Dyspnea, the subjective inability to breathe comfortably, is a common symptom, accounting for

3 to 4 million ED visits annually.1,2 Dyspnea can be acute, subacute, or chronic, with chronic
dyspnea defined as the presence of symptoms for more than 1 to 2 months, and subacute dyspnea
as symptoms lasting for hours to days.3,4

Dyspnea, ketidakmampuan untuk bernafas dengan nyaman yang sifatnya subjektif, adalah gejala
yang umum, tercatat 3 sampai 4 juta kunjungan ED setiap tahunnya.1,2 Dyspnea dapat bersifat
akut, subakut, atau kronis, dimana dispnea kronis merupakan adanya gejala lebih dari 1 sampai 2
bulan, dan dyspnea subakut merupakan gejala yang berlangsung berjam-jam sampai berhari-hari.
3,4

The reported prevalence of dyspnea based on etiology presenting to the ED is as follows:

malignancy (16% to 77%), chronic heart failure (18% to 88%), chronic obstructive pulmonary
disease (56% to 98%), or renal disease (11% to 82%).5 Irrespective of time course and etiology,
dyspnea can be a debilitating symptom affecting up to 50% of patients admitted to acute, tertiary
care hospitals, and a quarter of patients seeking care in the ambulatory setting.6-13

Prevalensi dyspnea yang dilaporkan berdasarkan etiologi yang dipresentasikan ke ED adalah

sebagai berikut: keganasan (16% sampai 77%), gagal jantung kronis (18% sampai 88%),
penyakit paru obstruktif kronik (56% sampai 98%), atau penyakit ginjal (11% sampai 82%) . 5
Terlepas dari waktu dan etiologi, dispnea dapat menjadi gejala yang melemahkan yang
mempengaruhi hingga 50% pasien yang dirawat di rumah sakit akut dan tersier, dan seperempat
pasien yang mencari perawatan di tempat rawat jalan. 6-13

Lung cancer, the most common cause of cancer-related death in men and women, is responsible
for 1.3 million deaths worldwide annually.1 Mortality from lung cancer remains very high
worldwide. Lung cancer is the leading cause of cancer death in the United States, with an
estimated 565,650 people dying from lung cancers in 2008.2 People with lung cancer experience
symptoms which vary between individuals, resulting in a range of symptoms which people might
find distressing.3 There are several common signs and symptoms associated with lung cancer,
which can be classified as a result of the primary tumor, intrathoracic spread, distant metastases,
paraneoplastic syndromes, or nonspecific symptoms.3 The most common signs and symptoms
relating to a primary lung tumor, and therefore corresponding to early stage disease, are
nonspecific symptoms such as weight loss or fatigue. Cough, dyspnea (distress with breathing or
breathing discomfort), hemoptysis (coughing up blood), and chest discomfort are also common
in the initial stages of lung cancer.3

Kanker paru, penyebab paling umum kematian pada pria dan wanita, bertanggung jawab atas 1,3
juta kematian di seluruh dunia setiap tahunnya.1 Kematian akibat kanker paru masih sangat
tinggi di seluruh dunia. Kanker paru adalah penyebab utama kematian akibat kanker di Amerika
Serikat, dengan perkiraan 565.650 orang meninggal akibat kanker paru pada tahun 2008.2 Orang
dengan kanker paru mengalami gejala yang bervariasi antar individu, mengakibatkan berbagai
gejala yang orang mungkin merasa tertekan.3 Ada beberapa tanda dan gejala umum yang terkait
dengan kanker paru, yang dapat diklasifikasikan sebagai akibat tumor primer, penyebaran
intrathoracal, metastasis jauh, sindrom paraneoplastik, atau gejala nonspesifik.3 Tanda dan gejala
yang paling umum terkait dengan tumor paru primer, dan karena itu sesuai dengan penyakit
stadium awal, adalah gejala nonspesifik seperti penurunan berat badan atau kelelahan. Batuk,
dyspnea (sulit bernapas atau ketidaknyamanan pernafasan), hemoptisis (batuk darah), dan
ketidaknyamanan dada juga umum terjadi pada tahap awal kanker paru.

Etiology

Dyspnea Directly Due to Cancer. Dudgeon et al29reported that the top three malignancies that
directly caused dyspnea are lung, head and neck cancer, and malignancies of genitourinary
origin.29 Reuben21 showed that 75% of patients with tumors involving the lung reported dyspnea
at some point. Metastasis to the mediastinum, especially to the ribs, was associated with higher
levels of dyspnea when compared to metastasis to lung.29

Dyspnea Akibat Kanker. Dudgeon dkk melaporkan bahwa tiga keganasan teratas yang secara
langsung menyebabkan dyspnea adalah kanker paru, kepala dan leher, dan keganasan pada regio
genitourinari.29 Reuben21 menunjukkan bahwa 75% pasien dengan tumor yang melibatkan paru
melaporkan adanya dispnea pada satu titik. Metastasis ke mediastinum, terutama pada tulang
costa, berhubungan dengan tingkat dyspnea yang lebih berat bila dibandingkan dengan
metastasis ke paru.29

Dyspnea Indirectly Due to Cancer. Dyspnea due to indirect causes such as anemia, pneumonia,
and pulmonary emboli may be easier to rectify once diagnosed.

Dyspnea bukan akibat kanker secara langsung. Dyspnea karena penyebab tidak langsung seperti
anemia, pneumonia, dan emboli paru mungkin lebih mudah untuk diobati begitu didiagnosis.

Dyspnea Due to Cancer Treatment. Treatment-related causes of dyspnea include the side effects
of surgery and lung irradiation. Patients with a history of pneumonectomy, lobectomy, or
pleurodesis report higher levels of dyspnea as do patients with a history of thoracic irradiation.
Radiation pneumonitis can occur 6 to 12 weeks following treatment, and radiation fibrosis can
occur 6 to 12 months following treatment.29

Dyspnea Karena Pengobatan Kanker. Penyebab terkait penanganan dyspnea meliputi efek
samping operasi dan iradiasi paru. Pasien dengan riwayat pneumonektomi, lobektomi, atau
pleurodesis melaporkan tingkat dyspnea yang lebih berat seperti pada pasien dengan riwayat
iradiasi toraks. Radiasi pneumonitis dapat terjadi 6 sampai 12 minggu setelah pengobatan, dan
fibrosis radiasi dapat terjadi 6 sampai 12 bulan setelah pengobatan.29

Dyspnea Unrelated to Cancer. Other medical conditions that must be considered when
diagnosing dyspnea include chronic obstructive pulmonary disease, asthma, and congestive heart
failure. Psychological distress—described as anxiety and depression in the cancer population—
may also cause the sensation of dyspnea.25

Dyspnea tidak terkait dengan kanker. Kondisi medis lain yang harus diperhatikan saat
mendiagnosis dyspnea meliputi penyakit paru obstruktif kronik, asma, dan gagal jantung
kongestif. Gangguan psikologis - digambarkan sebagai kecemasan dan depresi pada populasi
kanker - juga dapat menyebabkan sensasi dyspnea.25

Pathophysiology and Psychology

The cause of dyspnea in an oncology patient can be physiological and/or psychological in nature,
with more numerous and unique presentations as compared to dyspnea associated with cardiac or
lung disease. Chemoreceptor stimulation, mechanical stimuli originating in the lung and chest
wall receptors, and neuroventilatory effects all contribute to dyspnea.12,16 Physiological
modalities contributing to dyspnea are outlined in Table 2.

Patofisiologi dan psikologi

Penyebab dyspnea pada pasien onkologi dapat bersifat fisiologis dan / atau psikologis, dengan
presentasi yang lebih banyak dan unik dibandingkan dengan dyspnea yang berhubungan dengan
penyakit jantung atau paru-paru. Stimulasi kemoreseptor, rangsangan mekanis yang berasal dari
paru-paru dan reseptor dinding dada, dan efek neuroventilatory semua berkontribusi pada
dyspnea.12,16 Modalitas fisiologis yang berpengaruh terhadap dispnea dijelaskan pada Tabel 2.

Psychological Contributions to the Etiology of Dyspnea

Dyspnea is subjective and biopsychosocial factors play a large role in an oncologic patient’s self-
report of this condition. Multiple studies demonstrate that objective signs may not match the
patient’s perception of dyspnea.18,21,25 Other studies report a correlation between psychological
distress and worsened perception of dyspnea. Psychological distress is often measured by anxiety
and depression and is also augmented by the presence of pain.

Pengaruh Psikologis terhadap Etiologi Dyspnea

Dispnea bersifat subyektif dan faktor biopsikososial memainkan peran besar dalam laporan
kondisi pasien onkologis. Beberapa penelitian menunjukkan bahwa tanda-tanda objektif
mungkin tidak sesuai dengan persepsi pasien tentang dispnea.18,21,25 Penelitian lain melaporkan
adanya korelasi antara tekanan psikologis dan memburuknya persepsi mengenai dyspnea.
Tekanan psikologis sering diukur dengan kegelisahan dan depresi dan ditambah juga dengan
adanya rasa sakit.

Domain Outcome measure

Symptom intensity visual Analog Scale (vAS), edmonton
Symptom Assessment Scale (eSAS), Dyspnea
Numerical Scale (DNS), Grade of
Breathlessness Scale (GBS), european
Organization for the Research and Treatment
of Cancer Quality of Life Questionnaires
(eORTC-QLQ-C30 and eORTC-QLQ-LC13),
Assessment of Quality of Life at the end of
Life questionnaire (AQeL)
Quality of life Questionnaires

Symptom distress Thurstone Scale of Symptom Distress (TSSD),

Cancer Dyspnea Scale (CDS), Symptom
Distress Scale (SDS), Free-listing

Symptom prevalence Lung Cancer Symptom Scale (LCSS),

Questionnaire, Symptom experience Scale
(SeS), Rotterdam Symptom Checklist (RSCL),
verbal Rating Scale for Dyspnea (vRS), vAS,
interview, Dyspnea Assessment Guide (DAG)

Interview Interview, Free-listing

Domain Hasil terukur

Intensitas gejala visual Analog Scale (vAS), edmonton
Symptom Assessment Scale (eSAS), Dyspnea
Numerical Scale (DNS), Grade of
Breathlessness Scale (GBS), european
Organization for the Research and Treatment
of Cancer Quality of Life Questionnaires
(eORTC-QLQ-C30 and eORTC-QLQ-LC13),
Assessment of Quality of Life at the end of
Life questionnaire (AQeL)

Kualitas hidup Kuesioner

Berat gejala Thurstone Scale of Symptom Distress (TSSD),

Cancer Dyspnea Scale (CDS), Symptom
Distress Scale (SDS), Free-listing

Prevalensi gejala Lung Cancer Symptom Scale (LCSS),

Questionnaire, Symptom experience Scale
(SeS), Rotterdam Symptom Checklist (RSCL),
verbal Rating Scale for Dyspnea (vRS), vAS,
interview, Dyspnea Assessment Guide (DAG)

Wawancara Wawancara, Free-listing

It is clear that a variety of different outcome measures was used to assess the experience of
dyspnea and that varying results were obtained regarding the intensity, prevalence, and distress
associated with dyspnea. Overall, the studies report a high prevalence of dyspnea in lung cancer
patients, with subjects experiencing a moderate level of dyspnea intensity and interference with
activities of daily living. Distress associated with breathing appears to be variable, with

some studies reporting dyspnea to be the most distressing sensation, while others report lower
levels of distress. The language used to describe the qualitative sensation of dyspnea involves
both physical and affective words. Physical descriptors conveying “shortness of breath”,
“difficulty breathing”, and/or “labor” type words were common to all studies; however, with the
exception of “frightening”, the affective terms used to describe dyspnea differ between studies,
although all of the affective terms used indicate considerable distress associated with the
sensation of dyspnea. However, taking into account the prevalence, intensity, and distress of
dyspnea, the general consensus appears to be that the experience of dyspnea in people with lung
cancer is common, with varying degrees of intensity, but involves considerable unpleasantness.
Thus, if dyspnea is a distressing sensation for people with lung cancer, this has potential
implications for both clinical and academic areas with regards to both management strategies and
further research.

Jelas bahwa berbagai ukuran hasil yang berbeda digunakan untuk menilai kejadian dyspnea dan
bahwa hasil yang bervariasi yang diperoleh mengenai intensitas, prevalensi, dan kesulitan yang
terkait dengan dyspnea. Secara keseluruhan, penelitian ini melaporkan tingginya prevalensi
dyspnea pada pasien kanker paru, dengan subjek yang mengalami tingkat intensitas dyspnea
sedang dan gangguan pada aktivitas sehari-hari. Distress yang terkait dengan pernapasan
nampaknya bervariasi, dengan beberapa penelitian melaporkan dyspnea sebagai sensasi yang
paling sulit, sementara yang lain melaporkan tingkat kesulitan yang lebih rendah. Bahasa yang
digunakan untuk menggambarkan dyspnea secara kualitatif melibatkan kata-kata fisik dan
afektif. Gambaran fisik yang menyatakan "sesak napas", "sulit bernafas", dan / atau kata kata
"usaha nafas" biasa terjadi pada semua penelitian; Namun, dengan pengecualian "menakutkan",
istilah afektif yang digunakan untuk menggambarkan dyspnea berbeda antara penelitian,
walaupun semua istilah afektif yang digunakan menunjukkan adanya kesulitan besar terkait
dengan sensasi dyspnea. Namun, dengan mempertimbangkan prevalensi, intensitas, dan tekanan
dyspnea, konsensus umum memperlihatkan bahwa pengalaman dyspnea pada orang dengan
kanker paru sering terjadi, dengan tingkat intensitas yang bervariasi, namun melibatkan banyak
ketidaknyamanan. Jadi, jika dyspnea adalah sensasi yang menyusahkan bagi penderita kanker
paru, ini memiliki implikasi potensial untuk area klinis dan akademis berkaitan dengan strategi
manajemen dan penelitian lebih lanjut.

Lung cancer is the leading cause of cancer death worldwide (Dela Cruz et al, 2011; Kimman et
al, 2012; Siegel et al, 2013), and has had very little improvement in survival during the past 30
years compared with leukaemia and non-Hodgkin’s lymphoma (Siegel et al, 2013). Without
regard to histology, most patients suffer from one or more symptoms at the time of diagnosis
(Soni et al, 2002). The most common symptoms include weakness, cough, dyspnoea,
haemoptysis, chest pain and fever. Haemoptysis, defined as bleeding from lower respiratory
tract, is a common complication of lung cancer. It varies from bloody sputum to fatal pulmonary
haemorrhage. According to a prospective evaluation in a tertiary referral hospital, cancer was the
most common cause of haemoptysis, and was usually associated with mild to moderate amounts
of haemorrhage (Uzun et al, 2010). Based on the amount of haemorrhage per day, haemoptysis
was divided into four categories: mild (o30ml, including blood
sputum or less than two tablespoons), moderate (30–100ml), severe (100–600ml) and massive
(4600ml) (Fidan et al, 2002). Although haemoptysis is one of the most frequent clinical
manifestations of lung cancer, few robust data have been reported about its incidence in patients
before treatment, and the mechanisms of haemoptysis are poorly understood, especially for mild
or moderate haemoptysis. Possible mechanisms include neovascularisation, vascular invasion,
tumour necrosis, trauma due to invasive procedures or cough and so on. Lung adenocarcinoma
accounts for the most common type of lung cancer in many countries (Drilon et al, 2012), and
the presence of baseline gross haemoptysis was identified as a potential risk factor associated
with severe pulmonary haemorrhage in using bevacizumab (Sandomenico et al, 2012). Thus, we
hypothesised that haemoptysis played a more important role than a common clinical symptom.

The purpose of this study was to identify the prognostic value of haemoptysis in lung
adenocarcinoma and to further explore the possible mechanism

Haemoptysis is among the most common respiratory symptoms in lung cancer. It was reported in
B30% to 60% of patients (Reck et al, 2012). Generally, depending on the severity, haemoptysis
is divided into massive haemoptysis and submassive haemoptysis (nonlife-threatening
haemoptysis). According to one retrospective case series, the incidence rates of submassive and
massive haemoptysis in lung cancer were 16.0% and 3.3%,

respectively (Miller and McGregor, 1980). Massive haemoptysis was proved to be related to
tumour type (squamous-cell lung cancer) and location (central tumours). However, such
correlations were not found in nonlife-threatening haemoptysis (Miller and McGregor, 1980).
One previous study reported that 98% haemoptysis of lung cancer was submassive (Uzun et al,
2009). Different from squamous carcinomas, most adenocarcinomas arise from the peripheral
lung (Gazdar and Minna, 1997). In the present study, the incidence of haemoptysis was lower in
peripheral lesions; although central lesions accounted for only a small proportion of lung
adenocarcinomas, it was still a risk factor for submassive haemoptysis. We explored the
association between haemoptysis and clinicopathologic parameters as well as patients’ outcome,
and demonstrated that haemoptysis predicted poor OS, DSS and DFS in lung adenocarcinoma.
Therefore, patients with lung adenocarcinoma who present with haemoptysis can be expected to
have a worse outcome on the average. Our data also showed that central tumour with
haemoptysis group had the poorest outcome, which might be because the tumours in this group
more easily invaded larger blood vessels, despite a potentially countervailing effect of central
tumour location yielding earlier detection and treatment. This information might be important for
judgement on disease severity and treatment decision making. Of note, in our previous study
(Pingping Hu et al), haemoptysis did not predict poor outcome in lung squamous carcinoma (HR,
1.105; 95% confidence interval, 0.808–1.512; P¼0.531). Despite the high incidence and
importance of haemoptysis in lung carcinoma, its mechanisms have not been elucidated. Few
research studies have focussed on haemoptysis from lung cancer, especially submassive
haemoptysis from adenocarcinoma. In a study of haemorrhage in lung cancer, autopsies of
patients who had had massive haemoptysis disclosed extensive inflammation and necrosis of
vascular walls within the tumour bed, but only slight tumour invasion of arterial walls (Miller
and McGregor, 1980). In contrast to this study, vascular invasion by carcinoma was the
immediate cause of pulmonary haemorrhagerelated death in another recent study (Nichols et al,
2012). Inoue et al (2001) demonstrated that VEGF level was significantly higher in patients with
pulmonary haemorrhage (PH) than in those without PH in pulmonary aspergilloma. Our study
first explored the possible mechanisms of haemoptysis in adenocarcinoma; we analysed the
expression of VEGF, extratumoural MVD, tumour necrosis, vascular invasion as well as
coagulation function, and demonstrated that vascular invasion could be the most important
mechanism of haemoptysis in lung adenocarcinoma. Our study showed that patients with
haemoptysis had poor prognosis and a high frequency of vascular invasion. It can be inferred that
cancer cells in haemoptysis patients may have higher invasive potential. Further studies are
required to address this question. Extratumoural blood vessels take part in the pulmonary
vascular circuit and are assumed to be functional vasculature, whereas intratumoural blood
vessels are usually occluded by surrounding cells, and might not always be functional blood
vessels (Shimada et al, 2010). Therefore, only extratumoural MVD were evaluated in our study.
We have demonstrated that the greatest dimension of tumour was larger in haemoptysis group,
which was in line with the former result that with the augment of tumour size, the frequency of
blood vessel invasion increased (Yano et al, 2010; Arame et al, 2012). The level of Fib was
higher in haemoptysis group than nonhaemoptysis group. Generally, high levels of Fib indicate
high risk of thrombosis (Wang et al, 2011; Reck et al, 2012); thus, the elevated Fib level may
reflect the enhanced coagulation associated with haemoptysis. Elevated WBC count was found
in haemoptysis group in the present study. Circulating inflammatory cells correlate with patients’
outcome, as has been demonstrated in a range of tumours. Different inflammatory cell subtypes
may play different prognostic roles. Zhu et al (2011) reported that high levels of peripheral
CD4þCD69þCD25 T cells in hepatocellular carcinoma patients
were significantly correlated with vascular invasion. Distinct subsets of tumour-infiltrating
myeloid-derived suppressor cells (MDSCs) including monocytic-MDSC and granulocytic-
MDSC favoured tumour progression and dissemination, and granulocytic MDSC subset was
shown to be greatly increased in the blood of xenotransplantation model and was also shown to
be upregulated in renal cell carcinoma patients (Ko et al, 2009; Toh et al, 2011; Toh and
Abastado, 2012). Thus, several lines of evidence suggest that there may be some relationship
between tumour invasion, tumour-infiltrating inflammatory cells and circulating inflammatory
cells, which need further experiments to determine.

In conclusion, this is the first study to quantitate the prognostic value of haemoptysis in patients
with lung primary adenocarcinoma. It highlights haemoptysis as an independent predictor of
poor OS, DSS and DFS in lung adenocarcinoma after curative resection. In addition, vascular
invasion rather than angiogenesis or tumour necrosis could be the most important mechanism of
haemoptysis. Therefore, studies of the invasive ability of lung adenocarcinoma in patients
presenting with haemoptysis could supply important information for therapeutic strategy. Such
information may help to predict patient’s outcome early and to provide a rationale for individual
treatment.