A 70-year-old woman who formerly used tobacco was referred for evaluation of a lung nodule incidentally discovered during hematologic follow-up. Her medical history was notable for a stage IV follicular lymphoma (G2/G3A stage IV, for pleural and perinephric involvement, FLIPI4) in September 2022, for which she received 6 courses of obinutuzumab plus bendamustine. After the second cycle of therapy, an increase in transaminases was detected; the subsequent diagnostic workup showed a positive real-time polymerase chain reaction blood test for human herpesvirus 6 DNA with more than 13,000 copies/mL. The human herpesvirus 6 infection was successfully treated with acyclovir, followed by normalization of liver enzymes. The treatment was then completed regularly, obtaining a complete metabolic response. One month after completing therapy, the patient developed systemic cytomegalovirus infection with associated pneumonia, requiring 3 weeks of hospitalization. Considering the severity of the infectious event, a further maintenance with obinutuzumab was excluded. Persistent cytomegalovirus-DNA levels necessitated valganciclovir. Sustained neutropenia partially improved with granulocyte colony-stimulating factor administration.

A 67-year-old man who currently smoked (45 pack-years) was referred to the emergency department for fever and exacerbation of cough over the last week. The current illness began 1 month earlier with nonproductive cough and exertional dyspnea. He did not report anorexia, hemoptysis, or weight loss. Outpatient treatment with cefditoren and moxifloxacin did not improve his symptoms. No remarkable medical history was reported. The patient was admitted for further evaluation.

A 57-year-old man presented to the hospital with a 6-year history of slowly progressive persistent cough, shortness of breath, and wheezing. He had been prescribed budesonide and oxygen therapy 2 months prior for presumable asthma, but his symptoms had not subsided. He had been intermittently using 2 L oxygen via nasal canula with exertional activities until the day of hospitalization. He first experienced similar symptoms 5 years prior, and a workup at that time showed multiple tiny pulmonary nodules. His history was notable for a remote 27-pack-year smoking history, quitting 10 years prior, and he was diagnosed with asthma 2 years before his presentation. His occupational history included 17 years working in Israel with polished granite, quartz, and artificial marble. He denied exposure to asbestos, beryllium, radon, or chemicals, aluminum, semiconductors, dental materials, cosmetic powders, or talc. The patient denied environmental exposures such as black mold, hot tubs, or birds. Preceding our assessment, the patient had undergone a chest CT scan 6 years prior, revealing profound chronic alterations in the pulmonary architecture alongside mediastinal adenopathy. Three of his previous chest CT scans found numerous nodules of varying sizes throughout both lung fields, which had remained relatively stable over the years.

Dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway rarely results in parenchymal lung disease, prototypically multifocal multinodular pneumocyte hyperplasia (MMPH) and lymphangioleiomyomatosis (LAM). Although LAM can occur sporadically, to our knowledge, MMPH has not previously been described independent of tuberous sclerosis complex (TSC), a syndrome caused by germline mutations in the tumor suppressor genes TSC1 or TSC2. We report the case of a man with a history of multiple malignancies who presented with incidental chest imaging findings of innumerable ground-glass nodules and several air-filled cysts, offering a diagnostic challenge. Histopathologic findings on lung biopsy identified nodular foci of pneumocyte hyperplasia with negative Human Melanoma Black-45 staining. Next-generation DNA sequencing of the tissue showed a previously described gain-of-function mutation in MTOR. We propose that this patient's TSC-like pulmonary disease is a direct result of this mutation, a novel finding that underscores the role of Next-generation DNA sequencing in cryptic histopathology.