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# Title
The Avocado Sign: A Novel Imaging Marker for Nodal Staging in Rectal Cancer

## Manuscript Type
Original Article
---

## Authors
Markus Lurz, M.D.
Department of Radiology and Nuclear Medicine, Klinikum St. Georg, Leipzig, Germany

Arnd-Oliver Schäfer, M.D.
Department of Radiology and Nuclear Medicine, Klinikum St. Georg, Leipzig, Germany

### Corresponding Author
Markus Lurz, M.D.  
Department of Radiology and Nuclear Medicine
Klinikum St. Georg
Delitzscher Straße 141, 04129 Leipzig, Germany
Email: <PRESIDIO_ANONYMIZED_EMAIL_ADDRESS>
Telephone: <PRESIDIO_ANONYMIZED_PHONE_NUMBER>
Fax: <PRESIDIO_ANONYMIZED_PHONE_NUMBER>

---

## Abstract

### Background
Accurate assessment of nodal status is crucial for treatment decision in rectal cancer. While MRI is widely recognized as the gold standard for local staging, its performance in predicting nodal involvement is still limited. We propose the Avocado Sign, a novel contrast-enhancement-based MR imaging marker, for prognostication of mesorectal lymph node spread in rectal cancer.

### Methods
In this retrospective study, we evaluated the diagnostic performance of the Avocado Sign, defined as a hypointense core within an otherwise homogeneously hyperintense lymph node on contrast-enhanced T1-weighted images, in predicting mesorectal lymph node metastasis. A total of 106 patients with rectal cancer were enrolled. Of these, 77 underwent neoadjuvant chemoradiotherapy followed by restaging MRI before surgery. Histopathologic examination of the resected specimens served as the reference standard. Diagnostic metrics were calculated, and statistical significance was assessed using chi-square tests. Interobserver agreement was evaluated using Cohen's kappa coefficient.

### Results
The Avocado Sign demonstrated high diagnostic accuracy for predicting lymph node involvement, with an overall sensitivity of 88.7%, specificity of 84.9%, PPV of 85.5%, NPV of 88.2%, and accuracy of 86.8%. The area under the ROC curve was 0.87. Subgroup analysis revealed excellent performance in both patients undergoing surgery alone and those receiving neoadjuvant therapy. Interobserver agreement was almost perfect (κ = 0.92).

### Conclusion
The Avocado Sign is a promising imaging predictor for mesorectal lymph node status in rectal cancer. Its straightforward application, high reproducibility, and remarkable diagnostic accuracy underline its potential to significantly refine MRI staging and impact therapeutic decision-making in rectal cancer.

---

## Keywords
Rectal cancer, magnetic resonance imaging, lymph nodes, contrast media, neoadjuvant therapy

---

## Introduction
Rectal cancer is a significant public health concern, with an estimated 44,850 new cases and 12,630 deaths in the United States in 2023.1 While neoadjuvant chemoradiotherapy followed by total mesorectal excision surgery has been the standard of care for locally advanced rectal cancer, new treatment options, such as total neoadjuvant therapy and nonoperative management, have emerged as potential alternatives.2–5 Consequently, refined imaging techniques are becoming increasingly important for the reliable stratification of patients, particularly regarding nodal status, which is a critical factor in treatment decision-making.
MRI is widely recognized as the gold standard for local staging of rectal cancer.6 However, MRI staging is typically based on T2-weighted sequences, with contrast administration not routinely recommended. For instance, a meta-analysis by Zhang et al. found that morphological criteria on T2-weighted MRI had limited accuracy, with a pooled sensitivity of 77% and specificity of 76% for predicting nodal involvement.7 Similarly, a study by Ale Ali et al. reported an accuracy of only 65% for nodal staging using T2-weighted MRI, emphasizing the limitations of current staging methods and highlighting the need for improved imaging techniques.8
We hypothesize that contrast administration may be useful in the prediction of locoregional lymph node involvement in rectal cancer patients. Specifically, we propose the "Avocado Sign," a hypointense core within mesorectal lymph nodes on contrast-enhanced T1-weighted fat-saturated sequences resembling the kernel of an avocado, as a potential imaging predictor of locoregional lymph node status. By leveraging the additional information provided by contrast enhancement, the Avocado Sign aims to address the limitations of T2-weighted MRI and improve the accuracy of nodal staging in rectal cancer.
The purpose of this study is to evaluate the diagnostic performance of the Avocado sign as an imaging predictor of mesorectal lymph node status in patients with rectal cancer. We aim to assess the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the Avocado sign for prognostication of locoregional lymph node involvement, and to investigate its performance by subgroup analysis. The results of this study may have important implications for refining MRI protocols and optimizing treatment strategies for rectal cancer patients.

---

## Methods

### Study Design and Patients
We conducted a single-institution retrospective study to evaluate the diagnostic performance of the Avocado Sign, a novel MR imaging marker, in predicting locoregional lymph node status in patients with rectal cancer. The study was approved by the institutional review board of Klinikum St. Georg Leipzig, Germany, and written informed consent was obtained from all patients before enrollment.
Patients were eligible for inclusion if they were 18 years of age or older and had histologically confirmed rectal cancer. Exclusion criteria were unresectable tumors and contraindications to MRI. From January 2020 through November 2023, 106 consecutive patients underwent baseline staging MRI. Of these patients, 77 received standard neoadjuvant chemoradiotherapy followed by restaging MRI prior to rectal surgery. Histopathological examination of the resected specimens served as the reference standard (Figure 1).

### MRI Protocol
All MRI examinations were performed on a 3.0T system (MAGNETOM Prisma Fit; Siemens Healthineers) using body and spine array coils. The imaging protocol included high-resolution sagittal, axial, and coronal T2-weighted turbo spin echo sequences; axial diffusion-weighted imaging; and contrast-enhanced axial T1-weighted volumetric interpolated breath-hold examination with Dixon fat suppression. Sequence parameters are detailed in Table 1. A weight-based dose (0.2 mL/kg of body weight) of a macrocyclic gadolinium-based contrast agent (Gadoteridol; ProHance; Bracco) was administered intravenously. Butylscopolamine was administered at the start and midpoint of each examination to reduce motion artifacts. Notably, the imaging protocol was identical for baseline staging and restaging.

### Image Analysis
Two radiologists with 29 and 7 years of experience in abdominal MRI independently assessed the images for the presence of the Avocado Sign, defined as a hypointense core within an otherwise homogeneous lymph node on contrast-enhanced T1-weighted images, regardless of node size or shape (Figure 2). Discrepancies were resolved by consensus with a third radiologist who had 19 years of experience in abdominal MRI. In the surgery alone subgroup, baseline MRI, and in the neoadjuvant subgroup, only the restaging MRI was used for assessment.
Lymph node status was categorized as positive if the Avocado Sign was present in at least one node and negative if the sign was absent. Histopathologic analysis of the surgical specimens served as the reference standard.

### Statistical Analysis
Descriptive statistics were used to summarize patient characteristics. The prevalence of the Avocado Sign and lymph node metastases was determined for the overall cohort, the surgery alone subgroup and the neoadjuvant subgroup. Diagnostic performance metrics, including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, were calculated using contingency tables and compared between subgroups using the chi-square test. Receiver operating characteristic (ROC) curve analysis was performed, and the area under the curve (AUC) was calculated to evaluate the diagnostic performance of the Avocado Sign. Interobserver agreement was assessed using Cohen's kappa coefficient. Analyses were performed using SPSS version 26 (IBM) for descriptive statistics, R (version 4.0.3; R Foundation for Statistical Computing) for ROC curve analysis and chi-square tests, and Python (version 3.8; Python Software Foundation) for additional data visualization and interobserver agreement assessment.

---

## Results

### Patient Characteristics
A total of 106 patients with histologically confirmed rectal cancer were included in the study (Table 2). The mean age was 65±8.4 years, and 75.5% were male. 29 patients (27.4%) underwent surgery alone, while 77 (72.6%) received neoadjuvant chemoradiotherapy. Histopathologic examination revealed lymph node metastases in 52 patients (49.1%).

### Diagnostic Performance of the Avocado Sign
In the overall cohort, the Avocado Sign was found in 55 patients and was negative in 51 patients. Histopathological examination revealed lymph node metastasis in 52 patients, while 54 patients were classified N0. In the neoadjuvant subgroup, 6 patients and in the surgery alone subgroup, 2 patients had a positive Avocado sign but no histologically confirmed lymph node involvement.
The Avocado Sign demonstrated high diagnostic accuracy for predicting lymph node involvement in the overall cohort and subgroups. Overall sensitivity was 88.7% (95% confidence interval [CI], 77.4 to 94.7), specificity was 84.9% (95% CI, 72.9 to 92.1), PPV was 85.5% (95% CI, 73.8 to 92.4), NPV was 88.2% (95% CI, 76.6 to 94.5), and accuracy was 86.8% (95% CI, 79.0 to 91.9). The area under the ROC curve (AUC) was 0.87 for the overall cohort, indicating high diagnostic performance (Figure 2A).
Subgroup analysis revealed excellent performance of the Avocado Sign in patients undergoing surgery alone, with a sensitivity of 100% (95% CI, 79.6 to 100), specificity of 83.3% (95% CI, 50.1 to 97.1), PPV of 88.2% (95% CI, 64.2 to 98.2), NPV of 100% (95% CI, 71.3 to 100), and accuracy of 92.6% (95% CI, 77.0 to 99.1). The AUC was 0.92 (95% CI, 0.80 to 1.00) (Figure 2B).
In patients receiving neoadjuvant chemoradiotherapy, the Avocado Sign showed a sensitivity of 84.2% (95% CI, 69.6 to 92.9), specificity of 85.4% (95% CI, 71.5 to 93.6), PPV of 84.2% (95% CI, 69.7 to 92.9), NPV of 85.4% (95% CI, 71.6 to 93.6), and accuracy of 84.8% (95% CI, 73.1 to 92.5). The AUC was 0.85 (95% CI, 0.77 to 0.93) (Figure 2C). 
Chi-square tests indicated no significant differences in diagnostic performance between subgroups (P = 0.34), affirming the robustness of the Avocado Sign across treatment types. An overview of nominal values and diagnostic performance metrics for overall collective and subgroups is provided in Table 3.

### Interobserver Agreement
There was almost perfect interobserver agreement between the two radiologists in assessing the Avocado Sign, with a Cohen's kappa value of 0.92 (95% CI, 0.85 to 0.99).

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## Discussion
This retrospective study demonstrates that the Avocado Sign can accurately predict mesorectal lymph node status in patients with rectal cancer. Its high diagnostic performance across the patient subgroups underlines its potential to ameliorate MRI nodal staging.
Earlier studies focused on morphological criteria on T2-weighted MRI sequences for lymph node assessment in rectal cancer. A systematic review by Koh et al. reported sensitivities of up to 85% using a combination of size and morphological criteria.9 However, the overall diagnostic accuracy of morphological criteria has been suboptimal. A meta-analysis by Al-Sukhni et al.10 found that morphological criteria on T2-weighted MRI had limited accuracy, with a pooled sensitivity of 77% and specificity of 71% for predicting nodal involvement, lower than the performance reported by Koh et al. Similarly, in the large prospective observational trial "Optimized surgery and MRI-based multimodal therapy in rectal carcinoma" (OCUM), Stelzner et al. reported an accuracy of only 56.5% for lymph node staging using morphological criteria on T2-weighted MRI.11 The authors concluded that selecting patients for neoadjuvant chemoradiotherapy based on mesorectal fascia status is superior to selection based on T- and N-staging due to the low reliability of the latter approach.
Recent studies have explored the potential of size-based criteria and contrast-enhanced MRI for improving nodal staging. Lambregts et al. investigated contrast-enhanced sequences in 33 patients and found that benign lymph nodes exhibited significant contrast enhancement after gadofosveset injection, whereas metastatic nodes did not.12 The authors hypothesized that the different contrast enhancement patterns were due to the presence of tumor cells in the metastatic nodes, leading to a disruption in the normal lymph node architecture and altered contrast uptake. Although this study provided initial evidence for the potential of contrast-enhanced MRI in differentiating benign from metastatic nodes, it was limited by the small number of patients and nodes evaluated. Furthermore, the contrast agent Gadofosveset (Vasovist, Lantheus Medical, MA, United States) used in this study is no longer commercially available, limiting the clinical applicability of their findings. 
Barbaro et al. evaluated the performance of MRI for identifying negative nodal status (ypN0) after neoadjuvant chemoradiotherapy in 191 patients with locally advanced rectal cancer.13 The study was conducted retrospectively and included patients who underwent both pre- and post-treatment MRI examinations at 6-8 weeks after completion of chemoradiotherapy, followed by total mesorectal excision surgery. The authors found that a short-axis diameter ≤2.2 mm cut-off was associated with an area under the curve of 0.83 for predicting ypN0, with 79.5% sensitivity and 91.1% negative predictive value. Horvat et al. also provided specific MRI criteria for assessing nodal response after neoadjuvant therapy, with nonvisualization of nodes on diffusion-weighted imaging, ≥70% decrease in node size, and nodes <0.5 cm in short axis being most reliably associated with negative lymph node status.14
To the best of our knowledge, the Avocado Sign currently provides the most accurate diagnostic performance reported in larger clinical trials. It demonstrates excellent accuracy in predicting nodal status, regardless of whether the assessment is conducted using baseline or restaging MRI after neoadjuvant therapy. This is particularly relevant given the evolving landscape of rectal cancer treatment that increasingly emphasizes risk-adapted approaches and organ-preserving strategies.4,5,15 Schrag et al. recently highlighted the expanding range of treatment options for locally advanced rectal cancer, which enables personalized treatment based on tumor-specific features.16 They noted that patients with high microsatellite instability tumors can achieve durable complete responses with immunotherapy alone. Furthermore, they emphasized the potential of newer approaches, such as total neoadjuvant therapy with the option of nonoperative management.
In the era of total neoadjuvant therapy, as demonstrated in the OPRA trial (Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy) by Garcia-Aguilar et al.17 and more recently in the PROSPECT trial (Preoperative Treatment of Locally Advanced Rectal Cancer) by Schrag et al.16, accurate nodal staging has become pivotal for optimizing treatment strategies and mitigating the risks of overtreatment or undertreatment.
It is essential to clarify that our objective was not to conduct a node-by-node analysis, which is particularly challenging after neoadjuvant chemoradiotherapy. Instead, our aim was to incorporate a simple and reproducible prognostic imaging marker for mesorectal lymph node status. Naturally, we observed some discrepant findings, where the Avocado Sign was positive, but histologic examination of the surgical specimen was negative for lymph node metastasis. As we hypothesize that the hypointense core reflects the presence of nodal tumor deposits, supported by the work of Zhou et al.18 and Lambregts et al.12, these discrepancies could be due to lymph node undersampling or postneoadjuvant fibrosis masking residual nodal metastasis. Therefore, we believe that the true diagnostic performance of the Avocado Sign may be even higher than reported in this study.
The straightforward application and high reproducibility of the Avocado Sign are additional strengths. Unlike some advanced MRI techniques, such as diffusion-weighted imaging or dynamic contrast-enhanced MRI, assessment of the Avocado Sign only requires routine high-resolution, thin-slice, fat-saturated contrast-enhanced T1-weighted sequences and can be easily incorporated into standard MRI protocols. Furthermore, the almost perfect interobserver agreement (κ = 0.92) indicates that the Avocado Sign can be reliably assessed by radiologists with varying levels of expertise.
Some limitations of our study have to be addressed. Although our study included a larger sample size than many similar studies, further validation in even larger multicenter cohorts would strengthen the evidence for the Avocado Sign and facilitate its wider distribution. Additionally, we did not assess the impact of the Avocado Sign on long-term clinical outcomes, such as local recurrence or survival.
In conclusion, the Avocado Sign is a promising imaging predictor for nodal status in rectal cancer with the potential to refine MRI staging and guide personalized treatment strategies. We strongly recommend contrast administration for improved detection of lymph node metastasis. The Avocado Sign specifies MRI assessment of rectal cancer and contributes to enhanced patient selection to the various therapeutic algorithms. Future prospective studies with larger sample sizes and long-term follow-up are warranted to validate these findings and assess the impact of the Avocado Sign on clinical decision-making and patient outcomes.

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## Author Contributions
Markus Lurz: Conceptualization, Methodology, Data Curation, Writing - Original Draft.
Arnd-Oliver Schäfer: Conceptualization, Supervision, Validation, Writing - Review & Editing.

---

## References

1.	Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
2.	Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.
3.	Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114-1123.
4.	Habr-Gama A, São Julião GP, Vailati BB, et al. Organ preservation in cT2N0 rectal cancer after neoadjuvant chemoradiation therapy: the impact of radiation therapy dose-escalation and consolidation chemotherapy. Ann Surg. 2019;269(1):102-107.
5.	Smith JJ, Chow OS, Gollub MJ, et al. Organ preservation in rectal adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy and total mesorectal excision or nonoperative management. BMC Cancer. 2015;15:767.
6.	Beets-Tan RG, Lambregts DM, Maas M, et al. Magnetic resonance imaging for clinical management of rectal cancer: updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol. 2018;28(4):1465-1475.
7.	Zhang H, Zhang C, Zheng Z, et al. Chemical shift effect predicting lymph node status in rectal cancer using high-resolution MR imaging with node-for-node matched histopathological validation. Eur Radiol. 2017;27(10):3845-3855.
8.	Ale Ali H, Kirsch R, Razaz S, et al. Extramural venous invasion in rectal cancer: overview of imaging, histopathology, and clinical implications. Abdom Radiol (NY). 2019;44(1):1-10.
9.	Koh DM, Chau I, Tait D, et al. Evaluating mesorectal lymph nodes in rectal cancer before and after neoadjuvant chemoradiation using thin-section T2-weighted magnetic resonance imaging. Int J Radiat Oncol Biol Phys. 2008;71(2):456-461.
10.	Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19(7):2212-2223.
11.	Stelzner S, Ruppert R, Kube R, et al. Selection of patients with rectal cancer for neoadjuvant therapy using pre-therapeutic MRI - Results from OCUM trial. Eur J Radiol. 2022;147:110113.
12.	Lambregts DM, Heijnen LA, Maas M, et al. Gadofosveset-enhanced MRI for the assessment of rectal cancer lymph nodes: predictive criteria. Abdom Imaging. 2013;38(4):720-727.
13.	Barbaro B, Carafa MRP, Minordi LM, et al. Magnetic resonance imaging for assessment of rectal cancer nodes after chemoradiotherapy: A single center experience. Radiother Oncol. 2024;193:110124.
14.	Horvat N, El Homsi M, Miranda J, et al. Rectal MRI Interpretation After Neoadjuvant Therapy. J Magn Reson Imaging. 2023;57(2):353-369.
15.	Kennedy ED, Simunovic M, Jhaveri K, et al. Safety and feasibility of using magnetic resonance imaging criteria to identify patients with "good prognosis" rectal cancer eligible for primary surgery: the phase 2 nonrandomized QuickSilver clinical trial. JAMA Oncol. 2019;5(7):961-966.
16.	Schrag D, Shi Q, <PRESIDIO_ANONYMIZED_PERSON>, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. 2023;389(4):322-334.
17.	Garcia-Aguilar J, Patil S, Kim J, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(24):2546-2556.
18.	Zhou H, Lei PJ, Padera TP. Progression of metastasis through lymphatic system. Cells. 2021;10(3):627.

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## Figures and Tables

### Figure Legends

#### Figure 1. Flowchart of Patient Enrollment and Study Design.

+---------------------------------------------------------------+
| 106 patients with histologically confirmed rectal cancer were |
| enrolled in the study                                         |
+---------------------------------------------------------------+
                              |
                              v
                 +-----------------------------+
                 | 106 Underwent baseline MRI  |
                 +-----------------------------+
                              |
          +-------------------+-------------------+
          |                                       |
          v                                       v
+-----------------------------+       +-----------------------------+
| 77 Received neoadjuvant     |       | 29 Underwent surgery alone  |
| chemoradiotherapy           |       | (Avocado Sign assessed on   |
|                             |       | baseline MRI)               |
+-----------------------------+       +-----------------------------+
          |                                       |
          v                                       |
+-----------------------------+                   |
| Restaging MRI in 77 patients |                  |
| followed by surgery          |                  |
| (Avocado Sign assessed on    |                  |
| restaging MRI)               |                  |
+-----------------------------+                   |
          |                                       |
          +-------------------+-------------------+
                              |
                              v
+---------------------------------------------------------------+
| 106 Patients were included in the final analysis comparing    |
| the Avocado Sign with histopathologic findings from surgical  |
| specimens                                                     |
+---------------------------------------------------------------+

A total of 106 patients with histologically confirmed rectal cancer were enrolled. Baseline MRI was performed for all patients. Of these, 77 patients received neoadjuvant chemoradiotherapy followed by restaging MRI and subsequent surgery. The remaining 29 patients underwent surgery alone, with baseline MRI assessed for the Avocado Sign. All 106 patients were included in the final analysis, comparing the presence of the Avocado Sign with histopathologic findings from surgical specimens.

#### Figure 2. Receiver Operating Characteristic (ROC) Curves for the Avocado Sign 
(A) ROC curve for the overall cohort, demonstrating the diagnostic accuracy of the Avocado Sign in predicting mesorectal lymph node involvement.
(B) ROC curve for patients undergoing surgery alone, highlighting the diagnostic performance in this subgroup.
(C) ROC curve for patients receiving neoadjuvant chemoradiotherapy, illustrating the effectiveness of the Avocado Sign post-therapy. 

#### Figure 3. Illustration of the Avocado Sign. 
(A) Photograph of an avocado without core symbolizes normal lymph node. (B) Contrast-enhanced image of local staging MRI displays a homogeneously enhancing mesorectal lymph node (arrow). (C) Photograph of an avocado with core symbolizes lymph node metastasis. (D) Contrast-enhanced image of local staging MRI detects a lymph node metastasis owing to the prominent hypointense center (arrow).

### Tables

#### Table 1. MRI Sequence Parameters.

| **Sequence**               | **Plane** | **TR (ms)** | **TE (ms)** | **FA (degrees)** | **FOV (mm)** | **Matrix** | **Slice Thickness (mm)** |
| -------------------------- | --------- | ----------- | ----------- | ---------------- | ------------ | ---------- | ------------------------ |
| T2-TSE                     | Sagittal  | 4170        | 72          | 90               | 220          | 394 x 448  | 3                        |
| T2-TSE                     | Axial     | 4400        | 81          | 90               | 220          | 380 x 432  | 2                        |
| T2-TSE                     | Coronal   | 4400        | 81          | 90               | 220          | 380 x 432  | 2                        |
| DWI (b100/500/1000)        | Axial     | 3700        | 59          | 90               | 220          | 140 x 140  | 2                        |
| Dixon-VIBE (post-contrast) | Axial     | 5.8         | 2.5/3.7     | 10               | 270          | 326 x 384  | 1.5                      |

Detailed parameters of the MRI sequences used in the study, including repetition time (TR), echo time (TE), flip angle (FA), field of view (FOV), matrix, and slice thickness. Sequences include T2-weighted turbo spin echo (TSE) in sagittal, axial, and coronal planes; axial diffusion-weighted imaging (DWI); and post-contrast axial volumetric interpolated breath-hold examination (VIBE) with Dixon fat suppression.

#### Table 2. Patient Characteristics.

| **Characteristic**           | **Value** |
| ---------------------------- | --------- |
| Age - mean ± SD              | 65 ± 8.4  |
| Male - no. (%)               | 80 (75.5) |
| Female - no. (%)             | 26 (24.5) |
| Treatment approach - no. (%) |           |
| Surgery alone                | 29 (27.4) |
| Neoadjuvant therapy          | 77 (72.6) |

Summary of patient demographics and treatment approaches.

#### Table 3. Diagnostic Performance and Nominal Values for the Avocado Sign in Predicting Nodal Status

| Metric                | Overall (n=106)      | Surgery Alone (n=29)    | Neoadjuvant Therapy (n=77) |
|-----------------------|----------------------|-------------------------|----------------------------|
| AS+                   | 55                   | 17                      | 38                         |
| AS-                   | 51                   | 10                      | 41                         |
| N+                    | 53                   | 15                      | 38                         |
| N0                    | 53                   | 12                      | 41                         |
| AS+N+                 | 47                   | 15                      | 32                         |
| AS+N0                 | 8                    | 2                       | 6                          |
| AS-N+                 | 6                    | 0                       | 6                          |
| AS-N0                 | 45                   | 10                      | 35                         |
| Sensitivity (95% CI)  | 88.7% (77.4-94.7)    | 100% (79.6-100)         | 84.2% (69.6-92.9)          |
| Specificity (95% CI)  | 84.9% (72.9-92.1)    | 83.3% (50.1-97.1)       | 85.4% (71.5-93.6)          |
| PPV (95% CI)          | 85.5% (73.8-92.4)    | 88.2% (64.2-98.2)       | 84.2% (69.7-92.9)          |
| NPV (95% CI)          | 88.2% (76.6-94.5)    | 100% (71.3-100)         | 85.4% (71.6-93.6)          |
| Accuracy (95% CI)     | 86.8% (79.0-91.9)    | 92.6% (77.0-99.1)       | 84.8% (73.1-92.5)          |
| AUC (95% CI)          | 0.87 (0.79-0.94)     | 0.92 (0.80-1.00)        | 0.85 (0.77-0.93)           |

Diagnostic performance metrics for the Avocado Sign in the overall cohort and subgroups. Metrics include the number of patients with positive and negative Avocado Signs (AS+ and AS-), histologically confirmed nodal metastasis (N+ and N0), and the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and area under the curve (AUC) for the Avocado Sign in predicting lymph node involvement.