A 31-year-old tailor in Kerala, India, spent eight months with a swelling in his right upper thigh that would not go away. Painkillers helped briefly. Walking became difficult. Then a tender swelling appeared on the back of his lower right chest wall.
Imaging found holes in his bones. An X-ray showed a lytic lesion in his right proximal femur. MRI added a lesion in his right pubic bone, with a collection of fluid in the thigh tracking into the femur. A CT scan of his chest revealed an expansile lytic lesion destroying his right ninth rib, with a soft tissue collection over it, plus a cavitary nodule under the pleura of his left lower lung.
The differential diagnosis his doctors started with was the obvious one: tuberculosis, malignancy, or osteomyelitis. He had weight loss, loss of appetite, and evening fevers. It fit.
They were all wrong. The case appears in the August 2025 issue of the Journal of Orthopaedic Case Reports.
Two Months of Tuberculosis Drugs, No Improvement
His sputum grew nothing. Acid-fast staining and TB culture were negative. Tumor markers, including prostate-specific antigen, carcinoembryonic antigen, and CA 19-9, were all normal, and imaging turned up no primary cancer.
With negative tests but a clinical picture that looked like TB, he was given a clinical tuberculosis diagnosis elsewhere and started on antitubercular therapy. In a country with a high TB burden, that is a defensible call.
Two months later, he was no better, and he presented to a tertiary hospital. Repeat imaging showed that the lesions in his thigh and chest wall had grown. A full repeat workup, including acid-fast staining, culture, nucleic acid amplification testing, and a QuantiFERON-TB Gold test, came back negative and ruled out tuberculosis.
The Answer Came from Fungal Cultures and a Question About Birds
Doctors aspirated fluid from the thigh lesion and from the right posterior chest wall, and performed fine-needle aspiration cytology on the affected rib. They sent cytology, extended culture for atypical organisms, and fungal culture.
Most of it was unrevealing. The fungal culture was not. Cryptococcus neoformans grew from the thigh, from the chest wall collection, and from his blood. Spinal fluid cultures were negative, which ruled out the meningitis that cryptococcosis most often causes.
That prompted a different question. Because Cryptococcus is strongly associated with bird droppings, doctors asked about exposure. He kept pigeons at his home. He had also had allergic respiratory symptoms since 2015, treated intermittently with an inhaler, suggesting the lung may have been the original site with spread through the bloodstream to bone.
According to the CDC, C. neoformans is found worldwide in the environment, is inhaled, and most people who are exposed never get sick. Serious disease is concentrated among people with weakened immune systems.
Why Fungal Bone Lesions Get Read as Cancer
Skeletal involvement is reported in roughly 5% to 10% of disseminated cryptococcosis cases, and the imaging offers no distinctive signature. The authors note that skeletal cryptococcosis frequently mimics metastatic malignancy because it lacks typical radiological features, a point made in earlier reports describing cryptococcal bone lesions that looked malignant on aspiration biopsy.
The pattern is not confined to bone. In a 2022 report published in Medicine, a 21-year-old college student with normal immune function presented with fever, cough, and red skin nodules. A PET/CT showed hypermetabolic lymph nodes above and below the diaphragm and hot skin nodules, and the scan read as malignant lymphoma. An inguinal lymph node biopsy and blood culture revealed cryptococcosis; after antifungal treatment, most of the abnormal nodes disappeared.
A 2024 case in BMC Infectious Diseases described an Indonesian man, previously healthy and immunocompetent, with osteolytic lesions across the sternum, ribs, and humeral head, plus a nodule in the right lower lung.
A Hidden Immune Defect Was Driving It
The Kerala patient's HIV test was negative. He had no diabetes, no transplant, no steroid use, no immunomodulators, and no malignancy.
So his doctors kept looking. Clinical exome sequencing, lymphocyte subset analysis, an immunoglobulin profile and immune function testing revealed isolated CD4 lymphocytopenia, with a CD4 count of 75. The CDC defines idiopathic CD4 lymphocytopenia as an unexplained deficiency of circulating CD4 cells below 300 per cubic millimeter in the absence of HIV or another identifiable cause. Its origins remain unclear, and management centers on treating and preventing opportunistic infections.
He was started on amphotericin B with fluconazole, and the antitubercular drugs were stopped. Treatment included an intravenous phase, a consolidation phase with oral fluconazole, and maintenance, along with trimethoprim-sulfamethoxazole prophylaxis to prevent pneumocystis pneumonia.
At one year, repeat MRI showed that the femur and pubic lesions had consolidated; CT of the chest showed that the lung and rib lesions had resolved completely; and his inflammatory markers remained normal. He was symptom-free.
The case is a reminder that a lesion that looks like cancer or tuberculosis is a hypothesis rather than a diagnosis, and that cultures and tissue samples settle arguments that imaging cannot.
For the general public in the United States, cryptococcosis remains uncommon and is concentrated among people with significant immune compromise. It is not a reason for healthy people to fear birds, and bone pain and lytic lesions have many causes, most of them not fungal.
The more useful lesson is about persistence. When treatment for a presumed diagnosis produces no improvement, and the lesions keep growing, that is information. Patients in that position are entitled to ask whether the original diagnosis was ever confirmed by culture or biopsy, and whether unusual infections have been excluded.
Key Questions Answered
What was wrong with this patient?
He had disseminated cryptococcosis, a fungal infection that had spread to his right femur, pubic bone, ninth rib and lung, producing bone-destroying lesions that initially looked like cancer or tuberculosis.
How was the correct diagnosis finally made?
Fine-needle aspiration and fungal cultures from the thigh lesion, the chest wall collection, and his blood all grew Cryptococcus neoformans; after repeated tuberculosis testing, they came back negative.
Where does this fungus come from?
Cryptococcus neoformans is found worldwide in the environment, including soil and bird droppings, and is inhaled. This patient kept pigeons at his home.
Why did he get so sick when most people do not?
Testing revealed isolated CD4 lymphocytopenia, an immune deficiency in which CD4 cells are low without HIV or another identifiable cause, leaving him vulnerable to opportunistic infection.
How often does cryptococcosis attack bone?
Skeletal involvement is reported in roughly 5% to 10% of disseminated cases. Because it produces no distinctive imaging pattern, it is frequently mistaken for metastatic cancer or tuberculosis.
Did he recover?
Yes. After antifungal treatment with amphotericin B and fluconazole, his chest lesions resolved completely, his bone lesions consolidated, and he remained symptom-free at one-year follow-up.
