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The great majority of primary pulmonary neoplasms are represented by non-small cell carcinomas-adenocarcinoma and squamous cell carcinoma. In addition, there is another group of neoplasms such as those of neuroendocrine origin that also represent a meaningful subset of primary lung neoplasms. Basically, any other tumor that is not in these groups of tumors may represent an unusual lung neoplasm. To highlight more recently described unusual tumoral entities that may represent a challenge in diagnosis and that require awareness of their existence. This is a review of 3 different entities: bronchiolar adenoma, adenofibroma, and hemangioblastoma-like clear cell stromal tumor. These tumoral conditions are rare, and a review of the literature is presented. The most relevant morphologic, immunohistochemical, and molecular aspects of bronchiolar adenoma, adenofibroma, and hemangioblastoma-like clear cell stromal tumor are presented. The difficulty of arriving at an unequivocal diagnosis in small biopsies is highlighted. The 3 entities represent uncommon tumors occurring primarily in the lung and a diagnostic challenge not only in biopsy specimens but also often in surgically resected specimens. The use of immunohistochemical stains and in some cases of molecular diagnostics is of aid in arriving at final interpretation.

Thymic epithelial neoplasms are rare tumors that are difficult to diagnose and treat. Programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed by various malignancies and are considered a prognostic factor and immunotherapeutic target. We examined the expression of both antibodies in 100 thymic epithelial neoplasms to assess their use as a biomarker and to correlate their expression with clinicopathological parameters. Whole-tissue sections of 74 thymomas and 26 thymic carcinomas were examined. Expression of PD-1 and PD-L1 was evaluated by immunohistochemistry and scored by the percentage of positive T-cells or tumor cells, respectively. Cases with strong membranous reactivity of the antibody in ≥5% of T-cells (PD-1) or tumor cells (PD-L1), respectively, were considered positive. Expression of PD-1 was detected in 52/100 cases (52%) including 6/26 thymic carcinomas (23%) and 46/74 thymomas (62%). PD-L1 was positive in 61/100 cases (61%) including 14/26 thymic carcinomas (54%) and 47/74 thymomas (64%). A total of 82 cases (82%) showed expression of PD-1 or PD-L1. PD-1+ cases were associated with higher stage in thymic carcinoma (P=0.01) and PD-1− cases with thymic carcinoma histology (P=0.0014), whereas PD-L1+ cases were associated with neoadjuvant therapy in thymoma (P=0.0065). There was no statistical difference between PD-1 or PD-L1 expression status and other clinicopathological parameters including overall survival. PD-1 and/or PD-L1 are expressed in up to 82% of thymic epithelial neoplasms. These results confirm that these tumors should be considered for PD-1/PD-L1-targeted therapy, however their predictive value in terms of prognosis remains uncertain.

Pure mediastinal yolk sac tumor is an uncommon and aggressive malignant germ cell neoplasm that presents considerable diagnostic difficulties owing to its pronounced clinical and morphological variability. Mediastinal yolk sac tumors, in contrast to their gonadal equivalents, typically occur at later stages, are typically associated with mixed germ cell components, and have a diverse array of histologic patterns that may resemble both germ cell and somatic malignancies. Accurate identification of these types of cancer is essential since diagnostic misclassification may significantly impact treatment and prognosis. This review provides a comprehensive overview of the morphologic spectrum of mediastinal yolk sac tumor, with emphasis on both classic and variant histologic patterns, including reticular, solid, glandular, papillary, hepatoid, and other less common growth forms. The immunohistochemical correlations of these patterns and their role in resolving diagnostic dilemmas are discussed, along with key differential diagnoses encountered in small mediastinal biopsy specimens. Particular attention is given to the limitations of limited tissue sampling, the impact of post-chemotherapy morphologic changes, and the potential for misinterpretation in this challenging anatomic site. By integrating morphologic features with clinical, radiologic, and laboratory findings, this review aims to enhance diagnostic accuracy and improve recognition of mediastinal yolk sac tumor across its diverse presentations.

The clinicopathologic and immunohistochemical features of 65 primary thymic carcinomas are reported (43 men and 22 women; 19-81 years old). Thymectomy was performed in all cases. Masaoka staging for 53 patients showed 3 patients in stage I, 14 in stage II, 17 in stage III, and 19 in stage IV. Histologic studies revealed 9 carcinoma subtypes. Immunohistochemically, the tumors showed high rates of expression for cytokeratin, Pax8, and FoxN1. Follow-up for 62 patients revealed that 36 patients were alive (mean follow-up, 51.1 months) and 26 had died (mean survival, 47.5 months). The 3- and 5-year overall survival rates were 76.6% and 65.7%, respectively. Our findings suggest that thymic carcinomas may behave less aggressively than commonly believed. Lymph node status and tumor size seem to be important prognostic factors. The Masaoka staging system does not seem to reliably predict outcome.

Primary carcinomas of the lung are vastly represented by the conventional types of adenocarcinomas or squamous cell carcinomas. However, there are other types of non-small cell carcinomas that although uncommon represent a meaningful group that often pose a problem not only in diagnosis but also in classification. Spindle cell and/or giant cell carcinomas, although uncommon represent an important group of primary lung carcinomas. Important to highlight is that current criteria are rather ambiguous and likely not up to date, which renders the classification of these tumors somewhat more obscure. In addition, with the daily use of immunohistochemical stains, the classification of these tumors may also pose a different problem in the proper allocation of these tumors. Proper classification is highly important in the selection process that takes place using such material for molecular analysis. The current molecular characteristics of these tumors are limited and lack more in-depth studies and analyses that can provide specific targets for the treatment of patients with these tumors. The current review attempts to highlight the shortcomings in the current classification and definitions of these neoplasms as well as the more current view regarding these tumors when the use of immunohistochemical stains is employed.

Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

Thymomas are rare tumors that usually manifest in the anterosuperior mediastinum. Occasionally, thymomas may also originate from ectopically dispersed thymic tissue and can arise in locations such as the neck, lung, or pleura or other locations in the thoracic cavity. The occurrence of thymomas in these ectopic locations can cause substantial diagnostic difficulty as the entity is almost never included in the differential diagnosis and its biphasic morphology can cause further complications during the diagnostic process. In this review, we summarize the clinical and pathological spectrum of ectopic thymomas and discuss the histogenesis, treatment, and prognosis of these extraordinary tumors.

Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A . To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4 -deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors. SMARCA4 loss in non-small-cell lung cancer creates a metabolic dependency on oxidative phosphorylation that can be targeted using a new small-molecule inhibitor.

Studying the cellular geographic distribution in non-small cell lung cancer is essential to understand the roles of cell populations in this type of tumor. In this study, we characterize the spatial cellular distribution of immune cell populations using 23 makers placed in five multiplex immunofluorescence panels and their associations with clinicopathologic variables and outcomes. Our results demonstrate two cellular distribution patterns—an unmixed pattern mostly related to immunoprotective cells and a mixed pattern mostly related to immunosuppressive cells. Distance analysis shows that T-cells expressing immune checkpoints are closer to malignant cells than other cells. Combining the cellular distribution patterns with cellular distances, we can identify four groups related to inflamed and not-inflamed tumors. Cellular distribution patterns and distance are associated with survival in univariate and multivariable analyses. Spatial distribution is a tool to better understand the tumor microenvironment, predict outcomes, and may can help select therapeutic interventions. The spatial distribution of cellular compartments within the tumour microenvironment in non-small cell lung cancer (NSCLC) remains to be investigated. Here, the authors identify distinct cell populations of tumour cells and tumour-associated immune cell phenotypes with different spatial distributions in NSCLC.

Five cases of an unusual variant of thymic carcinoma are described, which represent the counterpart of the so-called micronodular thymoma with lymphoid hyperplasia. The patients were three men and two women aged 42–78 years (mean 64 years). Three patients were asymptomatic and the tumors were found incidentally on chest radiographs performed for unrelated reasons. Two patients complained of dyspnea, chest pain and shortness of breath prompting further investigations. The tumors ranged in size from 3.2 to 10.0 cm and were described as infiltrative masses often invading adjacent structures. Prominent cystic changes were not identified. Histologically, the neoplasms were composed of epithelial tumor cells arranged in a micronodular growth pattern set in a stroma showing florid lymphoid hyperplasia. Contrary to micronodular thymoma, the epithelial cell component of the present cases showed unequivocal signs of malignancy characterized by cytological atypia and increased mitotic activity. Immunohistochemical studies showed the lymphoid component to be of mixed B- and T-cell lineage. None of the patients had a history of myasthenia gravis or other autoimmune disorder. Follow-up revealed that 4 patients were alive and well 3–26 months after diagnosis while 1 patient was dead of disease 21 months after diagnosis. The tumors in this series represent a distinct subtype of thymic carcinoma histologically strongly resembling micronodular thymoma with lymphoid hyperplasia. Awareness of this type of thymic carcinoma is important in order not to dismiss this tumor for a neoplasm of lower-grade malignancy.