Emerson, Lyska L.

Abstract Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel–Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. Experimental Design: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. Results: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. Conclusions: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

Mycobacterial spindle cell pseudotumor (MSP) is a rare benign spindle cell lesion containing acid-fact mycobacteria. These lesions are most commonly identified in the lymph nodes, skin, spleen, or bone marrow of immunocompromised patients and only rarely involve the lungs. We report 3 cases of pulmonary MSP, which include 2 patients who are known to be HIV-positive. The histopathological diagnosis of MSP in the lung lends itself to many challenges due to its rare incidence and its spindled tumor-like appearance. The differential diagnosis is broad and includes both benign and malignant entities. We highlight the importance of the clinical context in which these lesions typically present and the morphologic spectrum of features seen, and we offer a practical approach to the workup of pulmonary mycobacterial pseudotumor. Appropriate recognition of this entity should lead to an accurate diagnosis of a treatable benign condition despite the clinical presentation often favoring malignancy.