Circulating hybrid cells predict presence of occult nodal metastases in oral cavity carcinoma

Abstract

Background Levels of circulating hybrid cells (CHCs), a newly identified circulating tumor cell (CTC), correlate with disease stage and progression in cancer. We investigated their utility to risk‐stratify patients with clinically N0 (cN0) oral cavity squamous cell carcinoma (OCSCC), and to identify patients with occult cervical lymph node metastases (pN+). Methods We analyzed peripheral blood samples for CHCs with co‐expression of cytokeratin (tumor) and CD45 (leukocyte) from 22 patients with cN0 OCSCC using immunofluorescence microscopy, then correlated levels with pathologic lymph node status. Results CHC levels exceeded CTCs and correlated with the presence of both clinically overt (p = 0.002) and occult nodal metastases (p = 0.006). Conclusions For evaluated cN0 OCSCC patients, those with cN0 → pN+ status harbored elevated CHC levels compared to patients without occult disease. Our findings highlight a promising blood‐based biologic assay with potential utility to determine the necessity of surgical neck dissection for staging and treatment.

Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer

“…Similarly, monitoring the population of triple negative circulating cells in a patient with ER + or HER2 + breast cancer in targeted therapy may allow early identification of the emerging resistant disease. Additionally, for CHCs it is yet to be determined whether they are direct effectors of metastatic risk; however, longitudinal monitoring of CHCs or other circulating effector cell populations may have clinical utility in predicting the metastatic risk at diagnosis and after curative-intent procedures or therapeutics [ 104 , 105 ].…”

“…While cell fusion occurs in both homeostatic and noncancerous inflammatory states [ 91 , 92 , 93 ], it has recently been described in malignancy [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Heterotypic cell fusion hybrids are generated in cell co-culture [ 29 ], in vitro murine models of injury-regeneration [ 94 , 96 ], in tumorigenesis [ 29 , 103 ], and in human cancer patients [ 29 , 33 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. Much like the sampling of a tumor’s genome and proteome by CAMLs, tumor-immune hybrid cells harbor immune and neoplastic cell attributes, and thus provide important information with regard to tumor state and the tumor microenvironment.…”

“…Further, they demonstrated that the number of larger, so-called “giant” CHCs independently predicted survival [ 111 ]. Additionally, CHC enumeration showed promise in the pre-operative setting for oral cavity HNSCC by predicting the presence of both clinically overt and occult nodal metastases [ 105 ]. Strikingly, CHC levels following neoadjuvant therapy for either rectal or esophageal adenocarcinoma adequately discriminated a pathologic complete response from an incomplete response and were associated with the recurrence risk in esophageal adenocarcinoma [ 104 ].…”

Hybrid/Atypical Forms of Circulating Tumor Cells: Current State of the Art

“…It was established in different studies of the patients with various gastrointestinal cancers [ 80 , 82 ] that there was a decrease in the levels of hybrids in blood after chemotherapy. Increase of the CHCs concentration in blood of the patients with oral carcinomas allowed Henn et al (2021) predicting the emergence of hidden metastases in lymph nodes, thus providing an opportunity to avoid the highly invasive neck dissection, which leads to complications in 25% of the cases [ 81 ].…”

Clinical applications of liquid biopsy in HPV‐negative and HPV‐positive head and neck squamous cell carcinoma: advances and challenges

“…A recent study has demonstrated the so-called circulating hybrid cells (CHCs) in oral cavity squamous cell carcinoma [ 76 ], which consist of lineages that mix the profile of neoplastic cells with macrophages, expressing EPCAM and/or CKs, in addition to leukocyte-determining proteins, such as CD45. Interestingly, high levels of CHCs were correlated with the occult nodal metastases presence, but in contradiction, they were not correlated with the tumor stage [ 76 ]. Therefore, CTCs in HNSCC follow a traditional expression pattern of epithelial biomarkers, such as CKs.…”