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Pathologically confirmed diffuse alveolar haemorrhage in lymphangioleiomyomatosis
  1. Jane Kobylianskii1,
  2. Adam Hutchinson-Jaffe1,2,
  3. Michael Cabanero3,4 and
  4. John Thenganatt1,5
  1. 1Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  2. 2North York General Hospital, North York, Ontario, Canada
  3. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  4. 4Division of Anatomical Pathology, University Health Network, Toronto, Ontario, Canada
  5. 5Division of Respirology, University Health Network, Toronto, Ontario, Canada
  1. Correspondence to Dr John Thenganatt; John.Thenganatt{at}uhn.ca

Abstract

A 40-year-old woman was referred to pulmonology after presenting with dyspnoea and self-limiting haemoptysis. Chest CT revealed diffuse ground glass opacities and small thin-walled cysts. Bronchoalveolar lavage cultures were negative and cytology revealed haemosiderin-laden macrophages. Transthoracic echocardiogram was normal. Connective tissue disease and vasculitis work-up were negative. Vascular endothelial growth factor-D level was indeterminate. Lung function was normal. She underwent video-assisted thoracoscopic lung biopsy. In addition to findings consistent with lymphangioleiomyomatosis, histopathological examination identified haemosiderosis without capillaritis, confirming a diagnosis of diffuse alveolar haemorrhage in the context of the associated clinical and radiographic features. Follow-up imaging after 5 months showed resolution of the diffuse ground glass opacities. Pharmacotherapy with sirolimus was not initiated due to absence of deterioration in pulmonary function. Diffuse alveolar haemorrhage in patients with lymphangioleiomyomatosis is a rare but important presentation. The few previously reported cases progressed to respiratory failure requiring mechanical ventilation.

  • interstitial lung disease
  • pathology

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Background

Pulmonary lymphangioleiomyomatosis (LAM) is a rare, multisystem, low-grade neoplastic disorder that most commonly affects women within the third and fourth decade of life.1 2 It can occur sporadically or in association with tuberous sclerosis complex (TSC).1 2 Both TSC-associated and sporadic LAM are characterised by diffuse cystic lung changes and extrapulmonary manifestations including renal angiomyolipomas, lymphangioleiomyomas and chylous effusions.2 3 The pathophysiology of LAM involves the abnormal proliferation of smooth muscle-like cells, leading to progressive cystic lung destruction.2 3

In this report, we describe a patient who presented with diffuse alveolar haemorrhage (DAH) and LAM confirmed by histological examination of surgical lung biopsy. DAH in patients with LAM is a rare presentation.

Case presentation

A 40-year-old woman presented to the emergency department with dyspnoea and tachycardia 1 week post partum after an uncomplicated caesarean section. A CT pulmonary angiogram was performed to rule out pulmonary embolism and incidentally revealed small, regular, homogeneously distributed thin-walled cysts (figure 1A,B). Her acute presentation was attributed to postpartum anaemia and she was discharged from the emergency department after transfusion of packed red blood cells and intravenous iron supplementation. Three weeks later, the patient returned to hospital with acute progressive dyspnoea and haemoptysis of approximately 350 mL of blood over 5 hours. On examination, she was afebrile, her blood pressure was 118/64 mm Hg, her heart rate was 91 beats per minute, and her oxygen saturation was 90% while receiving supplemental oxygen at 2 L/min.

Figure 1

Chest CT (axial slices) demonstrating innumerable thin-walled cysts throughout both lungs at the patient’s initial presentation (A and B), with development of superimposed bilateral diffuse ground glass opacities during her subsequent presentation with haemoptysis (C and D). Resolution of the ground glass opacities is demonstrated on follow-up imaging 5 months later (E and F).

Investigations

Laboratory investigations revealed haemoglobin of 87 g/L and haematocrit of 27.8%.

A chest X-ray demonstrated diffuse bilateral nodular opacities. A chest CT was repeated and revealed new diffuse patchy ground glass opacities (GGOs) on the background of previously observed small thin-walled cysts (figure 1C and D). Flexible bronchoscopy was performed with bronchoalveolar lavage (BAL), which appeared blood-tinged. BAL cultures were negative and cytology revealed haemosiderin-laden macrophages. Her haemoptysis was self-limiting and she was discharged from hospital after 48 hours without intervention.

Further outpatient work-up was completed following discharge from hospital. An echocardiogram demonstrated normal biventricular size and function, with no echocardiographic features of pulmonary hypertension. Antinuclear antibody, extractable nuclear antigen panel, antineutrophil cytoplasm antibodies and antiglomerular basement membrane testing were negative. Coagulation indices and platelet count were normal.

Pulmonary function testing revealed the following: forced expiratory volume in 1 s to forced vital capacity ratio (FEV1:FVC) 0.82, FEV1 2.4 L (85% predicted), FVC 2.9 L (90% predicted), total lung capacity 4.5 L (95% predicted) and diffusing capacity 89% predicted. A 6 minute walk test was normal and revealed no hypoxaemia on exertion. Vascular endothelial growth factor-D level was 710 pg/mL (recommended diagnostic threshold for LAM ≥800 pg/mL).2 A CT of the abdomen and pelvis ruled out abdominal angiomyolipoma.

The patient ultimately underwent video-assisted thoracoscopic lung biopsy 5 months following her presentation with haemoptysis. Histological examination revealed scattered cystically dilated airspaces, with aggregates of spindle cells noted within the walls, as well as throughout the lung parenchyma, and occasionally associated with vessels and airways, consistent with LAM (figure 2A,B). By immunohistochemistry, the spindle cells exhibited coexpression of melanocytic and myoid markers (figure 2E–I), staining positive for human melanoma black-45, smooth muscle actin, desmin, caldesmon and microphthalmia transcription factor. Patchy moderate haemosiderosis without capillaritis was also observed (figure 2C), confirming a diagnosis of DAH in the context of the associated clinical and radiographic features.

Figure 2

Histological images from lung biopsy showing pulmonary tissue with cysts (A and B) and associated haemosiderosis (C). (A–D) H&E staining and (E–I) immunohistochemistry of cells within the cyst walls staining positive for human melanoma black-45 (E), smooth muscle actin (F), desmin (G), caldesmon (H) and microphthalmia transcription factor (I).

Differential diagnosis

A broad differential diagnosis was considered in the evaluation of both the patient’s underlying finding of cystic lung disease as well as the acute presentation with haemoptysis and diffuse GGOs.

The differential diagnosis for diffuse cystic lung disease is extensive. Neoplastic aetiologies include LAM, pulmonary Langerhans cell histiocytosis, and primary or metastatic malignancies.4 Congenital causes include Birt-Hogg-Dubé syndrome, Proteus syndrome and Ehlers-Danlos syndrome.4 Infectious aetiologies include Pneumocystis jiroveci pneumonia.4 Diffuse cystic lung disease may also develop in association with lymphoproliferative disorders, such as lymphocytic interstitial pneumonia and light-chain deposition disease, or alongside interstitial lung diseases such as hypersensitivity pneumonitis and desquamative interstitial pneumonia.4 Mimics of diffuse cystic lung disease include emphysema, cavities, cystic bronchiectasis and honeycombing associated with advanced fibrotic lung diseases.5 In the present case, the patient’s chest CT demonstrated multiple, bilateral, thin-walled, small air-filled cysts, findings which are characteristic of LAM.4 The histopathological findings in this case further supported the diagnosis of LAM, revealing spindle-shaped cells that infiltrated throughout the lung parenchyma, airways and vessels, exhibited coexpression of melanocytic and myoid immunohistochemical markers, and were associated with cystic changes.6

With respect to the patient’s presentation with haemoptysis, important diagnostic considerations in this clinical context included connective tissue disease, vasculitis, structural heart disease, infection, coagulation disorders and pulmonary embolism.7 The patient’s postpartum status was also considered. While the most common causes of haemoptysis are the same in pregnant and non-pregnant patients, pregnant patients are at higher risk of developing certain conditions that may present with haemoptysis, such as venous thromboembolism and pulmonary oedema.8 9 None of these aetiologies was identified in the present case despite a thorough work-up. One case series of patients with idiopathic haemoptysis during pregnancy postulated that higher circulating levels of oestrogen and other hormones in pregnancy may lead to increased angiogenesis and formation of abnormal pulmonary vasculature, predisposing pregnant patients to develop haemoptysis.9

The diagnosis of DAH was established in this case on the basis of the patient’s clinical presentation with haemoptysis and anaemia, radiographic finding of new diffuse GGOs, cytological finding of haemosiderin-laden macrophages within the BAL sample, and histopathological finding of haemosiderosis within the surgical lung biopsy specimen. Although the surgical lung biopsy was performed 5 months following the patient’s initial presentation with haemoptysis, by which point the clinical symptoms and radiographic abnormality had resolved, DAH remains the most likely diagnosis to explain this constellation of clinical, radiographic and pathological findings.

Outcome and follow-up

Following her hospitalisation with haemoptysis, the patient had one episode of recurrent dyspnoea and small volume haemoptysis, which resolved with oral tranexamic acid. She subsequently remained asymptomatic with normal serial pulmonary function testing. Follow-up chest CT after 5 months showed resolution of the diffuse GGOs (figure 1E,F). Sirolimus pharmacotherapy was not initiated due to the absence of deterioration in pulmonary function.

Discussion

In accordance with the current clinical guidelines, a definitive diagnosis of LAM may be established in a patient with a compatible clinical history with a characteristic high-resolution chest CT and one or more of the following features: renal angiomyolipoma, thoracic or abdominal chylous effusion, lymphangioleiomyoma, diagnosis of TSC, serum vascular endothelial growth factor-D level >800 pg/mL or histopathological confirmation.2 In the present case, the diagnosis was made based on characteristic high-resolution chest CT and histopathological confirmation, after non-invasive diagnostic work-up did not reveal other supportive features.

The guideline-supported indications for treatment of patients with LAM with sirolimus include abnormal or deteriorating pulmonary function and problematic chylous effusions.2 As the patient had normal pulmonary function and no persistent effusions, pharmacotherapy with sirolimus was not initiated. She experienced one episode of recurrent dyspnoea and small volume haemoptysis after discharge from hospital, which resolved with oral tranexamic acid. It remains unknown whether this event in isolation warrants the initiation of treatment with sirolimus.

In patients with LAM, pulmonary clinical manifestations most commonly include dyspnoea, cough, wheezing, spontaneous pneumothorax, chylous pleural effusion and haemoptysis.10 These have been attributed to proliferation of the abnormal smooth muscle around the airways, lymphatic vessels and blood vessels.11 While haemoptysis has been reported to occur in approximately 30% of patients with LAM, DAH is a rare presentation.10 11 Our literature review identified five prior reports of confirmed DAH in patients with LAM.12–16 In each case, progression to hypoxaemic respiratory failure requiring mechanical ventilation was described and three cases were fatal.12–14 Therapeutic regimens were variable and included positive end-expiratory pressure, systemic corticosteroids, empiric antimicrobials, and in one case endobronchial recombinant activated factor VII.15 Most cases were speculated to have resulted from pulmonary venular obstruction and congestion, with two reports identifying potential precipitants for the acute process: seizure-related neurogenic pulmonary oedema16 and influenza infection during pregnancy.15 16 One report noted histological evidence of pulmonary arterial involvement instead of venular obstruction as the underlying mechanism.14

It is possible that the patient’s postpartum status may have contributed to the severity of her presentation with LAM. Hormonal factors have been proposed to play an important role in LAM, supported by observations that LAM occurs predominantly in premenopausal women and that LAM cells express oestrogen and progesterone receptors.17 Clinical worsening in patients with LAM during or following pregnancy has been described. For example, Johnson and Tattersfield18 found that, in patients with LAM, the overall incidence of complications, such as pneumothorax and chylothorax, was 11 times higher during pregnancy than outside of pregnancy. The patient’s dramatic presentation of LAM with haemoptysis and DAH in this case might be attributable in part to hormonal changes occurring in the postpartum period.

In the present case, DAH occurred in a patient with LAM confirmed on biopsy. While haemosiderosis may be a routine finding on pathology in patients with LAM, the clinical and radiographic findings in this case support the diagnosis of DAH.6 11 19 The absence of an identifiable precipitant and the self-limiting course of the patient’s haemoptysis are distinct from previous reports.

Learning points

  • The differential diagnosis for cystic lung disease includes neoplastic, congenital and infectious causes, as well as processes associated with lymphoproliferative disorders and interstitial lung disease, and mimics include emphysema, cavities, bronchiectasis and honeycombing.

  • A definitive diagnosis of lymphangioleiomyomatosis may be established in a patient with a compatible clinical history with a characteristic high-resolution chest CT and at least one of renal angiomyolipoma, thoracic or abdominal chylous effusion, lymphangioleiomyoma, diagnosis of tuberous sclerosis complex, serum vascular endothelial growth factor-D level >800 pg/mL or histopathological confirmation.

  • Diffuse alveolar haemorrhage is a rare but important clinical presentation in patients with lymphangioleiomyomatosis.

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References

Footnotes

  • Contributors JK, JT: conception and design, acquisition and interpretation of data, drafting and revisions of the report. AH-J, MC: acquisition and interpretation of data, critical revisions of the report.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.