Introduction
Hemoptysis is often a life-threatening symptom and may cause severe
clinical conditions. Causes of hemoptysis are varied, and include
bronchiectasis, infection (e.g., tuberculosis, pneumonia, fungal
infection), trauma, pulmonary vascular disease, iatrogenic injuries, and
airway malignancies 1-4. Pulmonary artery pseudoaneurysm (PAP) is a rare
cause of hemoptysis, but careful consideration should always be given as
it is potentially fatal. In fact, there have been several reports on the
occurrence of PAP during radiation therapy against lung cancer. We
encountered a 65-year-old male lung cancer patient with hemoptysis due
to rupture of PAP induced by thoracic radiation therapy (TRT). An
autopsy was performed and we herein report the detailed clinical,
radiological, and pathological findings. Written informed consent was
obtained from his relatives.
Case report
A 65-year-old male was diagnosed with lung squamous cell carcinoma and
TRT at 60 Gy total in 30 daily fractions was started. Nausea and
vomiting were present at the end of the therapy. Decreased breathing
sounds was observed in the upper left side of the chest where TRT had
been performed. The laboratory results showed white blood cell (WBC)
count of 15,100/mm3 and C-reactive protein (CRP) level
of 16.14mg/dl. Chest CT revealed consolidation and cavity in the left
upper lobe. He was thus diagnosed as lung abscess and treated with the
intravenous antibiotics, meropenem, for three weeks. His clinical and
radiographic findings consequently showed improvement. However, he had
hemoptysis after the antibiotic treatment and intravenous contrasted
chest CT revealed left PAP (Figure 1). He coughed up a massive amount of
blood before his scheduled PAP-embolization and could not be
resuscitated due to airway occlusion.
Autopsy was performed on the next day after death. Macroscopic findings
showed cavity in the left upper lobe leading to the left pulmonary
artery and whole lung edema was observed (Figure 2A, 2B). Moreover,
blood coagulation was found in the trachea and main bronchus (Figure
2C). Microscopic findings showed that the arterial wall had been damaged
with fibrin drainage based on Elastica van Gieson stain (Figure 3A, 3B).
The lung abscess wall included squamous cell carcinoma cells (Figure
3C).
Discussion
Although the rate of PAP occurrence is rare, bronchiectasis, infection,
trauma, iatrogenic, vascular disease, and airway malignancy are its
major causes 1-3. Pseudoaneurysm is defined as focal blood vessel
dilation that does not involve all arterial wall layers, while aneurysm
is defined as that which involves all three arterial wall layers 5. The
precise mechanism of PAP formation has not yet been elucidated. In our
current case, microscopic findings showed arterial wall disruption by
inflammation together with invasion of squamous cell carcinoma, which
affected the adventitia and the tunica media (Figure 3A). Boerrigter et
al recently proposed that structural changes of elastin and collagen
under the influence of an increasing PA pressure may lead to PA dilation
and further PAP formation 6. This disruption and the abnormal formation
of the arterial vessel may be further exacerbated by radiation therapy.
Since PAP is a fatal condition, prompt and appropriate diagnosis is
essential in the clinical setting. Although pulmonary angiography is the
gold standard for PAP diagnosis 7- 9, contrast-enhanced CT enabled PAP
diagnosis with less invasiveness 10. AP is defined as an upper limit of
the main pulmonary artery (PA) diameter (29 mm) and an upper limit of
the right interlobar artery (17 mm) measured using CT images 10. The
present case fulfilled this criteria (upper limit of the main PA
diameter was 31 mm and upper limit of the right interlobar artery was 19
mm). In past reports, maximum intensity projection (MIP) and multi
planar reconstruction images on CT have been useful for PAP diagnosis
11.
Previous literature has indicated that lung cancer is associated with
PAP formation 12-20. In cases with lung cancer-associated PAP, it is
possible that tumor invasion to blood vessels may result in PAP
formation 14. To the best of our knowledge, there have been twelve cases
of pseudoaneurysm accompanied with lung cancer and squamous cell
carcinoma was the most frequent in the reported cases (Table 1). Six
patients survived without any intervention, while four patients died
(two were unknown). It is well known that lung squamous cell carcinoma
characteristically presents with hemoptysis 21. Razazi et al reported
that 125 patients had hemoptysis related to non-small cell lung
carcinoma, and in those patients, the proportion of squamous cell
carcinoma was 52% 21. Moreover, tumor cavitation during cancer
treatment has been suggested as a risk factor for hemoptysis 21. In the
present case, we hypothesize that PAP caused by squamous cell lung
carcinoma together with a tumor cavity may be a significant risk factor
for massive hemoptysis.
Additionally, radiation therapy is known to cause vascular diseases
including PAP 22. Schultz et al reported radiation therapy causes acute
up-regulation of pro-inflammatory cytokines and adhesion molecules in
the endothelium that recruits inflammatory cells to the sites of
vascular injury 23. Martin et al subsequently proposed a mechanism of
radiation-induced vascular disease whereby resultant oxidative stress
causes nuclear factor-kappa B (NF-κB) activation that in turn causes
inflammatory cytokine up-regulation 24. Moreover, pre-existing cardiac
disease has been significantly associated with development of cardiac
events in lung cancer patients who have received radiation therapy. In
Netherlands, 23% lung cancer patients had developed cardiovascular
disease 25. In Table1, four patients had received radiation therapy for
lung cancer treatment before PAP diagnosis (two had received combined
chemotherapy with radiation therapy, and two including our case had
received radiation therapy alone). As with these cases, there was
possibility that PAP development was accelerated by radiation therapy in
our case.
Endovascular and percutaneous interventional procedures are often used
for PAP treatment. Percutaneous intervention is a less invasive option
than surgical treatment. While the primary intervention is the
embolization of systemic arteries, other therapeutic options may be
considered depending on the size and location of the PAP 10.
Unfortunately the current case had died from massive hemoptysis before
receiving intervention therapy.
Conclusions
In summary, we encountered a lethal clinical course of pulmonary artery
pseudoaneurysm after thoracic radiation therapy against lung squamous
cell carcinoma. It is important to note that PAP could be a fatal cause.
In patients with hemoptysis or bloody sputum, it is critical to detect
and diagnose PAP, and if present, to conduct timely and appropriate
interventional therapy.
Acknowledgements
The authors gratefully acknowledge the support of the medical staff of
Department of Pathology at Showa University Hospital for great
assistance and contributions for our study.
Author contributions
Conceptualization: Yosuke Fukuda
Investigation: Tomoki Uno, Yasunori Murata, Shintaro Suzuki
Supervision: Tetsuya Homma, Eisuke Shiozawa, Masafumi Takimoto
Writing – original draft: Yosuke Fukuda
Writing – review & editing: Hironori Sagara
References
1 Corder R. Hemoptysis. Emerg Med Clin North Am . 2003;21:421-435.