# Revision Worksheet

**Manuscript:** Influence of Omental Sampling Extent on the Detection of Occult Metastases in Ovarian and Endometrial Carcinomas
**Journal:** Archives of Pathology & Laboratory Medicine

Below, each reviewer/editor comment is quoted (abbreviated) and followed by the change made. All new or changed text is marked in **red** in the revised manuscript. Statistics were recomputed directly from the study dataset.

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## Editor-in-Chief — formatting requirements

**1. Double-space the text, including the reference list.**
Done. Double line spacing is applied throughout the manuscript and the reference list.

**2. Spell out numbers that begin a sentence.**
Done. Sentence-initial numbers are spelled out (e.g., "Thirty-five of 46 cases…"). Verified programmatically that no sentence in body prose begins with a numeral.

**3. Remove heading colors; use the standard heading hierarchy (#1 ALL CAPS centered bold; #2 Cap and Lowercase centered bold; #3 indented bold Cap and Lowercase run-in after an em dash).**
Done. All colored headings removed. #1 heads (ABSTRACT, INTRODUCTION, MATERIALS AND METHODS, RESULTS, DISCUSSION, REFERENCES, etc.) are ALL CAPS, centered, bold. #2 heads are Cap-and-lowercase, centered, bold. #3 heads are indented, bold, and run into the text after an em dash. (Red font is used solely to mark revised text and can be turned to black for the final copyedited version.)

**4. Use "supplemental" rather than "supplementary" (e.g., "Supplemental Table 1").**
Done. All instances changed to "supplemental"/"Supplemental Table N" in both the manuscript and the Supplemental Digital Content file. Zero occurrences of "supplementary" remain.

**5. Abbreviate journal names and add issue numbers; AMA format Author(s). Title. Journal. Year;vol(issue):pages.**
Done. The reference list is reformatted to AMA style with Index Medicus journal abbreviations and issue numbers (e.g., "Int J Gynecol Pathol. 2015;34(3):281-287."). The reproducible Quarto `references.bib` was likewise updated and an AMA CSL wired into the build.

**6. Each figure requires a legend; list legends together at the end of the text; remove titles from above each figure.**
Done. A "FIGURE LEGENDS" section listing all four legends is placed at the end of the article text. Figures were re-exported without on-figure titles/subtitles; all descriptive information is now in the legends.

**7. In Table 2, add a statement describing the meaning of the bolded entries.**
Done. Table 2's caption now states: the bolded entries denote the values on which the sampling recommendation is based (the occult-focus, <0.5 cm, cases that are the subject of the detection analysis).

**8. Higher-quality figures: TIFF or EPS, 1200 dpi line art, 1- or 2-column width (3.37–7 in).**
Done. All figures re-exported at 1200 dpi as TIFF (LZW) and EPS. Figures 1–3 are single-column (3.37 in); Figure 4 is double-column (7.0 in). Reproducible via `R/export_figures.R`.

**9. Supplemental Digital Content header + per-table titles above each table.**
Done. The SDC file opens with the required line: "Supplemental Digital Content, containing 5 tables. The Supplemental Digital Content was not copyedited by Archives of Pathology & Laboratory Medicine." Each of the 5 supplemental table titles appears above its table; footnotes appear below.

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## Section Editor

**S1. "A Data-Driven Study" in the title may not be informative.**
Done. The subtitle "; A Comprehensive Data-Driven Study" is removed. Revised title: *Influence of Omental Sampling Extent on the Detection of Occult Metastases in Ovarian and Endometrial Carcinomas.* (Alternative options offered in the cover note if the editor prefers a more specific title, e.g., "…: How Many Blocks Are Enough?")

**S2. The term "micrometastasis" conflicts with its specific meaning elsewhere in GYN pathology — essential to address.**
Done. Throughout the manuscript, "micrometastasis" is replaced by "microscopically detected (occult) omental metastasis," with an explicit definition and a sentence noting the potential confusion with the size-specific nodal-staging meaning of "micrometastasis," which is why the term is avoided. The <0.5 cm criterion is retained as an operational definition of grossly occult disease.

**S3. Justify accepting 95% sensitivity; why not add one more block when it halves the deficit?**
Done. A new Discussion paragraph reframes 95% as a practical minimum, not a biologic endpoint, and quantifies the residual miss rate (≈4.5% at 4 blocks, ≈2% at 5, <1% at 6 under the geometric model). We now recommend 4 blocks as a defensible minimum and explicitly endorse submitting additional blocks when staging accuracy is prioritized. The abstract and conclusions were updated to match.

**S4. "1098 patients diagnosed with carcinoma" is imprecise — 27 had serous borderline tumor; and "metastasis" should not be used for borderline tumor.**
Done. The cohort is now described as "1071 patients with a carcinoma and 27 with a serous borderline tumor (1098 total)." Involvement by borderline tumors is described as "omental involvement/implants," not "metastasis." The abstract, methods, and results were corrected accordingly.

**S5. Table 1 should be split into endometrial vs ovarian columns with actual histologic diagnoses; specify where low-grade serous carcinoma of the ovary (LGSC) sits; discuss LGSC contribution; note high-grade heterogeneity.**
Done. Table 1 is rebuilt with separate endometrial (n=591) and tubo-ovarian (n=497) columns listing actual histologic diagnoses. We note that the 7 ovarian LGSCs were grouped with high-grade tumors for grade-based analyses and itemize them separately; a Discussion paragraph addresses LGSC under-representation (7 cases, 1 occult focus) and the heterogeneity of the "high-grade" category (high-grade serous, carcinosarcoma, clear cell, high-grade endometrioid), which may differ in metastatic propensity.

**S6. "Tracking data" is nonstandard — clarify in the methods what it means and whether it was practiced for the whole study period.**
Done. A new Methods subsection "Definition of Tracking Data" explains that the laboratory records the cassette-by-cassette origin of omental sections and the first block in which an occult focus is seen, and states that this practice was in place throughout 2014–2023, allowing first-detection ascertainment in all 46 cases.

**S7. Synchronous cases: can origin be assigned? With only 8 cases their contribution should be small; are the 2 high-grade cases truly not metastases?**
Done. A new Discussion paragraph clarifies that **none of the 8 synchronous cases contributed to the detection analysis**: 6 had no omental involvement and 2 had grossly evident (macroscopic) disease, so 0 of 8 are among the 46 occult-focus cases. The 2 with macroscopic disease had concordant grade at both sites; because neither entered the occult-focus analysis, we did not assign a single site of origin and they do not confound the results.

**S8. The low-grade "no micrometastasis" claim (line 270) could discourage sampling; only 13 low-grade ovarian cancers — likely only powered for endometrial.**
Done. The statement is softened. We now state that occult sub-gross foci are uncommon in low-grade **endometrioid** carcinoma (not that low-grade tumors cannot metastasize), note the cohort is essentially powered only for low-grade endometrial disease (13 low-grade ovarian cases), and add that 6 low-grade cases did have macroscopic omental metastasis.

**S9. Cannot determine overall % of low- vs high-grade cases with metastases; did low-grade tumors have macrometastases? 33% low-grade admixture (mainly endometrial) may downplay real-world risk.**
Done. New Table 5 and a Results paragraph give omental involvement by grade for the full cohort: low-grade 1.6% (0 occult, 6 macroscopic), high-grade 52.7% (43 occult, 322 macroscopic), borderline 14.8%. The Discussion notes that the low-grade-heavy case mix means the overall 4.2% occult rate understates the risk in the high-grade tumors for which sampling matters most (occult rate 6.2%, any involvement 52.7% among high-grade).

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## Reviewer #1

**R1.1. Explain why <0.5 cm was chosen for micrometastasis and whether alternative thresholds were explored.**
Done. The Introduction now gives the rationale (0.5 cm approximates the lower limit of reliable gross/palpatory detection, so foci below it depend on histologic sampling) and states explicitly that alternative thresholds were not tested and the cutoff is operational rather than biologically derived.

**R1.2. Clarify whether the omentum in the 46 cases was grossly normal (a 4 mm focus could be grossly visible); confirm alignment with staging protocols.**
Done. Methods now state that in all 46 cases the omentum was recorded as grossly unremarkable, and that the archived gross descriptions were re-checked to confirm no macroscopic lesion. Results add that 23 of 46 foci measured 0.1 cm and only 2 measured exactly 0.5 cm, i.e., the great majority were well below the threshold of reliable gross detection.

**R1.3. Address selective sampling at grossing — the grosser may preferentially submit subtly abnormal tissue, inflating apparent 4-block sensitivity.**
Done. Added to Methods (Model Assumptions) and expanded in a dedicated Discussion paragraph acknowledging that informal targeting of firmer/fibrotic areas could raise the yield of the first blocks and inflate the sensitivity attributed to a 4-block protocol; we state our estimates reflect real-world grossing behavior and that random-sampling or spatially mapped studies would be needed to separate the effects.

**R1.4 (minor). What percentage of the 46 cases had the omentum as the stage-defining specimen? Were any advanced-stage by other sites?**
Done. Results now report that the omentum was the sole stage-defining specimen in **24 of 46 cases (52.2%)**; in the remaining 22 the stage was already established by other metastatic sites. (Case-level detail in Supplemental Table 2.)

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## Reviewer #2

**R2.1. Use "tubo-ovarian carcinoma" instead of "ovarian tumor/carcinoma" throughout.**
Done. "Ovarian carcinoma/tumor" changed to "tubo-ovarian carcinoma" throughout the manuscript, tables, and figure legends (where referring to the tumor group).

**R2.2. Micrometastasis reported as <0.5 cm — a 0.5 cm lesion is usually palpable/grossly identifiable; define size criteria in the Introduction.**
Done. The size criterion is now defined in the Introduction, with a note that 0.5 cm approximates the limit of gross/palpatory detection; foci in this study clustered well below it (median 0.15 cm). See also R1.2.

**R2.3. Provide the size of the micrometastatic foci for the 46 cases.**
Done. On re-review the greatest dimension of the occult foci ranged from 0.1 to 0.5 cm (median 0.15 cm; mean 0.20 cm); 23 (50.0%) were 0.1 cm and only 2 (4.3%) were 0.5 cm. Per-case sizes are in Supplemental Table 2.

**R2.4. Clarify the indication for omentectomy in low-grade endometrial carcinoma; was it performed for synchronous primaries?**
Done. The Discussion notes that omental staging is often not performed for low-grade endometrial carcinoma unless gross disease is present, and that our cohort reflects institutional practice in which omentectomy was performed across a broad range of tumors. Of the 8 synchronous cases, 5 were low-grade at both sites (see S7); none had an occult focus.

**R2.5. Sampling is increasingly important with NACT before debulking; were there differences between chemonaive and NACT groups?**
Done. A new Results subsection "Detection by Chemotherapy Status" (and Supplemental Table 4) reports that any omental involvement was far more frequent after neoadjuvant chemotherapy (100/113; 88.5%) than in chemonaive patients (275/985; 27.9%; chi-square P < .001), as was the occult focus specifically (16.8% vs 2.7%). Among occult-focus cases the mean first-detection cassette did not differ (1.95 vs 1.81; P = .95), so the number of blocks needed to find a focus is similar regardless of chemotherapy status — reinforcing the case for adequate sampling in this expanding group.

**R2.6. Address the optimal block number relative to the size of omental tissue removed; provide omentum size for the 46 cases.**
Done. Results now report that the greatest dimension of the omental specimen (available for 45 of 46 cases) ranged from 6.5 to 90 cm (median 23 cm; IQR 16–30 cm), indicating that occult foci were being sought within substantial volumes of grossly normal tissue. Per-case omentum sizes are in Supplemental Table 2.

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## Files submitted

- **Revised manuscript (Word):** `Article, Influence of Omental Sampling Extent … - REVISED.docx` — changes marked in red; figure legends collated at end.
- **Supplemental Digital Content (Word):** `Supplemental Digital Content.docx` — 5 tables with required header and per-table titles.
- **Figures:** `figures/revised/Figure1–4` — TIFF (1200 dpi, LZW) + EPS, 1- or 2-column width.
- **Reproducible sources:** updated `.qmd` chapters, `references.bib` (AMA), `american-medical-association.csl`, `R/export_figures.R`.

*All statistics were computed directly from the study dataset and are reproducible from the provided R code.*