Although CM is much more common in non-HIV patients with predisposing factors, including malignancy [2, 12], there has been little information about the clinical features and prognosis of these patients. To our knowledge, the present study was the largest and most detailed series of CM cases in non-HIV patients with malignancy. In this study, we found that a longer time to diagnosis and worse prognosis in CM patients with malignancies and PET-CT might be a useful tool for screening malignancy in such patients.
Early researches have shown that malignancies, especially lymphomas [7–9], appear to be closely associated with cryptococcosis. Since then, there have been many case reports of cryptococcal infections as malignancy complications [13–15]. These pioneering studies warned a close relationship between malignancy and CM, and this may be due to the malignancy-related immune alteration or lymphocyte-depleting chemotherapeutic regimens . Unlike previous studies that found CM in malignancy patients, our present study focused on CM patients, retrospectively analyzed and looked for potential malignant tumors. We found that most patients in our study had solid malignancies (except one lymphoma), and they were all epithelial origin. In immunocompromised genetically modified mice and immunodeficiency populations, the incidence of malignancy has increased significantly [16–18]. These phenomena were thought to be related to the decline in the ability of immunosurveillance. According to this perspective, CM and malignancy may share the same immune abnormality mechanism.
In current study, the incidence of CM with malignancy was 3.75%, which was much higher than that of the general population . Two recent retrospective studies have reported even higher rates of malignancy in CM patients [20, 21]. We found that malignancy was usually found in older CM patients, older than 50 years should be more vigilant about the possibility of malignancy. Up to 50% of CM patients with malignancy were hospitalized between 1 and 3 months after clinical symptoms appear, while 70.78% of non-malignancy CM patients were within one month of onset. This discrepancy suggested a significant difference in the severity of clinical symptoms between the two groups, which might be more prominent in patients without malignancy. Comparing the intracranial pressure between the two groups did not reach a statistical difference, we considered the possible reason was that CM patients with malignancy were older. It is generally believed that the elderly are less sensitive to pain. Therefore, the clinical symptoms in CM patients with malignancy were atypical, which caused a delay in CM diagnosis.
Literature review analysis found that only less than 15% of patients with cryptococcus infection associated with malignancy were solid . However, recent studies have found that the incidence of CM patients with solid malignancies was roughly equivalent with haematologic [20, 21]. The present study described 12 malignancies in 320 CM patients, of which only one was haematologic. In the 7 MBC patients, the types of malignancy and the affected organs were varied, and they had good antifungal response and low mortality. In contrast, 5 MAC patients mainly involved the digestive and respiratory systems, with a mortality rate of 80%. We suggest that three main reasons might respond for the poor prognosis of MAC: 1) they were older, and senior has been confirmed to indicate a poor prognosis of CM [21, 22], 2) when the malignancy was found, most of the patients lost the chance to treat the malignancy due to CM, 3) the patients and his family abandoned active therapy.
Early screening of malignancies is difficult . The sensitivity of different tests in screening of different types of malignancies is inconsistent. Of the 5 MAC patients in this study, only one patient found a lung cancer in routine chest CT. PET-CT is a non-invasive imaging test that has a unique advantage in the detection of early malignancies [24, 25]. In a variety of solid tumor and organ infiltrating leukemias, lesions of less than 5 mm can be found by PET-CT with 18F-FDG radioactive probes [26, 27]. In the 104 patients who underwent PET-CT examinations, five patients were prompted to have suspected malignancies, and 4 were eventually confirmed. Therefore, we recommend routine PET-CT examinations for CM patients older than 50 years in order to detect possible early malignancy in time.
Our study had limitation. In view of the economic cost, not all patients undergo detailed malignancy screening. The possibility of missed malignancy diagnosis may exist. The clues of this possibility can be observed in the lower malignancy rate in without PET-CT patients than in PET-CT ones.