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.