the lowerlimbs) and should thus be searched for.

Dr. M. Flicker’s diagnosis

Lymphangioleiomyomatosis

Discussion of case

Dr. H. Flick: LAM is a rare cystic lung disease thatwas suspected by the physicians taking care of thispatient. To confirm the diagnosis, serum levels ofVEGF-D were analyzed and results of the biopsy ofthe retroperitoneal mass were obtained as suggestedby Dr. Flicker. VEGF-D is a diagnostic biomarker, andan elevated serum level (≥800pg/mL) can help con-firm the diagnosis of LAM in women with a compati-ble medical history and characteristic CT scan of thechest [16]. VEGF-D acts as a lymphangiogenic growthfactor and may reflect the burden of LAM cells in thehuman body. LAM cells produce VEGF-C and VEGF-Dwhich are involved in cell proliferation and lymphan-giogenesis via VEGFR3; however, only VEGF-D is el-evated in serum [25]. In this patient, serum VEGF-Dwas very high at 2623pg/mL.

Dr. L. Brcic: Histology of the retroperitoneal massbiopsied 2 months before admission in a hospitalin another state showed mesenchymal tumor tissue

Fig. 3 Histological presentation of the retroperitoneal mass.Spindle tumor cells without marked atypia are present, dis-playing eosinophilic cytoplasm and interspersed blood vesselstructures (hematoxylin-eosin staining, objective ×4 and ×20inlet)

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composed of spindle cells intermixed with blood ves-sels (Fig. 3). Tumor cells demonstratedminimal atypiaand 1 mitosis per 10 high power fields (HPF) was de-tected. In immunohistochemical analysis, tumor cellswere positive for human melanoma black 45 (HMB45)and microphthalmia transcription factor (MITF), andsome cells even for α-smooth muscle actin (αSMA),caldesmon and desmin. Staining was negative forpan-cytokeratin, epithelial membrane antigen (EMA),melan A, S100 and murine double minute 2 (MDM2).These results are consistent with lymphangioleiomy-omatosis.

Lung biopsy is not required for the definite diag-nosis of LAM [16] and will only be performed if thediagnosis cannot be made non-invasively. Histologi-cal and pathological features are proliferation of neo-plastic smooth muscle cells, i.e. LAM cells which maybe sparse in early stage disease. Immunohistochem-ical staining with αSMA, HMB45, estrogen receptorand progesterone receptor may be required to identifythem. LAM cells consist of two types of cell subpopu-lations, fibromyoblast-like spindle-shaped cells whichexpress smooth muscle specific proteins (e.g. α-actin,desmin, vimentin) and epithelioid-like cells which ex-press glycoprotein gp100, a marker of melanoma cellsand immature melanocytes [14].

Dr. H. Flick: After the diagnosis of LAM had been es-tablished, treatment with sirolimus was initiated witha dose of 4mg per day. After 1 month of therapy andrepetitive drainage of a total of 17L of chylous pleuraleffusion, the patient’s condition stabilized and therewas no recurrence of chylothorax (Fig. 4). Duringthis treatment, VEGF-D decreased from 2623pg/mLto 595pg/mL and the retroperitoneal mass decreasedin size and was radiologically no longer detectable at6 months follow-up. Dosage adjustment was carriedout to achieve a serum drug concentration between 5and 10ng/mL [14]. During therapy with sirolimus, norelevant obstruction or restriction was found in the

Fig. 4 Normal follow-upchest X-ray a; p.a. and b;lateral) after treatment withsirolimus for 6 months

pulmonary function test (forced vital capacity, FVC:128.5L, FEV1% FVC: 75.5%); however, DLCO remainedimpaired (5.41mmol/min/kPa corresponding to 60%of predicted) even on therapy, reflecting the damagethat has occurred in the lung parenchyma, present-ing as multiple lung cysts. Formation of lung cysts inLAM is complex: Mutation and loss of function of theTSC genes in LAM precursor cells leads to activationof mTOR signaling and the clonal expansion of LAMcells expressing smooth muscle proteins and markersof melanogenesis. In early stage disease these cells aresparse but form nodules in more advanced disease.These contain fibroblasts and lymphatic endothelialcells which are recruited or perhaps transdifferentiateunder stimulation by lymphangiogenic growth factors,particularly VEGF-D [26]. Inflammatory cells includ-ing T cells and mast cells are recruited and gener-ate a mature LAM nodule [27]. Lung cyst formationmay then occur by unregulated protease activity withthe cysteine protease cathepsin K expressed in LAMnodules [28–30] and ineffective lymphatic remodeling[16].

LAM is a rare, systemic disease that is associatedwith cystic lung destruction, chylous fluid accumula-tion and abdominal tumors, including angiomyolipo-mas and lymphangioleiomyomas. Untreated LAM hasa median survival of about 20 years after diagnosis[15]. In Austria, about 80 women carry the diagnosisof LAM; 12 of them are currently treated at the clinicfor rare lung diseases of the Graz University MedicalCenter.

Dr. G.J. Krejs: For rare diseases, therapeutic optionsare often limited. Besides sirolimus, are there anyother therapeutic options for patients with LAM?

Dr. H. Flick: Although there is evidence of estro-gen involvement in the pathogenesis, the evidencefor hormonal therapy in LAM is very limited andinconsistent. For example, a prospective study in

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premenopausal women with LAM did not find a ben-eficial effect of triptorelin (a gonadotropin receptorhormone analogue) on lung function during a 3-year observation period [31]. Data of another studyin which letrozole (an aromatase inhibitor) was in-vestigated in postmenopausal LAM patients wereinconclusive, but suggested a potential beneficial ef-fect on lung function and VEGF-D levels [32]. Thecurrent American Thoracic Society/Japanese Respira-tory Society (ATS/JRS) guidelines do not recommendusing hormonal therapy, including progesterone, go-nadotropin receptor hormone agonists, tamoxifen,aromatase inhibitors or oophorectomy [16].

Since levels of matrix metalloproteinases (MMP)-2and MMP-9 have been found to be increased in pa-tients with LAM in serum and lung biopsies [33, 34],doxycycline, which inhibits the production and ac-tivity of several MMPs, has also been investigated asa therapeutic agent; however, a randomized, double-blind, placebo-controlled trial revealed no differencesbetween doxycycline and placebo in the rate of FEV1decline and quality of life [35]. Therefore, doxycy-cline is not recommended as a therapeutic approachin LAM [16].

Experimental studies further suggest a benefit ofstatins (atorvastatin and simvastatin) in LAM [36–38],but additional studies are required to investigate theeffect in humans. Moreover, autophagy inhibitorssuch as chloroquine and hydroxychloroquine havebeen proposed as potential therapeutic agents inLAM. In vivo and in vitro studies found decreasedTSC2 null cell survival and reduction in tumor sizeby chloroquine. This effect increased in combinationwith sirolimus [39]. The combination with hydroxy-chloroquine and sirolimus revealed improved lungfunction at 24 weeks, but lung function decreased atthe 48-week time point [40].

In patients with severe LAM and hypoxemia dueto a decrease in DLCO and/or FEV1, long-term oxy-gen therapy based on the experience in patients withchronic obstructive lung disease is recommended[41]. Long-term oxygen is particularly helpful inpatients with PaO2≤ 55mmHg or SpO2≤ 88%, or inthose with PaO2≤ 60mmHg if peripheral edema, poly-cythemia or pulmonary hypertension are present [14].Patients with FEV1 below 40% of predicted are con-sidered candidates for lung transplantation [42].

Patients with LAM are encouraged to maintaina healthy lifestyle, exercise regularly and avoid cigarettesmoking. A balanced diet is recommended. In pa-tients with chylothorax, a low-fat diet may be advised[14].

Dr. G.J. Krejs: LAM is a rare disease; in our 33-yearhistory of holding clinical-pathological conferencesat the Medical University of Graz, we had only oneother case discussed in 1988 by Dr. Otto Brändlifrom Zurich, Switzerland. Sirolimus was not availableback then. Although the disease is rare, interesting

case reports are regularly published [43]. The diseasepresents with pulmonary features including dyspnea,pneumothorax, chylothorax and multiple thin-walledcysts in the lungs as well as extrapulmonary mani-festations, such as abdominal angiomyolipomas andlymphangioleiomyomas. Elevated D-dimer levels inthis case are not a typical finding in LAM and arecommented on by Dr. Olschewski.

Dr. H.Olschewski: Although the finding of increasedD-dimer levels may hint at the presence of a thrombussomewhere in the body, we should keep in mind thatup to 70% of laboratory results with this biomarker inclinical routine are false positives in older patients. Inthe discussed (young) patient, the increased D-dimerlevels may be due to the mechanical stress of vesselsin the chest caused by chylothorax and a mediastinalshift. However, this parameter may also be a usefulindicator for other conditions since data of the LipidStudy recently identified D-dimer as a global predic-tor of mortality, i.e. not only cardiovascular, but alsocancer-associated and all-cause mortality [44].

Final diagnosis

Lymphangioleiomyomatosis

Acknowledgements The authors express their sincere grati-tude toDr. AlinaFakin for language editing of themanuscript.

Information Information on Clinical-Pathological Con-ferences from the Medical University of Graz are alsoavailable under https://www.medunigraz.at/cpc-klinisch-pathologischekonferenz/ (in German).

Funding Openaccess fundingprovidedbyMedicalUniversityof Graz.

Conflict of interest P.K. Bauer, M. Flicker, E. Fabian, H. Flick,L. Brcic, B. Liegl-Atzwanger, M. Janisch, M. Fuchsjäger,H. Olschewski and G.J. Krejs declare that they have nocompeting interests.

Open Access This article is licensed under a Creative Com-mons Attribution 4.0 International License, which permitsuse, sharing, adaptation, distribution and reproduction inanymedium or format, as long as you give appropriate creditto the original author(s) and the source, provide a link tothe Creative Commons licence, and indicate if changes weremade. The images or other third party material in this articleare included in the article’sCreativeCommons licence, unlessindicated otherwise in a credit line to thematerial. If materialis not included in the article’s Creative Commons licence andyour intended use is not permitted by statutory regulation orexceeds the permitted use, you will need to obtain permis-sion directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.

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