Contrast-enhanced and indirect computed tomography lymphangiography accurately identifies the cervical lymphocenter at risk for metastasis in pet dogs with spontaneously occurring oral neoplasia

PLOS ONE RESEARCH ARTICLE Contrast-enhanced and indirect computed tomography lymphangiography accurately identifies the cervical lymphocenter at risk for metastasis in pet dogs with spontaneously occurring oral neoplasia Stephanie Goldschmidt ID1*, Nikia Stewart2, Christopher Ober1, Cynthia Bell3, Amber Wolf-Ringwall ID1, Michael Kent4, Jessica Lawrence ID1 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States of America, 2 VETCT, Orlando, Florida, United States of America, 3 Specialty Oral pathology for Animals, Geneseo, Illinois, United States of America, 4 Department of Surgical and Radiologic Sciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America * Abstract OPEN ACCESS Citation: Goldschmidt S, Stewart N, Ober C, Bell C, Wolf-Ringwall A, Kent M, et al. (2023) Contrastenhanced and indirect computed tomography lymphangiography accurately identifies the cervical lymphocenter at risk for metastasis in pet dogs with spontaneously occurring oral neoplasia. PLoS ONE 18(3): e0282500. https://doi.org/10.1371/ journal.pone.0282500 Editor: Sameh Attia, Justus Liebig University Giessen, GERMANY Received: December 15, 2022 Accepted: February 16, 2023 Published: March 2, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0282500 Copyright: © 2023 Goldschmidt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For dogs with oral tumors, cervical lymph node (LN) metastasis alters treatment and prognosis. It is therefore prudent to make an accurate determination of the clinical presence (cN+ neck) or absence (cN0 neck) of metastasis prior to treatment. Currently, surgical LN extirpation with histopathology is the gold standard for a diagnosis of metastasis. Yet, recommendations to perform elective neck dissection (END) for staging are rare due to morbidity. Sentinel lymph node (SLN) mapping with indirect computed tomography lymphangiography (ICTL) followed by targeted biopsy (SLNB) is an alternative option to END. In this prospective study, SLN mapping followed by bilateral END of all mandibular LNs (MLNs) and medial retropharyngeal LNs (MRLNs) was performed in 39 dogs with spontaneously occurring oral neoplasia. A SLN was identified by ICTL in 38 (97%) dogs. Lymphatic drainage patterns were variable although most often the SLN was identified as a single ipsilateral MLN. In the 13 dogs (33%) with histopathologically confirmed LN metastasis, ICTL correctly identified the draining lymphocentrum in all (100%). Metastasis was confined to the SLN in 11 dogs (85%); 2 dogs (15%) had metastasis beyond the SLN ipsilaterally. Contrast enhanced CT features had good accuracy in predicting metastasis, with short axis measurements less than 10.5 mm most predictive. ICTL imaging features alone were unable to predict metastasis. Cytologic or histopathologic SLN sampling is recommended prior to treatment to inform clinical decision-making. This is the largest study to show potential clinical utility of minimally invasive ICTL for cervical LN evaluation in canine oral tumors. PLOS ONE | https://doi.org/10.1371/journal.pone.0282500 March 2, 2023 1 / 22 PLOS ONE Data Availability Statement: All relevant data are within the paper and its Supporting information files. Funding: University of Minnesota Grant in Aid PI: SG, CO-I: JL,CO,NS Grant #: 1801 - 11652 - 20562 - 4214572 https://research.umn.edu/fundingawards/grant-aid The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. CT lymphangiography for canine oral tumors Introduction Cervical lymph node (LN) metastasis is a negative prognostic factor for oral malignant melanoma (OMM), mast cell tumor (MCT), and oral squamous cell carcinoma (OSCC) [1–9]. Yet, there is currently a lack of consensus among specialists for LN staging methodologies in canine oral tumors [10]. The gold standard for diagnosis of LN metastasis remains histopathologic diagnosis; however, palpation, computed tomography (CT) features, and fine needle aspiration cytology are commonly utilized to provide an assessment of the clinical presence (cN+ neck) or absence (cN0 neck) of metastasis [10]. In dogs with OMM, LN palpation is inaccurate in detecting metastatic disease with up to 40% of LNs deemed normal on palpation harboring metastasis [11]. CT allows evaluation of the shape and size of the cervical LN to predict metastasis, but sensitivity varies widely from 12–83% [12,13]. FDG-PET-CT does not improve detection of metastasis compared to contrast-enhanced CT alone [13]. Fine needle aspiration cytology has moderate accuracy for canine cervical LNs, with one study reporting a false negative rate of 8.1% for head and neck tumors [14]. Specific neoplastic types present additional challenges for cytologic detection, with reported false negative rates of up to 36% in dogs with OMM and oral fibrosarcoma compared to histopathological assessment [3,15,16]. The lack of consistent detection of cervical LN metastasis prior to treatment limits the ability to quantify the absolute impact of metastasis on progression-free survival. Furthermore, canine oral lymphatic drainage is unpredictable and up to 62% of oral tumors have contralateral dissemination [17]. Clinicians often sample ipsilateral and contralateral LNs in dogs with oral tumors. However, only the lateral mandibular LNs (MLNs) or grossly abnormal LNs on palpation are often sampled due to their superficial, accessible location. Two histopathologic studies evaluated all 3 lymphocentrums ipsilateral to head and neck neoplasia and found that 26.7–45.5% of neoplasms spread to LNs other than the MLNs [14,18]. In another study of OSCC and OMM, 6% of dogs had medial retropharyngeal LN (MRLN) metastasis without concurrent spread to an ipsilateral MLN [19]. This highlights the potential for incomplete staging if only the lateral MLN is sampled, which could affect surgical or radiotherapy approaches. Concerns surrounding missing occult cervical metastasis have led to recommendations for pathologic staging (pN+ versus pN0 neck) of all, or a subset of, cervical LNs with elective neck dissection (END) [20–22]. END carries a risk of surgical morbidity including post-operative edema, seroma formation and infection. While major compl (...truncated)