Breaking the mold! A rare lung neoplasm in childhoodTo The Editor,A previously healthy 8-year-old Caucasian male presented to his primary care provider (PCP) for evaluation of cough and fever for 1 month. A viral respiratory panel detected rhinovirus/enterovirus, and a chest X-ray obtained was concerning for a right middle lung nodule measuring 1.3 centimeters (cm) by 1.4 cm, without calcification (Figure 1A-B). The remainder of the lung fields were normal. Chest computed tomography (CT) scan without contrast redemonstrated the nodule in the right upper lobe, now described as a lobulated solid nodule without calcification or fat, extending from the parenchyma to the pleural surface measuring 1.5 x 1.6 x 1.2 cm (Figure 1C), without any lymphadenopathy.Patient was referred to pulmonary. His onset of fever occurred around the time that the family moved into a new home where mold exposure was detected. Overall, the fevers were low grade between 100.4- 101 F and sporadic. Cough was described as dry and had been improving since his PCP visit. No other pertinent medical or environmental history other than a paternal history of BRCA1 gene pathogenic variant was noted. The examination was normal and a full set of pulmonary function testing including basic spirometry, plethysmography, and diffusing capacity of the lungs for carbon monoxide (DLCO), which were all normal for age.The patient was referred to infectious disease, where he underwent a comprehensive workup. Evaluation included inflammatory markers, CBC, fungal antibody panel (histoplasma, blastomycoses, aspergillus, and coccidioides by complement fixation and immunodiffusion), histoplasma IgM/IgG EIA, histoplasma antigen (blood and urine), tuberculosis interferon gamma release assay, cat scratch disease antibodies, uric acid, and lactate dehydrogenase. Results were all within normal limits, except for an intermediate histoplasmosis EIA IgM. Repeat testing three weeks later was negative for histoplasma IgM EIA and remained negative for histoplasma antibody by IgG EIA, immunodiffusion, and complement fixation. Collectively, these results indicated a low probability of acute histoplasmosis or other infectious etiology.The decision to proceed with a biopsy was conferred. Patient underwent CT guided needle biopsy by interventional radiology and tolerated the procedure well. The sample obtained was three 1 cm 18-gauge cores. Pathologic analysis revealed a lesion with small spaces lined by cuboidal cells with hyperchromatic, hobnail nuclei resembling pneumocytes, containing focal papillary structures. The stroma was focally fibrotic and, in some areas, round to oval larger, paler cells were found. Both cell populations appeared positive for Thyroid transcription factor 1 (TTF-1) and Epithelial Membrane Antigen (EMA) staining (Figure 1E-F). Both of these stainings are used to detect lung epithelial cells. Overall, these findings were consistent with pulmonary sclerosing pneumocytoma (PSP).The patient was referred to cardiothoracic surgery for excisional biopsy. A video-assisted thoracoscopy (VATS) wedge resection was performed and well tolerated. The nodule was successfully removed with clear negative margins (Figure 1D). Histologic evaluations demonstrated similar findings as those observed in the biopsy specimen. Considering that AKT1 pathogenic variants have been reported in many cases of PSP, the patient’s tumor and blood were subjected to Somatic Disease/Germline Comparator Exome (SDGC) testing that identified a somatic AKT1 variant [c.236_243delins AKT1- NM_001382430.1] and a germline pathogenic variant in BRCA1 [c.4182_4183dup BRCA1- NM_007294.4]. The germline BRCA1 variant correlated with that in the father who had not developed any neoplasm, and in a paternal aunt with breast carcinoma. He remains in good health 3 months following resection.This unique case highlights a rare benign lung tumor and a further atypical patient demographic considering the propensity of PSP to occur in middle-aged Asian women. Previously known as pulmonary sclerosing hemangioma, it was first described in 1956 by Liebow and Hubbell1, due to belief that these tumors were sclerosing variants of hemangiomas2. However, recent immunohistochemical studies strongly suggest the origin from respiratory epithelium, particularly type II pneumocytes. Most recently, the World Health Organization (WHO) classified these to adenomas/epithelial tumors1.This condition is typically diagnosed in the fifth decade of life with a high female predominance (female:male ratio of 5:1) and more commonly found in the Asian population. Most patients are asymptomatic (50-70%) with tumors incidentally detected on chest imaging1. However, when symptoms are present, they present commonly hemoptysis, cough, or chest pain1,3. Despite the common occurrence in middle-aged individuals, there are reports of occurrence in children as young as 1 years old3.PSP is often considered as a solitary, peripheral, well-defined, homogenous nodule with rare cases of bilateral presentation. There are no pathognomonic radiological characteristics for PSP. On a gross examination, lesions appear as well-circumscribed, firm tan masses that usually measure 0.3-7 cm in size with focal areas of hemorrhage, usually located close to the pleural surface1. Occasionally, they contain areas of calcification and may even show an air-meniscus sign: crescentic radiolucency at the periphery of a lung nodule2. PSP is histologically characterized by the presence of two cell types: cuboidal surface epithelial cells and round stomal cells. The surface cells resemble type 2 pneumatocytes2,4 and both cell populations have identical immunophenotype with expression of EMA and TTF-1. The principal growth patterns encountered include: papillary, solid, angiomatoid, sclerotic, or a combination of these four patterns2,5,6.Genomic studies found recurrent pathogenic variants in AKT1 , which encodes a protein kinase in the mammalian target of rapamycin (mTOR) pathway6. Although these variants occur in 78% of PSP cases, it is relatively uncommon in human neoplasm, found only in 1.6% of all cancers. The mTOR pathway is an intracellular signaling pathway that plays a critical role in regulation of the cell cycle4,5. Given this evidence, it seems AKT1 pathogenic variants are particularly responsible for most of the aberrant cell signaling that drive PSP pathogenesis4,5. The AKT1 variant was identified in our patient.Even though PSP is a rare benign neoplasm, it does have a rare potential to metastasis to the lymph nodes, especially to mediastinal and hilar nodes. One reported case series even suggested that younger male patients are more likely to metastasize5. However, hematogenous spread has not been detected in patients to date. Given the risk of metastasis, limited resection is highly recommended, which is curative without the need for adjunctive therapies1.Eric S. Mull, DOab, Rachel Gaudio, DOab, Brent Adler, MDc, Sergio A. Carrillo, MDd, Jonathan R. Honegger, MDeb, Rachel Supinger MS, LGCf, Nicoleta C. Arva, MD, PhDg, Miriam Conces, MDg, Melanie Babcock, PhDbgi, Nathan Fagan, MDh, Grace R. Paul, MDabaDivision of Pulmonary Medicine;bDepartment of Pediatrics;cDepartment of Radiology;dDepartment of Cardiothoracic Surgery;eDivision of Infectious Diseases;fDivision of Pediatric Genetics;gDepartment of Pathology and Laboratory Medicine;hDepartment of Interventional Radiology;iThe Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s HospitalColumbus, OhioInstitution: Nationwide Children’s Hospital; Columbus, OHFunding Source: NoneFinancial Disclosure: NoneConflicts of Interest: NoneConsent: Obtained and on fileIRB: Reviewed and letter of exemption on filePer my institution’s policy:“For a case report (1-2 cases), an investigator does not need prior IRB review and approval if: (a) the records accessed are available to the investigator for clinical reasons (i.e., they or direct colleagues were involved in the care of this patient), (b) the records being reviewed contain data that were collected as part of routine clinical care (i.e., this policy does not deal with the use of existing research databases), and (c) the data are reviewed in a retrospective manner (because knowing upfront that a case report may be written could potentially lead to additional evaluations being done which would not have been obtained for clinical care reasons). If any of these do nothold, then the case report needs to be reviewed and approved by the IRB.For any case series or case report (regardless if IRB reviewed or not), every reasonable attempt should be made by the author to contact the patient and/or family or the primary caregiver of the patient so as to inform them of the proposed publication. If applicable, the author must comply with the patient’s/family’s request not to publish the report OR to present the case in a more deidentifiable manner. HIPAA may still apply to case reports. Please contact the Privacy Office (privacyoffice@nationwidechildrens.org) for guidance and possible patient authorization required.” (pages 7-8)Reference:Manickam R, Mechineni A. Pulmonary Sclerosing Pneumocytoma: An Essential Differential Diagnosis for a Lung Nodule. Cureus. 2022 Jan 10;14(1):e21081.Bara A, Adham I, Daaboul O, Aldimirawi F, Darwish B, Haffar L. Sclerosing pneumocytoma in a 1-year-old girl presenting with massive hemoptysis: A case report. Ann Med Surg (Lond). 2021 Jan 8;62:49-52.Pal P, Chetty R. Multiple sclerosing pneumocytomas: a review. J Clin Pathol. 2020 Sep;73(9):531-534.Boland JM, Lee HE, Barr Fritcher EG, Voss JS, Jessen E, Davila JI, Kipp BR, Graham RP, Maleszewski JJ, Yi ES. Molecular Genetic Landscape of Sclerosing Pneumocytomas. Am J Clin Pathol. 2021 Feb 11;155(3):397-404.Boland JM, Lee HE, Barr Fritcher EG, Voss JS, Jessen E, Davila JI, Kipp BR, Graham RP, Maleszewski JJ, Yi ES. Molecular Genetic Landscape of Sclerosing Pneumocytomas. Am J Clin Pathol. 2021 Feb 11;155(3):397-404.Nasr Y, Bettoli M, El Demellawy D, Sekhon H, de Nanassy J. Sclerosing Pneumocytoma of the Lungs Arising in a Child With PTEN Mutation. Pediatr Dev Pathol. 2019 Nov-Dec;22(6):579-583.