Baldi, Bruno Guedes

Bernardi, Fabíola Del Carlo

Carvalho, Carlos Roberto Ribeiro

de Melo Kawassaki, Alexandre

Dolhnikoff, Marisa

Pimenta, Suzana Pinheiro

English

PubMed

Bruno Guedes Baldi

Suzana Pinheiro Pimenta

Alexandre de Melo Kawassaki

Fabíola Del Carlo Bernardi

Marisa Dolhnikoff

Carlos Roberto Ribeiro Carvalho

Directory of Open Access Journals

Clinics

Pulmonary arterial involvement leading to alveolar hemorrhage in lymphangioleiomyomatosis

BALDI, Bruno Guedes

PIMENTA, Suzana Pinheiro

KAWASSAKI, Alexandre de Melo

BERNARDI, Fabíola Del Carlo

DOLHNIKOFF, Marisa

CARVALHO, Carlos Roberto Ribeiro

Biblioteca Digital da Produção Intelectual da Universidade de São Paulo (BDPI/USP)

CASE REPORT
Pulmonary arterial involvement leading to alveolar
hemorrhage in lymphangioleiomyomatosis
Bruno Guedes Baldi,I Suzana Pinheiro Pimenta,I Alexandre de Melo Kawassaki,I Fabı´ola Del Carlo
Bernardi,II Marisa Dolhnikoff,II Carlos Roberto Ribeiro CarvalhoI
I Pulmonary Division, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil. IIDepartment of Pathology, University of Sao Paulo
Medical School, Sao Paulo, Brazil.
Email: bruno.guedes2@terra.com.br
Tel.: 55 11 3069 5695
INTRODUCTION
Lymphangioleiomyomatosis (LAM) is a rare disorder of
unknown cause that affects women of reproductive age. The
disorder is characterized by the proliferation of atypical
smooth muscle cells (LAM cells) around airways, blood
vessels, and lymphatics with cystic destruction of the lung.1-3
LAM may occur sporadically or may be associated with
tuberous sclerosis complex (TSC).1
Clinically, patients may develop progressive dyspnea,
cough, wheezing, spontaneous pneumothorax, chylothorax,
and hemoptysis.3 The diagnosis is confirmed by the
identification of diffuse thin-walled lung cysts via thoracic
high resolution computed tomography (HRCT) that are
associated with a positive tissue biopsy or by the presence of
chylothorax, angiomyolipoma, or TSC.1,2 Acute respiratory
failure that is secondary to diffuse alveolar hemorrhage is
an extremely rare manifestation in LAM patients, with only
two previous cases described. The mechanism responsible
for the comorbid presentation of acute respiratory failure
and diffuse alveolar hemorrhage, however, is unknown.
Nonetheless, it is speculated to be secondary to the
obstruction of pulmonary venules by LAM cell prolifera-
tion, thereby promoting pulmonary venous hypertension.4,5
In the present work, we describe a patient with a diffuse
alveolar hemorrhage that led to acute respiratory failure and
death. A diagnosis of LAM and pulmonary arterial
disruption caused by LAM cells was confirmed during the
autopsy.
CASE DESCRIPTION
A 39-year-old woman of reproductive age presented with
progressive dyspnea and was being treated as an asthmatic
patient for seven years. A recent spirometry revealed a
moderate obstruction that did not respond to bronchodila-
tors. There was no history of cardiovascular comorbidity. In
the last month of the patient’s life, the dyspnea worsened,
and the patient complained of mild hemoptysis, which
required hospital admission. A chest examination revealed
a respiratory rate of 20/min and diffuse wheezing during
expiration without hypoxia.
The patient progressed to acute respiratory failure and
rapidly deteriorated with hypoxia. Mechanical ventilation
with positive end-expiratory pressure was necessary.
Laboratory studies revealed a decrease in the patient’s
hemoglobin levels from 10.4 to 6.7 g/dl. The patient’s white
blood cell count was 12,200/mm3, with normal values for
the coagulation parameters. The patient’s blood sodium,
potassium, urea, creatinine, and glucose levels were within
normal ranges. The patient’s arterial blood gas on 60%
oxygen was PO2 68 mmHg, PCO2 45 mmHg, HCO3
2 20
mmol/l, a base excess-3,1 mmol/l, and a pH of 7.25. The
antinuclear antibody, anti-neutrophil cytoplasmic antibody,
and rheumatoid factor tests were all negative.
Thoracic computed tomography demonstrated bilateral
and diffuse ground-glass attenuation opacities, which were
predominant in the lower lobes of the lungs, and thin-
walled cysts (Figure 1). A bronchoscopic examination
revealed a moderate amount of blood in the segments of
both lungs, and the lavage aliquots were progressively more
hemorrhagic, which was consistent with the diagnosis of
diffuse alveolar hemorrhage. The patient developed hemo-
dynamic instability that resulted in the patient’s death.
A histological examination during the autopsy revealed
cystic lesions in the pulmonary tissue, with alveolar
Copyright  2011 CLINICS – This is an Open Access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Figure 1 - Thoracic computed tomography. Bilateral and diffuse
ground-glass attenuation opacities predominant in the lower
lung lobes and thin-walled cystic lesions diffusely distributed in
both lungs, as identified using thoracic computed tomography.
CLINICS 2011;66(7):1301-1303 DOI:10.1590/S1807-59322011000700031
1301
hemorrhaging and atypical smooth muscle cell proliferation
at the cyst wall (Figures 2A and 2B). These cells were
positive for antibodies against melanoma-associated antigen
(HMB-45) and alpha-smooth muscle actin in the immuno-
histochemical analysis, which is consistent with LAM
(Figures 2C and 2D). These HMB-45-positive LAM cells
were observed within the small pulmonary artery walls. A
disruption of the arterial elastic layer was also observed
(Figures 2E and 2F). Hemosiderin-laden macrophages in the
adjacent alveolar spaces were also identified (top right in
Figures 2E and 2F).
DISCUSSION
Due to the rarity of LAM and the non-specific symptoms
associated with this disease, it is common for patients with
LAM to have a delayed diagnosis or an incorrect diagnosis
of diseases such as asthma. When women of childbearing
age present with progressive dyspnea and spontaneous
pneumothorax, LAM should be considered as a potential
diagnosis. The likelihood of LAM increases if the HRCT
reveals thin-walled lung cysts and if an obstructive pattern is
observed through spirometry. HRCT can reveal abnormal-
ities in the chest radiograph before the identification of LAM,
and these abnormalities may vary from a few scattered cysts
to cysts that are diffusely distributed. Ground-glass opacities
may also be observed in HRCT, and hemorrhaging is a
mechanism that may be responsible for these abnormalities.
Other common clinical features associated with LAM include
the presence of chylothorax and chylous ascites and the
worsening of these ascites during pregnancy or after the
administration of estrogen.1-3 The pathologic characteristics
of LAM include cysts and the multifocal nodular prolifera-
tion of immature smooth muscle cells and perivascular
epithelioid cells. In immunohistochemical analyses, these
muscle cells are positive for HMB-45 and alpha-actin. In
addition, the estrogen and/or progesterone receptor can be
detected using immunohistochemistry.1
Figure 2 - Histological evaluation. Photomicrographs show pulmonary changes observed during the autopsy. A and B) Pulmonary tissue
with LAM cysts (*) associated with alveolar hemorrhage (he). Note the smooth muscle tissue proliferation at the cyst wall (B, arrow).
HMB-45 and alpha-smooth muscle actin-positive LAM cells at the cysts wall (arrows) are shown in C and D, respectively. E) HMB45-
positive LAM cells within the small pulmonary artery wall (arrows). F) Disruption of the arterial elastic layer (*). The adjacent alveolar
spaces indicate the presence of hemosiderin-laden macrophages (top right in E and F). A and B: H&E staining; C, D and E:
immunohistochemistry; F: Verhoeff staining. Scale bars = 50 mm.
Alveolar hemorrhage in LAM
Baldi BG et al.
CLINICS 2011;66(7):1301-1303
1302
Acute respiratory failure that is secondary to diffuse
alveolar hemorrhage is a very rare manifestation in LAM
patients, with only two case reports to date.4,5 The obstruc-
tion of pulmonary venules due to LAM cell proliferation,
promoting pulmonary venous hypertension, has been sug-
gested as the underlying mechanism of this manifestation.1,5
The patient in the present case complained of mild
hemoptysis and had foci of hemosiderin-laden macrophages
in the alveoli, both of which were indicative of past
hemorrhaging. In the present case, however, we demon-
strated pulmonary arterial involvement by LAM cells with
the disruption of the arterial elastic layer, which may explain
the observed clinical emergency. The presence of venous
obstructions or any signs indicative of pulmonary hyperten-
sion were not found during the histological examination.
In conclusion, LAM should be included in the differential
diagnosis when a woman of reproductive age presents with
acute respiratory failure, a significant decrease in hemoglobin,
anddiffuseground-glass attenuationopacities. These symptoms
are suggestive of diffuse alveolar hemorrhage combined with
bilateral thin-walled cysts in thoracic computed tomography.
To our knowledge, the present paper is the first report
of an LAM patient presenting with diffuse pulmonary
hemorrhage with a histological examination. Contrary to
previous speculations, we have shown that pulmonary
arterial involvement is likely the primary underlying factor
for this severe clinical presentation.
REFERENCES
1. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, et al.
European Respiratory Society guidelines for the diagnosis and manage-
ment of lymphangioleiomyomatosis. Eur Respir J. 2010;35:14-26, doi: 10.
1183/09031936.00076209.
2. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest.
2008;133:507-16, doi: 10.1378/chest.07-0898.
3. Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, et al. The
NHLBI lymphangioleiomyomatosis registry: characteristics of 230
patients at enrollment. Am J Respir Crit Care Med. 2006;173:105-11,
doi: 10.1164/rccm.200409-1298OC.
4. Yamamoto K, Anzai F, Kusajima K, Yamanishi N, Yamada M. Acute
respiratory failure with gross hemoptysis in a patient with lymphangio-
leiomyomatosis as part of tuberous sclerosis complex. Int Med.
2004;43:755-8, doi: 10.2169/internalmedicine.43.755.
5. Fliegel E, Chitkara RK, Azueta V, Steinberg H. Fatal hemoptysis in
lymphangiomyomatosis. NY State J Med. 1991;91:66-7.
CLINICS 2011;66(7):1301-1303 Alveolar hemorrhage in LAM
Baldi BG et al.
1303


Universidade de São Paulo

Crossref

CASE REPORTPulmonary arterial involvement leading to alveolarhemorrhage in lymphangioleiomyomatosisBruno Guedes Baldi,I Suzana Pinheiro Pimenta,I Alexandre de Melo Kawassaki,I Fabı´ola Del CarloBernardi,II Marisa Dolhnikoff,II Carlos Roberto Ribeiro CarvalhoII Pulmonary Division, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil. IIDepartment of Pathology, University of Sao PauloMedical School, Sao Paulo, Brazil.Email: bruno.guedes2@terra.com.brTel.: 55 11 3069 5695INTRODUCTIONLymphangioleiomyomatosis (LAM) is a rare disorder ofunknown cause that affects women of reproductive age. Thedisorder is characterized by the proliferation of atypicalsmooth muscle cells (LAM cells) around airways, bloodvessels, and lymphatics with cystic destruction of the lung.1-3LAM may occur sporadically or may be associated withtuberous sclerosis complex (TSC).1Clinically, patients may develop progressive dyspnea,cough, wheezing, spontaneous pneumothorax, chylothorax,and hemoptysis.3 The diagnosis is confirmed by theidentification of diffuse thin-walled lung cysts via thoracichigh resolution computed tomography (HRCT) that areassociated with a positive tissue biopsy or by the presence ofchylothorax, angiomyolipoma, or TSC.1,2 Acute respiratoryfailure that is secondary to diffuse alveolar hemorrhage isan extremely rare manifestation in LAM patients, with onlytwo previous cases described. The mechanism responsiblefor the comorbid presentation of acute respiratory failureand diffuse alveolar hemorrhage, however, is unknown.Nonetheless, it is speculated to be secondary to theobstruction of pulmonary venules by LAM cell prolifera-tion, thereby promoting pulmonary venous hypertension.4,5In the present work, we describe a patient with a diffusealveolar hemorrhage that led to acute respiratory failure anddeath. A diagnosis of LAM and pulmonary arterialdisruption caused by LAM cells was confirmed during theautopsy.CASE DESCRIPTIONA 39-year-old woman of reproductive age presented withprogressive dyspnea and was being treated as an asthmaticpatient for seven years. A recent spirometry revealed amoderate obstruction that did not respond to bronchodila-tors. There was no history of cardiovascular comorbidity. Inthe last month of the patient’s life, the dyspnea worsened,and the patient complained of mild hemoptysis, whichrequired hospital admission. A chest examination revealeda respiratory rate of 20/min and diffuse wheezing duringexpiration without hypoxia.The patient progressed to acute respiratory failure andrapidly deteriorated with hypoxia. Mechanical ventilationwith positive end-expiratory pressure was necessary.Laboratory studies revealed a decrease in the patient’shemoglobin levels from 10.4 to 6.7 g/dl. The patient’s whiteblood cell count was 12,200/mm3, with normal values forthe coagulation parameters. The patient’s blood sodium,potassium, urea, creatinine, and glucose levels were withinnormal ranges. The patient’s arterial blood gas on 60%oxygen was PO2 68 mmHg, PCO2 45 mmHg, HCO32 20mmol/l, a base excess-3,1 mmol/l, and a pH of 7.25. Theantinuclear antibody, anti-neutrophil cytoplasmic antibody,and rheumatoid factor tests were all negative.Thoracic computed tomography demonstrated bilateraland diffuse ground-glass attenuation opacities, which werepredominant in the lower lobes of the lungs, and thin-walled cysts (Figure 1). A bronchoscopic examinationrevealed a moderate amount of blood in the segments ofboth lungs, and the lavage aliquots were progressively morehemorrhagic, which was consistent with the diagnosis ofdiffuse alveolar hemorrhage. The patient developed hemo-dynamic instability that resulted in the patient’s death.A histological examination during the autopsy revealedcystic lesions in the pulmonary tissue, with alveolarCopyright  2011 CLINICS – This is an Open Access article distributed underthe terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided theoriginal work is properly cited.Figure 1 - Thoracic computed tomography. Bilateral and diffuseground-glass attenuation opacities predominant in the lowerlung lobes and thin-walled cystic lesions diffusely distributed inboth lungs, as identified using thoracic computed tomography.CLINICS 2011;66(7):1301-1303 DOI:10.1590/S1807-593220110007000311301hemorrhaging and atypical smooth muscle cell proliferationat the cyst wall (Figures 2A and 2B). These cells werepositive for antibodies against melanoma-associated antigen(HMB-45) and alpha-smooth muscle actin in the immuno-histochemical analysis, which is consistent with LAM(Figures 2C and 2D). These HMB-45-positive LAM cellswere observed within the small pulmonary artery walls. Adisruption of the arterial elastic layer was also observed(Figures 2E and 2F). Hemosiderin-laden macrophages in theadjacent alveolar spaces were also identified (top right inFigures 2E and 2F).DISCUSSIONDue to the rarity of LAM and the non-specific symptomsassociated with this disease, it is common for patients withLAM to have a delayed diagnosis or an incorrect diagnosisof diseases such as asthma. When women of childbearingage present with progressive dyspnea and spontaneouspneumothorax, LAM should be considered as a potentialdiagnosis. The likelihood of LAM increases if the HRCTreveals thin-walled lung cysts and if an obstructive pattern isobserved through spirometry. HRCT can reveal abnormal-ities in the chest radiograph before the identification of LAM,and these abnormalities may vary from a few scattered cyststo cysts that are diffusely distributed. Ground-glass opacitiesmay also be observed in HRCT, and hemorrhaging is amechanism that may be responsible for these abnormalities.Other common clinical features associated with LAM includethe presence of chylothorax and chylous ascites and theworsening of these ascites during pregnancy or after theadministration of estrogen.1-3 The pathologic characteristicsof LAM include cysts and the multifocal nodular prolifera-tion of immature smooth muscle cells and perivascularepithelioid cells. In immunohistochemical analyses, thesemuscle cells are positive for HMB-45 and alpha-actin. Inaddition, the estrogen and/or progesterone receptor can bedetected using immunohistochemistry.1Figure 2 - Histological evaluation. Photomicrographs show pulmonary changes observed during the autopsy. A and B) Pulmonary tissuewith LAM cysts (*) associated with alveolar hemorrhage (he). Note the smooth muscle tissue proliferation at the cyst wall (B, arrow).HMB-45 and alpha-smooth muscle actin-positive LAM cells at the cysts wall (arrows) are shown in C and D, respectively. E) HMB45-positive LAM cells within the small pulmonary artery wall (arrows). F) Disruption of the arterial elastic layer (*). The adjacent alveolarspaces indicate the presence of hemosiderin-laden macrophages (top right in E and F). A and B: H&E staining; C, D and E:immunohistochemistry; F: Verhoeff staining. Scale bars = 50 mm.Alveolar hemorrhage in LAMBaldi BG et al.CLINICS 2011;66(7):1301-13031302Acute respiratory failure that is secondary to diffusealveolar hemorrhage is a very rare manifestation in LAMpatients, with only two case reports to date.4,5 The obstruc-tion of pulmonary venules due to LAM cell proliferation,promoting pulmonary venous hypertension, has been sug-gested as the underlying mechanism of this manifestation.1,5The patient in the present case complained of mildhemoptysis and had foci of hemosiderin-laden macrophagesin the alveoli, both of which were indicative of pasthemorrhaging. In the present case, however, we demon-strated pulmonary arterial involvement by LAM cells withthe disruption of the arterial elastic layer, which may explainthe observed clinical emergency. The presence of venousobstructions or any signs indicative of pulmonary hyperten-sion were not found during the histological examination.In conclusion, LAM should be included in the differentialdiagnosis when a woman of reproductive age presents withacute respiratory failure, a significant decrease in hemoglobin,anddiffuseground-glass attenuationopacities. These symptomsare suggestive of diffuse alveolar hemorrhage combined withbilateral thin-walled cysts in thoracic computed tomography.To our knowledge, the present paper is the first reportof an LAM patient presenting with diffuse pulmonaryhemorrhage with a histological examination. Contrary toprevious speculations, we have shown that pulmonaryarterial involvement is likely the primary underlying factorfor this severe clinical presentation.REFERENCES1. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, et al.European Respiratory Society guidelines for the diagnosis and manage-ment of lymphangioleiomyomatosis. Eur Respir J. 2010;35:14-26, doi: 10.1183/09031936.00076209.2. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest.2008;133:507-16, doi: 10.1378/chest.07-0898.3. Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, et al. TheNHLBI lymphangioleiomyomatosis registry: characteristics of 230patients at enrollment. Am J Respir Crit Care Med. 2006;173:105-11,doi: 10.1164/rccm.200409-1298OC.4. Yamamoto K, Anzai F, Kusajima K, Yamanishi N, Yamada M. Acuterespiratory failure with gross hemoptysis in a patient with lymphangio-leiomyomatosis as part of tuberous sclerosis complex. Int Med.2004;43:755-8, doi: 10.2169/internalmedicine.43.755.5. Fliegel E, Chitkara RK, Azueta V, Steinberg H. Fatal hemoptysis inlymphangiomyomatosis. NY State J Med. 1991;91:66-7.CLINICS 2011;66(7):1301-1303 Alveolar hemorrhage in LAMBaldi BG et al.1303

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Kawassaki, Alexandre de Melo

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Acute respiratory failure with gross hemoptysis in a patient with lymphangioleiomyomatosis as part of tuberous sclerosis complex. Int Med.

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis.

Fatal hemoptysis in lymphangiomyomatosis.

Lymphangioleiomyomatosis: a clinical update.

The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment.

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Pulmonary arterial involvement leading to alveolar hemorrhage in lymphangioleiomyomatosis

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