3 DISCUSSION
We report a case of IPA occurring three weeks after the initiation of
corticosteroid treatment for hepatocellular carcinoma. Most solid tumors
associated with IPA are reported to be lung or head and neck cancers
[4], but to the best of our knowledge, there have been no previous
reports of cases of coexisting hepatocellular carcinoma. We suspect that
the development of IPA was induced by the addition of corticosteroid to
hepatocellular carcinoma in the background of cirrhosis, and
prophylactic administration of antifungal drugs may be an option to
consider when corticosteroid is used, especially in patients with
cirrhosis.
IPA is recognized as an infection that occurs in patients with
hematologic malignancies, especially during neutropenia, but in recent
years, it has been estimated that 43–80% of patients with IPA do not
have hematologic malignancies [5]. The non-hematological populations
at risk are diverse and include patients with solid organ
transplantation, AIDS, solid tumors, COPD, and influenza infection.
However, patients with these various conditions were frequently excluded
from past studies of antifungal agents, and often, they do not meet the
European Organization for Research and Treatment of Cancer/Invasive
Infectious Diseases Study Mycoses Group diagnostic criteria of IPA,
leaving several clinical aspects unexplored [6]. Limited reports
indicate that the prevalence of IPA in solid tumors ranges from 0.7 to
2.6% [7,8]. The most common type of cancer is lung cancer, followed
by head and neck, breast, and gastrointestinal cancers, but there have
been no reports of hepatocellular carcinoma. However, it was recently
pointed out that cirrhosis is also one of the risk factors for the
development of IPA [9,10], and it is speculated that
cirrhosis-related immune dysfunction, which involves immunodeficiency
and disturbance of specific immune system cells, including not only
neutrophils and monocytes but also T and B cells, may be the root cause
[11]. Therefore, we believe that evaluating the complication of
cirrhosis in patients with hepatocellular carcinoma is important to
accurately assess the risk of IPA.
Corticosteroid treatment has been widely reported to be a risk factor
for the development of IPA, with a higher incidence in non-neutropenic
patients, critically ill non-cancer patients, and patients with COPD,
cirrhosis, and AIDS [7,12–15]. The suppression of neutrophil
function by corticosteroid is a contributing factor in the promotion ofAspergillus colonization and infection [16]. It is also noted
that approximately two-thirds of patients who develop IPA while on
corticosteroid do not have a fever, which can easily lead to a delay in
diagnosis [17]. Corticosteroid can place patients at high risk of
developing IPA at cumulative doses of more than 700 mg of prednisolone
equivalent [17], and careful consideration should be given to
long-term or high-dose corticosteroid treatment in general. The use of
prophylactic antifungal drugs should be considered as an option if the
risk of developing IPA is considered high [5], and risk assessment
must take into account both the underlying disease and the treatment
received. Our patient developed IPA shortly after the start of
corticosteroid therapy, and we hypothesize that the presence of both
cirrhosis and corticosteroid use may have triggered the development of
IPA. However, it is interesting to note that the patient developed
pneumomediastinum and subcutaneous emphysema shortly before the onset of
IPA. A definitive interpretation of this process is difficult to make,
but possible causes include tissue fragility due to corticosteroid and
bronchial wall damage due to a central airway lesion called
pseudomembranous tracheobronchitis caused by Aspergillus[18,19]. Bronchoscopy could have been useful in evaluating airway
lesions, although it could not be performed in this case due to the
extremely poor general condition.
Although the association of nontuberculous mycobacterium (NTM) infection
with pulmonary aspergillosis, especially chronic progressive pulmonary
aspergillosis, has been noted before [20–22], few reports have
pointed out an association between NTM and IPA. The CT scans of our
patient showed predominantly infiltrative shadows and ground-glass
opacities without centrilobular nodules, and we presumed these findings
to indicate a vascular-invasive IPA rather than an airway-invasive IPA.
The chest images also showed that the right upper lobe lesion caused by
the M. avium pulmonary disease remained improved whereas new left
lower lobe infiltrative shadows appeared in a normal lung with no
pre-existing lesions, suggesting that IPA may have occurred without
apparent association with the M. avium pulmonary disease. We
believe that M. avium pulmonary disease is unlikely to have
played a significant role in the development of IPA in this case and
speculate that the effects of cirrhosis and corticosteroid, which can
affect systemic immune function, may have been more significant than the
localized lung disease.
We often use corticosteroid to reduce symptoms in the palliative care of
patients with solid tumors, and in many of these attempts, the
corticosteroid can be effective [23–25]. However, the overall
picture of adverse events from corticosteroid is not fully clarified,
and it is also noted that the implementation of antifungal prophylaxis
is low in solid tumors compared to hematologic malignancies [26].
The prognosis of IPA is extremely poor, and clinicians need to discuss
with patients whether to provide prophylaxis when using corticosteroid
or to conduct surveillance for the early detection of IPA.
In conclusion, we experienced a case of invasive pulmonary aspergillosis
in a patient with hepatocellular carcinoma. The patient had underlying
alcoholic liver cirrhosis, and the initiation of systemic corticosteroid
may have triggered development of IPA. When starting corticosteroid in
patients with hepatocellular carcinoma, it is important to confirm the
presence of cirrhosis and, if necessary, to provide prophylactic
treatment for IPA with antifungal agents and to monitor the incidence of
IPA.