Diffuse Alveolar Hemorrhage Caused by Metastatic Breast Cancer

Abstract

A 68-year-old woman presented with a history of hemoptysis. She had been receiving hormone therapy and chemotherapy for recurrent breast cancer. She was diagnosed with diffuse alveolar hemorrhage caused by metastatic breast cancer, as evidenced by increasingly bloody bronchoalveolar lavage fluid and malignant cells in multiple lung lobes. This condition was associated with tumor emboli in the pulmonary vasculature and transformation into a hormone receptor-negative state. Serial changes in chest computed tomography findings, from diffuse patchy ground-glass opacities to multiple nodules, are notable. This rare mode of metastasis may be associated with a poor prognosis.

Introduction

Diffuse alveolar hemorrhage is a life-threatening condition characterized by hemoptysis, diffuse lung opacities, and acute respiratory failure (1). It often develops as a manifestation of autoimmune disease (1-3). One of the most common immune-related causes is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which encompasses granulomatosis with polyangiitis and microscopic polyangiitis. Additional causes include anti-glomerular basement membrane antibody disease and systemic lupus erythematosus (1-3). Non-immune-related causes include congestive heart failure, respiratory infections, and anti-thrombotic drugs (1-3). Direct invasion by neoplastic diseases is an extremely rare cause of diffuse alveolar hemorrhage.

We herein report a case of diffuse alveolar hemorrhage caused by the direct invasion of metastatic breast cancer, presenting serial chest computed tomography (CT) findings.

Case Report

A 68-year-old woman was referred to the Department of Respiratory Medicine and Clinical Immunology at the hospital with a history of hemoptysis and abnormal pulmonary opacities for several weeks. Approximately seven years earlier, she had been diagnosed with right breast cancer, for which she underwent partial mastectomy and a sentinel lymph node biopsy. Subsequently, she began adjuvant therapy with letrozole, which was discontinued after approximately four months owing to hepatotoxicity. Approximately three and a half years after the surgery, her breast cancer recurred in the axillary lymph nodes. A histopathological examination confirmed the tumor's positivity for estrogen and progesterone receptors (100% and 50%, respectively) and human epidermal growth factor receptor 2 (HER2) negativity (1+). She subsequently received hormone therapy and chemotherapy regimens, including tamoxifen, a combination of fluorouracil, epirubicin, and cyclophosphamide, and weekly paclitaxel. At the time of referral, she had been treated with a combination of abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, and exemestane, an aromatase inhibitor, for approximately one year. She was also being treated for latent hepatitis B virus infection with tenofovir alafenamide, and for diabetes mellitus with oral antihyperglycemic agents. The patient had no history of smoking.

On referral, the patient appeared well and reported no dyspnea. She was afebrile, with a blood pressure of 122/66 mmHg, pulse rate of 84 beats per minute, and oxygen saturation level of 98% while breathing ambient air. She reported coughing small amounts of bloody sputum several times daily, particularly in the morning. Chest CT revealed diffuse patchy ground-glass opacities, predominantly in the right lung (Fig. 1A). Laboratory tests revealed elevated lactate dehydrogenase levels, mild leukopenia, and mild thrombocytopenia (Table). Prothrombin and activated partial thromboplastin times were normal, and myeloperoxidase-ANCA and proteinase 3-ANCA test results were negative. Abemaciclib and exemestane were discontinued because of concerns regarding drug-related pulmonary toxicity.

Figure 1.

Chest CT findings. A) On referral, diffuse patchy ground-grass opacities were seen predominantly in the right lung. B) Approximately two weeks after the referral, ground-glass opacities in both lungs worsened. C) Approximately two months after the referral, multiple pulmonary nodules appeared, while the ground-grass opacities disappeared. D) Approximately three months after the referral, multiple pulmonary nodules grew rapidly. Bilateral pleural effusions appeared simultaneously.

Table.

Laboratory Data on Referral.

Variable	On referral	Reference range, this hospital
White blood cell count (/μL)	2,850	3,300-8,600
Differential count (%)
Neutrophils	60.3	45-70
Lymphocytes	32.3	22-48
Eosinophils	2.1	1-5
Basophils	0.7	0-2
Monocytes	4.6	2-8
Hemoglobin (g/dL)	11.7	11.6-14.8
Hematocrit (%)	34.4	35.1-44.4
Platelet count (/μL)	127,000	116,000-148,000
Sodium (mmol/L)	140	138-145
Potassium (mmol/L)	3.9	3.6-4.8
Urea nitrogen (mg/dL)	15	8-20
Creatinine (mg/dL)	0.77	0.46-0.79
Glucose (mg/dL)	183	73-109
Glycated hemoglobin (%)	7.2	4.9-6.0
Lactate dehydrogenase (U/L)	741	124-222
Total bilirubin (mg/dL)	0.8	0.4-1.5
Aspartate aminotransferase (U/L)	50	13-30
Alanine aminotransferase (U/L)	19	7-23
Total protein (g/dL)	7.8	6.6-8.1
Albumin (g/dL)	4.8	4.1-5.1
C-reactive protein (mg/dL)	0.10	0.00-0.14
Prothrombin time (s)	11.8	9.5-12.5
INR for prothrombin time	0.94	0.85-1.15
Activated partial-thromboplastin time (s)	32.1	24-36
MPO-ANCA (U/mL)	<1.0	0-3.4
PR3-ANCA (U/mL)	<1.0	0-3.4
Krebs von den Lungen-6 (U/mL)	2,024	0-499

MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 anti- neutrophil cytoplasmic antibody, INR: international normalized ratio.

Bronchoscopy revealed streaks of blood of an unknown origin around the carina (Fig. 2A). Bronchoalveolar lavage was performed in the middle lobe of the right lung (RB5b) using three 50 mL aliquots of saline, of which 83 mL was recovered. The lavage fluid became increasingly bloody (Fig. 2B). The total cell count of the bronchoalveolar lavage fluid was 2.7×10⁵/mL, with a differential count of 2% neutrophils, 37% lymphocytes, and 61% macrophages. A cytological examination of the lavage fluid revealed clusters of atypical cells with high nuclear-to-cytoplasmic ratios and hyperchromatic irregular nuclei, suggesting adenocarcinoma (Fig. 2C). Hemosiderin-laden macrophages were also observed.

Figure 2.

Bronchoscopic findings. A) Streaks of blood of unknown origin were seen around the carina. B) Bronchoalveolar lavage fluid obtained from the middle lobe of the right lung became increasingly bloody. C) A cytological examination of the lavage fluid revealed clusters of atypical cells with high nuclear-to-cytoplasmic ratios and hyperchromatic, irregular nuclei suggestive of adenocarcinoma (Papanicolau stain). Hemosiderin-laden macrophages were also noted. D) A histopathological examination of the transbronchial lung biopsy revealed tumor emboli in the pulmonary vasculature (Hematoxylin and Eosin staining).

Transbronchial lung biopsies were performed on the upper and lower lobes of the right lung (RB3a and RB8a). A histopathological examination of a transbronchial lung biopsy specimen revealed tumor emboli in the pulmonary vasculature; however, fibrocellular intimal proliferation was not evident in the vessel walls (Fig. 2D). Inflammatory cells were scarce. Immunohistochemistry revealed that the tumor was negative for estrogen and progesterone receptors and positive for GATA-3. Based on these findings, the patient was diagnosed with diffuse alveolar hemorrhage caused by metastatic breast cancer.

Approximately two weeks after referral, chest CT showed worsening ground-glass opacities in both the lungs (Fig. 1B). She started receiving eribulin and subsequently nab-paclitaxel. A small amount of hemoptysis persisted but was manageable with oral or intravenous hemostatic drugs as needed. Despite chemotherapy, the disease progressed. Serial chest CT revealed that multiple pulmonary nodules appeared and grew rapidly, whereas ground-glass opacities disappeared (Fig. 1C, 1D). Bilateral pleural effusion developed simultaneously. Multiple liver and bone metastases also progressed. The patient experienced respiratory failure and required supplemental oxygen therapy. She was transitioned to comfort care and died approximately four and a half months after being diagnosed with diffuse alveolar hemorrhage.

Discussion

The present patient developed diffuse alveolar hemorrhage due to metastatic breast cancer, as evidenced by increasingly bloody bronchoalveolar lavage fluid and malignant cells in multiple lung lobes. This condition was associated with tumor emboli in the pulmonary vasculature and transformation into a hormone receptor-negative status. The patient's clinical course suggests that this rare mode of metastasis may be associated with a poor prognosis. Serial changes in chest CT findings, from diffuse patchy ground-glass opacities to multiple nodules, are notable.

While the possibility of drug-related pulmonary toxicity due to abemaciclib or exemestane cannot be completely excluded, evidence strongly supports metastatic breast cancer as the primary cause of diffuse alveolar hemorrhage. First, the patient had been treated with these drugs for nearly a year without significant side effects. Second, inflammatory cells were scarce in the transbronchial lung biopsy specimens. Third, serial chest CT findings suggested that disease progression, rather than drug toxicity, triggered the hemorrhage. Finally, malignant cells were identified in both bronchoalveolar lavage and transbronchial lung biopsy specimens obtained from different lung lobes, suggesting diffuse pulmonary invasion of the cancer.

De Prost et al. retrospectively analyzed 112 consecutive patients admitted to the hospital for the treatment of diffuse alveolar hemorrhage (2). Among them, 39 had an immune-related cause, including 27 with ANCA-associated vasculitis (16 with microscopic polyangiitis and 11 with granulomatosis and polyangiitis). Two cases were cancer-related: one involving uterine leiomyosarcoma and the other involving small-cell lung cancer. In a similar study, Prasad et al. retrospectively screened 1,000 bronchoalveolar lavage samples and identified 47 patients with diffuse alveolar hemorrhage (3). Of these, 21 were immune-related, including 8 tested positive for myeloperoxidase-ANCA, and 4 for tested positive proteinase 3 ANCA. None of the patients in this cohort had cancer. These findings suggest that diffuse alveolar hemorrhage caused by a neoplastic disease is extremely rare.

However, some specific tumor types appear to be particularly prone to diffuse alveolar hemorrhage. Choriocarcinoma syndrome, a life-threatening complication of poor-risk germ cell tumors characterized by extremely high human chorionic gonadotropin levels, can lead to diffuse alveolar hemorrhage (4-6). In addition, there have been reports of diffuse alveolar hemorrhage associated with angiosarcoma, a rare malignant disease originating from vascular endothelial cells, which is associated with a poor prognosis (7-9). Both neoplastic diseases may predispose patients to hemorrhage. Although several reports have linked diffuse alveolar hemorrhage with hematologic malignancies, these cases are likely caused by immune responses, stem cell transplantation, or chemotherapy drugs (10,11). Other neoplastic diseases reported to cause diffuse alveolar hemorrhage include melanoma (12), gallbladder cancer (13), and lymphangioleiomyomatosis (14).

Triple-negative breast cancer, characterized by the absence of estrogen receptors, progesterone receptors, and HER2, is associated with a more aggressive clinical course and poorer prognosis than hormone receptor-positive breast cancer. Epithelial-mesenchymal transition, marked by the loss of cell polarization and adhesion, has been suggested as an important mechanism involved in the predisposition to metastasis and chemoresistance in triple-negative breast cancer (15). Thus, the epithelial-mesenchymal transition associated with the transformation into hormone receptor-negative might have played an important role in the rapid pulmonary invasion of the cancer in the present patient.

We hypothesize that the alveolar hemorrhage in this case resulted from pulmonary congestion caused by tumor emboli in the pulmonary vasculature, combined with the destruction of vascular structures due to the direct invasion of cancer. However, the precise pathogenesis underlying the transition from diffuse ground-glass opacities to multiple nodules on serial chest CT remains unclear. Pulmonary tumor thrombotic microangiopathy, characterized by rapidly deteriorating respiratory failure associated with widespread tumor microemboli in the pulmonary vasculature (16), might have underlain the pathogenesis of the present patient. However, this could not be confirmed because characteristic pathological findings, including fibrocellular intimal proliferation, were not observed in the transbronchial lung biopsy specimens. We speculated that the patient might have been in the early phase of this condition, as the symptoms were mild when the transbronchial lung biopsy was performed.

In conclusion, metastatic breast cancer can lead to diffuse alveolar hemorrhage, a condition associated with a poor prognosis.

Written informed consent for publication of this case report was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).