Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers.

Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Metastatic merkel cell carcinoma to the thyroid gland: Case report and review of the literature.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive and rare neuroendocrine tumor, accounting for less than 1% of skin cancers. Metastasis primarily manifests in the cervical lymph nodes but rarely affect the thyroid. METHODS: We report a case of primary head and neck cutaneous MCC with metastasis to the thyroid gland. A review of the literature of MCC with thyroid metastasis was conducted. RESULTS: We identified five cases of MCC with thyroid metastasis. Primary sites included the distal upper and lower extremities, axilla, buttock, and groin. Treatment courses varied including thyroidectomy, immunotherapy, and expectant palliative measures. Time from initial diagnosis to thyroid metastasis ranged from four months to four years. Tissue diagnosis was achieved in 5 of 6 cases. CONCLUSIONS: MCC with thyroid metastasis is rare and likely represents aggressive disease. Despite advances in treatment and surveillance, outcomes for MCC remain poor. Ongoing research may establish predictors for treatment response.

Thyroid cancer necrosis not evident on imaging: A cautionary case series on poorly differentiated thyroid carcinoma diagnosed only on final pathology.

OBJECTIVE: Poorly-differentiated thyroid cancer (PDTC) is a highly aggressive malignancy which is recently defined and understudied in the radiologic literature. Necrosis is a key histopathologic criterion for the diagnosis of PDTC. We illustrate the current difficulty in accurate identification of histopathologic necrosis on preoperative imaging. METHODS: A series of seven patients with the final diagnosis of PDTC from our institution were identified. Multimodality preoperative imaging was analyzed by two head and neck radiologists. Final pathology reports were queried confirming histopathologic evidence of necrosis. RESULTS: Patients presented with a wide range of preoperative imaging features. A consistent imaging appearance confirming necrosis was not identified. All patients were subsequently upstaged to PDTC following final pathological analysis. CONCLUSION: A lack of definitive evidence of necrosis on preoperative imaging does not exclude the possibility of PDTC. We demonstrate the need for further research to establish a clear methodology for the preoperative diagnosis of PDTC.

Extratumoral invasion: A unique phenomenon of aggressive recurrent oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous carcinomas cause significant morbidity and mortality. Poor prognosticators include lymphovascular and perineural invasion. Extratumoral phenotypes of these histologic findings confer worse prognoses. METHODS: We report eight cases of recurrent oropharyngeal cancer with diffuse extratumoral lymphovascular invasion (ELVI) or extratumoral perineural invasion (EPNI) and review the existing literature. RESULTS: On salvage resection for recurrence following primary radiation or chemoradiation, six patients manifested ELVI and two showed EPNI. These patterns conferred difficulty with complete surgical clearance; final pathologic analysis demonstrated positive margins for all eight patients. The six patients with ELVI were p16+ and the two with EPNI were p16-. Currently, two patients are deceased and six patients are alive at an average follow-up of 17.4 months. Of the six living patients, 2 have a new recurrence and are in hospice while 4 have no evidence of disease. CONCLUSIONS: ELVI and EPNI have received little consideration in the literature as unique histopathologic features of oropharyngeal squamous carcinoma. We present the first series on these adverse extratumoral features in recurrent disease. We call attention to these unique histologic features in the setting of recurrent oropharyngeal cancer to encourage others to track the results of therapeutic intervention and to identify successful strategies for treatment.

Positive Lymph Node Counts in American Thyroid Association Low-Risk Papillary Thyroid Carcinoma Patients.

BACKGROUND: Current American Thyroid Association (ATA) guidelines state that patients with intermediate-risk papillary thyroid cancer (PTC) may benefit from remnant ablation. One criterion for intermediate-risk classification is >5 positive lymph nodes (LNs). We investigate whether performing step-sectioning of LNs increases the metastatic detection rate, thereby influencing ATA risk of recurrence (ROR) classification. METHODS: A retrospective review was conducted of cases in which ≥ 5 LNs were removed during thyroidectomy and ≤5 LNs were found positive for PTC. Step-sectioning was performed on the original tissue blocks. All slides were re-reviewed by a senior pathologist. RESULTS: Twenty patients met study criteria. Step-sectioning significantly increased LN yield compared to standard sectioning. In total, we found 12 new positive lymph nodes; seven (58%) were in totally new lymph nodes, while five (42%) were in lymph nodes previously read as negative. All newly discovered metastases were classified as micrometastases (≤2 mm). Of the 15 patients originally classified as low-risk, the step-sectioning protocol impacted two patients (13%), increasing ROR stratification. CONCLUSION: Intensive step-sectioning reveals additional micrometastases. More detailed analysis did not identify clinically significant nodal disease likely to impact the clinical course of patients in this study. Our study supports current standards of pathology specimen handling related to LN assessment and the impact on ATA ROR classification. Nonetheless, it is important for clinicians to understand their institution's sectioning protocol utilized to report positive and total LN counts, which could impact ATA risk stratification and denote the comprehensive nature of the LN dissection that was performed.

NUTM1-rearranged neoplasia: a multi-institution experience yields novel fusion partners and expands the histologic spectrum.

Poorly differentiated neoplasms lacking characteristic histopathologic features represent a significant challenge to the pathologist for diagnostic classification. Classically, NUT carcinoma (previously NUT midline carcinoma) is poorly differentiated but typically exhibits variable degrees of squamous differentiation. Diagnosis is genetically defined by NUTM1 rearrangement, usually with BRD4 as the fusion partner. In this multi-institutional next-generation sequencing and fluorescence in situ hybridization study, 26 new NUTM1-rearranged neoplasms are reported, including 20 NUT carcinomas, 4 sarcomas, and 2 tumors of an uncertain lineage. NUTM1 fusion partners were available in 24 of 26 cases. BRD4 was the fusion partner in 18/24 (75%) cases, NSD3 in 2/24 cases (8.3%), and BRD3 in 1/24 (4.2%) cases. Two novel fusion partners were identified: MGA in two sarcomas (myxoid spindle cell sarcoma and undifferentiated sarcoma) (2/24 cases 8.3%) and MXD4 in a round cell sarcoma in the cecum (1/24 cases 4.2%). Eleven cases tested for NUT immunoexpression were all positive, including the MGA and MXD4-rearranged tumors. Our results confirm that NUTM1 gene rearrangements are found outside the classic clinicopathological setting of NUT carcinoma. In addition, as novel fusion partners like MGA and MXD4 may not be susceptible to targeted therapy with bromodomain inhibitors, detecting the NUTM1 rearrangement may not be enough, and identifying the specific fusion partner may become necessary. Studies to elucidate the mechanism of tumorigenesis of novel fusion partners are needed.

Osteoradionecrosis of the hyoid bone complicated by pharyngocutaneous fistula: A case report and literature review.

BACKGROUND: Osteoradionecrosis (ORN) is a well-known complication following irradiation of head and neck malignancies. ORN commonly occurs in the mandible but is rarely reported in the hyoid bone. CASE PRESENTATION: A 76-year-old female with a history of oropharyngeal squamous cell carcinoma presented with pharyngocutaneous fistula 14 years after primary chemoradiation. Imaging showed necrosis of the hyoid bone. She underwent excision of the hyoid to rule out malignancy. Pathology was negative for carcinoma, but did show extensive fragmentation and bony necrosis consistent with ORN. The patient's clinical course, surgical treatment, and management considerations are discussed here. CONCLUSIONS: Hyoid ORN should remain in the differential during diagnostic workup of previously irradiated head and neck cancer patients. The presentation of a pharyngocutaneous fistula should prompt workup to rule out malignancy before assigning a diagnosis of ORN.

A rare primary leiomyosarcoma of the parotid gland: A case report and literature review.

BACKGROUND: Leiomyosarcoma of the head and neck region is very rare. Primary parotid leiomyosarcoma has only been reported nine times in the medical literature. METHODS: A 68-year-old female presented with a left facial mass. Physical examination revealed a firm immobile mass at the level of the left parotid tail. No facial nerve dysfunction or palpable adenopathy was noted at the time of presentation. This patient underwent a superficial parotidectomy with a facial nerve dissection and left selective neck dissection. RESULTS: Pathologic findings revealed a sarcoma of intermediate to high-grade, composed of spindle cells with herringbone pattern, eosinophilic fibrillary cytoplasm, and focal granularity. Immunohistochemistry was positive for vimentin and smooth muscle actin and negative for desmin, S100 and CD34. The findings are consistent with a leiomyosarcoma. Following complete surgical resection, adjuvant radiation therapy was administered. CONCLUSION: Primary sarcomas of the parotid gland, specifically parotid leiomyosarcomas, are extremely rare. Based on this patient's tumor size, grade and resectability, this case met the criteria for a primary leiomyosarcoma. We present only the tenth case of a primary parotid leiomyosarcoma to be reported in the English literature.

Frozen Section Timeout: Pilot Study to Reconcile Margins Using 3D Resected Specimen and Defect Scans.

OBJECTIVE: Opportunities exist to improve intraoperative communication and documentation of resection margin details. We instituted a "frozen section timeout" that centers around visualization of the paired resection specimen and surgical defect-facilitating effective, bidirectional exchange of information. METHODS: We designed an interactive form for use during the "frozen section timeout" including annotated 3D virtual models of the resected specimen and surgical defect, plus a "line-item" table for primary and supplemental margin results. The "timeout" was conducted over a Zoom call between the operating room and frozen section laboratory. The form was simultaneously projected and discussed while all members of the surgical care team stopped activities. Nurses, co-surgeons, and all other members of the surgical team were encouraged to take part in this process. RESULTS: Twenty-six frozen section timeouts were conducted during head and neck surgeries in the Department of Otolaryngology at Mount Sinai West Hospital. These timeouts were facilitated by the lead surgeon, and all other activities were halted to ensure that critical information was shared, documented, and agreed upon. During the timeout, the annotated specimen and defect scans were displayed, clearly demonstrating the at-risk margins and the corresponding location and breadth of supplemental margins harvested. CONCLUSION: Incorporating a frozen section timeout can improve intraoperative communication, increase transparency, and potentially eliminate uncertainty regarding margin status and tumor clearance. Visualization of at-risk margins and the corresponding location and breadth of supplemental margins promises an unprecedented level of documentation and understanding. This novel technique can establish a new and improved standard of care. LEVEL OF EVIDENCE: NA Laryngoscope, 134:725-731, 2024.

Improving Interdisciplinary Communication and Pathology Reporting for Head and Neck Cancer Resections: 3D Visualizations and Margin Reconciliation.

PURPOSE: Surgical pathology reports play an integral role in postoperative management of head and neck cancer patients. Pathology reports of complex head and neck resections must convey critical information to all involved clinicians. Previously, we demonstrated the utility of 3D specimen and defect scanning for communicating margin status and documenting the location of supplemental margins. We introduce a newly designed permanent pathology report which improves documentation of intraoperative margin mapping and extent of corresponding supplemental margins harvested. METHODS: We test the hypothesis that gaps in understanding exist for head and neck resection pathology reports across providers. A cross-sectional exploratory study using human-centered design was implemented to evaluate the existing permanent pathology report with respect to understanding margin status. Pathologists, surgeons, radiation oncologists, and medical oncologists from United States-based medical institutions were surveyed. The results supported a redesign of our surgical pathology template, incorporating 3D specimen / defect scans and annotated radiographic images indicating the location of inadequate margins requiring supplemental margins, or indicating frankly positive margins discovered on permanent section. RESULTS: Forty-seven physicians completed our survey. Analyzing surgical pathology reports, 28/47 (60%) respondents reported confusion whether re-excised supplemental margins reflected clear margins, 20/47 (43%) reported uncertainty regarding final margin status, and 20/47 (43%) reported the need for clarity regarding the extent of supplemental margins harvested intraoperatively. From this feedback, we designed a new pathology report template; 61 permanent pathology reports were compiled with this new template over a 12-month period. CONCLUSION: Feedback from survey respondents led to a redesigned permanent pathology report that offers detailed visual anatomic information regarding intraoperative margin findings and exact location/size of harvested supplemental margins. This newly designed report reconciles frozen and permanent section results and includes annotated radiographic images such that clinicians can discern precise actions taken by surgeons to address inadequate margins, as well as to understand the location of areas of concern that may influence adjuvant radiation planning.

Utilizing 3D head and neck specimen scanning for intraoperative margin discussions: Proof of concept of our novel approach.

BACKGROUND: The current standard of documenting and communicating frozen section margin results is inefficient. We present a novel method of generating 3D digital models of gross tumor specimens to more clearly visualize histopathological margin results. METHODS: Fifty-five head and neck specimens were scanned and virtually "inked" using 3D software. These 3D specimen maps were displayed in the operating room to provide the surgeon with a real-time specimen-to-defect relationship by which further resections could be guided. RESULTS: Margin results were reported within an average of 34 min using the proposed workflow. The scanner rendered accurate models of specimens that exceeded 3.0 × 3.0 × 3.0 cm. Critical specimen features to consider were size, color, textural complexity, and the presence of discernible anatomic landmarks. CONCLUSIONS: Optical 3D scanning technology can improve the quality of head and neck margin documentation and the efficiency with which results are communicated between the pathologist and surgeon.

Intraoperative three-dimensional scanning of head and neck surgical defects: Enhanced communication and documentation of harvested supplemental margins.

BACKGROUND: We have demonstrated the effectiveness of 3D resection specimen scanning for communicating margin results. We now address the corresponding surgical defect by debuting 3D defect models, which allow for accurate annotations of harvested supplemental margins. METHODS: Surgical defects were rendered into 3D models, which were annotated to document the precise location of harvested supplemental margins. 3D defect scans were also compared with routine 2D photography and were analyzed for quality, clarity, and the time required to complete the scan. RESULTS: Forty defects were scanned from procedures including segmental mandibulectomy, maxillectomy, and laryngopharyngectomy. Average duration of defect scan was 6 min, 45 s. In six of ten 2D photographs, the surgeon was unable to precisely annotate the extent of at least one supplemental margin. CONCLUSION: 3D defect scanning offers advantages in that this technique enables documentation of the precise location and breadth of supplemental margins harvested to address margins at-risk.

Frozen Section Analysis in Head and Neck Surgical Pathology: A Narrative Review of the Past, Present, and Future of Intraoperative Pathologic Consultation.

Frozen section has remained the diagnostic gold standard for intraoperative pathological evaluation of surgical margins for head and neck specimens. While achieving tumor-free margins is of utmost importance to all head and neck surgeons, in practice, there are numerous debates and a lack of standardization for the role and method of intraoperative pathologic consultation. This review serves as a summary guide to the historical and contemporary practice of frozen section analysis and margin mapping in head and neck cancer. In addition, this review discusses current challenges in head and neck surgical pathology, and introduces 3D scanning as a groundbreaking technology to bypass many of the pitfalls in the current frozen section workflow. The ultimate goal for all head and neck pathologists and surgeons should be to modernize practices and take advantage of new technology, such as virtual 3D specimen mapping techniques, that improves the workflow for intraoperative frozen section analysis.

Synchronous thyroid cancer and malignant struma ovarii: concordant mutations and microRNA profile, discordant loss of heterozygosity loci.

BACKGROUND: Struma ovarii is an unusual ovarian teratoma containing predominantly thyroid tissue. Less than 10% of cases undergo malignant transformation in the thyroid tissue and are considered malignant struma ovarii (MSO). MSO have been reported with concurrent thyroid lesions, but molecular data is lacking. CASE PRESENTATION: A 42-year-old female developed MSO and synchronous multifocal subcentimeter papillary thyroid carcinoma (PTC). The patient underwent a salpingo-oophrectomy, thyroidectomy, and low-dose radioactive iodine ablation. Both the thyroid subcentimeter PTC and MSO were positive for BRAF V600E mutation, and microRNA expression profiles were similar across all tumor deposits. However, only the malignant component demonstrated extensive loss of heterozygosity (LOH) involving multiple tumor suppressor gene (TSG) chromosomal loci. CONCLUSIONS: We present the first reported case of MSO with synchronous multifocal subcentimeter PTC in the thyroid containing concordant BRAF V600E mutations and resulting with discordant LOH findings. This data suggests that loss of expression in tumor suppressor gene(s) may be an important contributor to phenotypic expression of malignancy.

iPad Annotation of 3D Surgical Models Using Procreate®: Novel Documentation of Supplemental Margins.

We present a novel, efficient approach to demonstrating supplemental margins during oncologic resection. Surgeons and pathologists annotated 10 virtual models of surgical defects and resection specimens in 3D using an iPad-based application, Procreate®. Incorporating this method into the surgical workflow can improve interdepartmental communication and provide visual documentation of surgical steps taken to address at-risk margins. Laryngoscope, 2023.

WPOI-5: Accurately Identified at Intraoperative Consultation and Predictive of Occult Cervical Metastases.

BACKGROUND: Frozen section analysis of oral cancer specimens is ideal for assessing margin distances and depth of invasion (DOI); the latter impacts intraoperative decisions regarding elective neck dissection (END). Here, we show that intraoperative determination of worst pattern of invasion (WPOI), specifically WPOI-5, has a high level of accuracy. This relates to our demonstration herein that WPOI-5 predicts occult cervical metastases (OCM) for pT1 oral squamous carcinoma (OSC). METHODS: The presence of OCM was correlated with WPOI in 228 patients with primary T1/T2/cN0 OSC undergoing resection and END. Concordance between intraoperative and final pathology WPOI determination was assessed on 51 cases of OSC. RESULTS: WPOI-5 predicts OCM in pT1 patients, compared with WPOI-4/WPOI-3 (p < 0.0001). Most pT1 WPOI-5 tumors had DOI of 4-5 mm (24/59 or 40.7%). Only two pT1 WPOI-5 tumors had DOI < 4 mm (3.0 and 3.5 mm). If END were performed in this pT1 cohort for all WPOI-5 OSC patients regardless of DOI, OR all OSC patients with DOI ≥ 4 mm regardless of WPOI, then no OCM would be missed (p = 0.017, 100% sensitivity, 29% specificity, 77% positive predictive value, 23% negative predictive value). With respect to intraoperative WPOI-5 determination, the accuracy, sensitivity, and specificity was 92.16, 73.33, and 100.0%, respectively. CONCLUSIONS: DOI ≥ 4 mm is the dominant predictor of OCM. For the rare WPOI-5 OSC with DOI < 4 mm, it is reasonable to suggest that surgeons perform END. WPOI-5 may be accurately determined intraoperatively. As microscopic instruction is needed to accurately assess WPOI-5, a teaching link is included in this manuscript.

Functional loss of tumor suppressor genes detected by loss of heterozygosity, but not driver mutations, predicts aggressive lymph node status in papillary thyroid carcinoma.

BACKGROUND: Recognizing aggressive tumor biology is essential to optimizing patient management for papillary thyroid carcinomas (PTC). Aggressive lymph node (ALN) status is one feature that influences decision-making. We evaluated genomic deletions in regions of tumor suppressor genes, detected by loss of heterozygosity (LOH) analysis, to understand causal alterations linked to thyroid cancer aggressiveness and to serve as a molecular diagnostic biomarker for ALN status. METHODS: We analyzed 105 primary PTC enriched for patients with ALN (64% with, 36% without). We also analyzed 39 positive lymph nodes (79% with, 21% without ALN). LOH was determined using a panel of 25 polymorphic microsatellite alleles targeting 10 genomic loci harboring common tumor suppressor genes. Additionally, ThyGeNEXT® and ThyraMIR® assays were performed. RESULTS: LOH was detected in 43/67 primary PTC from patients with ALN status, compared with only 5/38 primary PTC without ALN (minimal metastatic burden) (P=0.0000003). This is further supported by post hoc analyses of paired primary and metastatic samples. Paired samples from patients with ALN are more likely to harbor LOH, compared to the ALN negative group (P=0.0125). Additionally, 12/31 paired samples from patients with ALN demonstrated additional or different LOH loci in metastatic samples compared to the primary tumor samples. No association was seen between ALN and mutational, translocation, or microRNA data. CONCLUSIONS: LOH detected in primary PTC significantly predicts ALN status. Analysis of paired primary and metastatic samples from patients with / without ALN status further supports this relationship. The acquisition of LOH at additional loci is common in lymph nodes from patients with ALN status. SIMPLE SUMMARY: A subset of patients with papillary thyroid carcinoma (PTC) will develop recurrent disease. One known predictor of recurrence is the American Thyroid Association category "Aggressive Lymph Node" (ALN) disease, considering metastatic burden. Loss of heterozygosity (LOH) - chromosomal loss in regions of tumor suppressor genes - has yet to be investigated as a possible mechanism driving ALN status in PTC. The ability to predict ALN status prior to surgery can guide the extent of surgery and postoperative treatment options. We found that paired samples from patients with ALN are more likely to harbor LOH, compared to patients without ALN disease. 38% of patients with ALN demonstrated additional or different LOH loci in metastatic samples compared to the primary tumor samples. LOH complements current molecular analysis of thyroid cancer when searching for evidence of aggressive biology.

Oncocytoid Variant of High-Grade Salivary Duct Carcinoma: A Potential Diagnostic Pitfall. A Report on Two Patients.

Salivary duct carcinoma (SDC) is an uncommon and aggressive salivary malignancy. The oncocytoid variant of salivary duct carcinoma (OSDC) has only been reported in the English literature once before. Here we detail two new patients. A 71-year-old female presented with a painless enlarging left parotid mass. Imaging and fine-needle aspiration were nondiagnostic. The second patient, a 79-year-old male, presented with painless swelling in the right cheek. Imaging was nondiagnostic. Both patients underwent surgical resection. Histopathology revealed bland yet infiltrative OSDC in both cases. These tumors were AR+ (androgen receptor) by immunohistochemistry. Potential difficulty exists in distinguishing the oncocytoid variant of SDC, a rare and relatively bland tumor, from oncocytoma, a more commonly encountered entity. AR expression can aid in the correct diagnosis.

Histology segmentation using active learning on regions of interest in oral cavity squamous cell carcinoma.

In digital pathology, deep learning has been shown to have a wide range of applications, from cancer grading to segmenting structures like glomeruli. One of the main hurdles for digital pathology to be truly effective is the size of the dataset needed for generalization to address the spectrum of possible morphologies. Small datasets limit classifiers' ability to generalize. Yet, when we move to larger datasets of whole slide images (WSIs) of tissue, these datasets may cause network bottlenecks as each WSI at its original magnification can be upwards of 100 000 by 100 000 pixels, and over a gigabyte in file size. Compounding this problem, high quality pathologist annotations are difficult to obtain, as the volume of necessary annotations to create a classifier that can generalize would be extremely costly in terms of pathologist-hours. In this work, we use Active Learning (AL), a process for iterative interactive training, to create a modified U-net classifier on the region of interest (ROI) scale. We then compare this to Random Learning (RL), where images for addition to the dataset for retraining are randomly selected. Our hypothesis is that AL shows benefits for generating segmentation results versus randomly selecting images to annotate. We show that after 3 iterations, that AL, with an average Dice coefficient of 0.461, outperforms RL, with an average Dice Coefficient of 0.375, by 0.086.