Lung-Seeking Metastases

Abstract

Metastases from different cancer types most often affect the lung parenchyma. Moreover, the lungs are among the most frequent sites of growth of metastatic masses of uncertain/unknown lineage of origin. Thus, with regards to pulmonary neoplastic parenchymal nodules, the critical issue is to determine if they are IN the lung or OF the lung. In this review, we highlight the clinical, instrumental and molecular features which characterize lung metastases, mainly focusing on recently advancing and emerging concepts regarding the metastatic niche, inflammation, angiogenesis, immune modulation and gene expression. A novel issue is related to the analysis of biomechanical forces which cooperate in the expansion of tumor masses in the lungs. We here aim to analyze the biological, genetic and pathological features of metastatic lesions to the lungs, here referred to as site of metastatic growth. This point should be a crucial part of the algorithm for a proper diagnostic and therapeutic approach in the era of personalized medicine.

Keywords: biomarkers; biomechanics; lung; metastases; metastatic niche.

Figure 1

Lung metastases: imaging and immunostaining. In patients with known primary tumors, the appearance of multiple bilateral pulmonary nodules is highly suggestive of metastatic dissemination and no further invasive procedures are generally required to confirm diagnosis. Chest X-Ray (CXR) has shown little sensitivity over the years, relegating it to marginal use in low-risk patients or to be abandoned entirely as a surveillance method. While lung metastases can still be detected by CXR in specific scenarios, such as incidental findings in the emergency room, computed tomography is the main imaging modality employed for detection and follow-up of lung metastases. Panel (A) CT scan presentation of lung metastases: (a) usual features of lung metastases from colorectal cancer, (b) squamous cell lung cancer of unknown primary (CUP), (c) miliary distribution of secondary lesion from ovarian cancer, (d) multiple metastatic nodules from breast cancer. Hematogenous spread to the lungs most often characterizes those tumors which arise in organs with anatomical venous drainage towards the lungs, such as head and neck, thyroid, adrenals, kidneys, testes, melanoma, and osteosarcoma. Panel (B) Computed tomography (CT) presentation of lung metastases. Computed tomography is the main imaging modality employed for detection and follow-up of lung metastases. They generally appear as round and non-calcific nodules of variable dimensions, with smooth margins and a variable degree of vascularization. However, more unusual patterns can be detected as well (such as a miliary distribution or metastatization in the form of a single lung nodule). CRC = colorectal cancer, SCC = squamous cell carcinoma, CUP = Cancer of unknown primary.

Figure 2

Immunohistochemical evaluation to detect the major origin of metastatic lesions: Panel (A) key screening antibody panel to detect the lineage of origin. It should be noted that melanoma is positive for vimentin but not for desmin, except for rare cases such as osteogenic melanoma which might express desmin [22] and sinovial mucosal melanoma [23]. In sarcoma desmin is not always expressed. For instance, solitary fibrous tumors and hemangioperycitoma like tumors are generally negative for desmin, as well as epitheliod sarcomas [24]. EMA = Epithelial Membrane Antigen, PLAP = Placenta Alkaline Phosphatase, Panel (B) once the diagnosis of carcinoma is reached, the cytokeratin expression may be useful to further delineate the tissue or organ of origin. The differential expression of CK 7 and CK 20 is among the most relevant discriminants of carcinomas of epithelial origin.

Figure 3

The journey of metastatic clones towards the lungs. The growth of metastatic masses into the lung parenchyma is orchestrated by tumor-derived signals (e.g., exosomes and genetic signatures). Once detached from the primary mass, metastatic clones invade blood (or lymphatic) vessels. Based on the interaction with adhesion molecules and based on the cross talk with chemokines and cytokines, cells reach the lung parenchyma and extravasate and colonize the pre-metastatic niche. Here, they undergo an epithelial-to-mesenchymal transition and interact with the surrounding stroma, which contributes to cell survival and growth. Moreover, smoke-induced chronic inflammation and hypoxia promote macrophage recruitment and immunotolerance.