Cryptococcal Granulomatous Inflammation in Immunocompetent Pediatric Patients Presenting as Hepatic Space-occupying Lesions

To the Editors: Certain infectious or inflammatory hepatic conditions, such as inflammatory pseudotumor, liver abscess, tuberculoma and syphilitic gingival tumor, may exhibit imaging characteristics that closely resemble those of malignant neoplasms.1 Cryptococcosis is an infection triggered by Cryptococcus, a fungus encountered globally and particularly prevalent among individuals with immunocompromised conditions or chronic illnesses.2 This fungus is typically derived from pigeon droppings and soil. Once its spores are inhaled into the lungs through the respiratory tract, they can subsequently enter the bloodstream and spread throughout the body. However, dissemination to the liver and mesentery is rare. When the condition is identified early and treated with antifungal medication promptly, a full recovery is achievable. A 5-year-old Chinese girl was admitted to a local hospital with a 5-day history of high fever (40 °C), cough and intermittent abdominal pain. Following 3 consecutive days of ineffective piperacillin-tazobactam treatment and an abdominal computed tomography (CT) examination, the patient was referred to our hospital with an initial diagnosis of a liver tumor. She exhibited no signs of chronic respiratory disorders, neurological disturbance or bone pain. General physical examination revealed no evidence of pallor, jaundice, cyanosis, finger clubbing or superficial lymphadenopathy. The abdomen exhibited slight distension; however, neither the liver nor the spleen demonstrated palpable enlargement beneath the costal margins. The laboratory findings were as follows: a white blood cell count of 26 × 109/L, a hemoglobin level of 116 g/L, a platelet count of 307 × 109/L, a C-reactive protein level of 89 mg/L, and coagulation function was normal. Serum biochemical analyses revealed that both renal and hepatic function tests remained within normal limits. Serological analyses for Brucella, hepatitis B surface antigen, HIV and hepatitis C antigen, along with chest radiography and GeneXpert assays for acid-fast bacilli, all yielded negative results. The Mycoplasma pneumoniae DNA test result was negative, and similarly, the detection of parasite-associated antigen also yielded a negative result. The profiles of T and B cell subsets remained within normal limits. Peripheral blood and bone marrow smears appeared unremarkable. An enhanced CT scan revealed numerous soft tissue density lesions throughout the abdomen, accompanied by multiple hepatic lesions (Fig. 1A). Additionally, a small amount of pelvic effusion was detected, although its etiology remained indeterminate. Further differential diagnosis was warranted to distinguish these findings from lymphoma or neuroblastoma, the latter known for widespread tissue and organ infiltration. CT imaging of the chest revealed evidence of pneumonia. Ultrasound imaging revealed several focal hepatic lesions, which are highly suggestive of hematological diseases, and there was notable enlargement of the hepatic hilum and mesenteric lymph nodes accompanied by diffuse hepatomegaly (Fig. 1B). At the same time, the serum test detecting the Cryptococcus capsular polysaccharide antigen produced a positive outcome. The next step entails determining the primary location of the infection.FIGURE 1.: A: Multiple nodular soft tissue masses of varying sizes were observed in the liver, hilar region and hepatogastric space. These masses exhibited heterogeneous mild enhancement on contrast-enhanced scans, with a degree of enhancement lower than that of the surrounding normal liver parenchyma. Additionally, blood vessels were visible within the hilar mass. B: B-ultrasound imaging revealed an enlargement of the mesenteric lymph nodes.Under ultrasound guidance, a puncture biopsy was performed on the liver and mesenteric mass. Hematoxylin and eosin staining (H&E) revealed granulomatous inflammation with evidence of fungal invasion (Fig. 2A), and subsequent Hexamine silver staining (Fig. 2D) and periodic acid-schiff staining (Fig. 2C) confirmed the presence of cryptococcal infection. The distinct outline of Cryptococcus is observable via fluorescence staining (Fig. 2B). Examination of the specimens revealed no malignant cells. High-throughput sequencing of pathogenic microbial nucleic acids using biopsy specimens revealed a sequence count of 5657 for C. neoformans, representing a relative abundance of 74.78%. Routine blood culture further confirmed the presence of cryptococcal infection. These findings provide compelling evidence supporting the diagnosis of hepatic granulomatous inflammation secondary to cryptococcosis. However, her parents unequivocally denied prior exposure to pigeon droppings. The cerebrospinal fluid assay for cryptococcal polysaccharide antigen yielded a negative result.FIGURE 2.: Staining of liver biopsy samples. A: Hematoxylin and eosin(H&E) staining revealed a significant number of spherical, encapsulated structures(black arrow). B: The distinct outline of Cryptococcus is observable via fluorescence staining(red arrow). C: Periodic acid-Schiff staining revealed a substantial number of spherical structures, each delineated by a red outer membrane (red arrows). D: Hexamine silver staining identified numerous small, black, yeast-like organisms (yellow arrow).Following the diagnosis of cryptococcosis in the liver and mesenteric lymph nodes, the patient underwent a 3-week intravenous fluconazole treatment at a daily dose of 12 mg/kg, accompanied by nutritional support therapy. In addition, a 2-week course of oral fluconazole at 200 mg per day was administered. After a 2-week post-treatment period during which the patient's body temperature remained within the normal range, the patient was discharged from the hospital. Following discharge, the patient continued antifungal therapy for 5 months. During 6 months of routine follow-up, abdominal B-ultrasound examinations documented the gradual resolution of the lesions. The uniqueness of this case lies in that, given the child's age and the presence of abdominal lesions observed in imaging studies, neuroblastoma was initially suspected; however, the detection of a positive serum cryptococcal capsular polysaccharide antigen result raises the possibility of an alternative diagnosis, and subsequent biopsy findings established a diagnosis of disseminated cryptococcosis. In addition to well-documented impacts on the pulmonary and central nervous systems, atypical clinical manifestations of cryptococcosis may complicate diagnosis and contribute to delays in treatment. Cryptococcosis is a rare but often fatal disease that primarily affects immunocompromised individuals. This case describes a patient with cryptococcosis presenting with atypical symptoms and immunocompetence. Following a comprehensive review and analysis of the case, 3 critical factors have been identified that warrant careful consideration during the diagnostic process. First, within our hospital, cryptococcosis occurs more frequently in children with normal immune function than in those with immunodeficiency. According to a survey conducted by Chinese scholars, most children diagnosed with Cryptococcus exhibited normal immune function, without underlying diseases or identifiable risk factors.3 Young individuals who do not present apparent immune deficiencies remain at risk for cryptococcosis, despite its increased prevalence among immunocompromised hosts. Second, the selection of diagnostic methods for cryptococcal infection is critically important. A positive cryptococcal antigen test serves as a critical indicator for establishing a conclusive diagnosis in this case, although the precise location of the infection remains undetermined. A variety of laboratory techniques are available for diagnosing cryptococcosis, including India ink microscopy, fungal culture, antigen detection and molecular biology methods. Notably, detecting the Cryptococcus capsular polysaccharide antigen significantly streamlines the diagnostic process and reduces the time required to obtain results. Compared with alternative diagnostic methods, antigen detection demonstrates superior performance due to its sensitivity, specificity and overall effectiveness, enabling early diagnosis, often preceding the onset of clinical symptoms, and thereby mitigating the progression of the disease to life‐threatening cryptococcosis.4 Third, hepatic cryptococcosis is characterized by tumor-like lesions in the liver, which are nonspecific. Since the patients are preschool-aged children, certain imaging examination features, such as multiple abdominal density shadows and hepatomegaly, are indicative of abdominal metastasis associated with neuroblastoma. Based on previous reports, the radiological features of hepatic cryptococcosis exhibit considerable variability, reflecting a diverse array of underlying pathological characteristics.5 When we were unable to determine whether the liver lesions identified through imaging were benign or malignant, antigen detection provided invaluable diagnostic guidance. Subsequent examinations further validated the accuracy of these antigen results, allowing us to avoid unnecessary surgical interventions. If pathogen infection cannot be definitively ruled out despite comprehensive examination, it is imperative to improve our understanding of Cryptococcus neoformans, particularly among immunocompetent children. This case underscores the critical importance of prioritizing the sequence of diagnostic assessments for hepatic cryptococcosis.