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The PROSACC Study: A Detailed Overview

What is PROSACC?

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1. Background and Rationale

The Problem with Standard SLN Mapping in Cervical Cancer

Why an Anatomy-First Approach?

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2. Study Design

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3. The Upper and Lower Paracervical Pathways - Detailed Anatomy

3.1 Upper Paracervical Pathway (UPP)

Cervix
   |
   ↓  (via broad ligament / parametrial tissue superiorly)
Upper Paracervical Lymphatic Pathway (UPP)
   |
   ├─── Interiliac position (medial external iliac)
   |         → Along the external iliac vein, medial aspect
   |
   └─── Proximal Obturator Fossa (MOST IMPORTANT)
             → Lymph nodes in the proximal (cranial) obturator space
             → Deep to external iliac vessels, above the obturator nerve
             → Contains PARAUTERINE LYMPHOVASCULAR TISSUE (PULT)

• Runs in the broad ligament and upper parametrium
• The interiliac and proximal obturator positions are "anatomically typical" SLN locations
• The PULT (Parauterine Lymphovascular Tissue) = the tissue at the junction of the uterus and the proximal parametrium, which travels with the uterine artery - it harbors lymph nodes that are inside the parametrium itself
• These nodes are NOT retrieved by standard lateral pelvic lymphadenectomy - they are only removed as part of the radical hysterectomy parametrial tissue OR by explicit PULT dissection

3.2 Lower Paracervical Pathway (LPP)

Cervix
   |
   ↓  (via cardinal ligament / parametrial tissue inferiorly)
Lower Paracervical Pathway (LPP)
   |
   ├─── Internal iliac nodes
   |         → Along internal iliac vessels
   |
   └─── Presacral nodes
             → Anterior to sacrum
             → Variable, less consistently displayed with ICG

• Runs in the lower parametrium (cardinal ligament / paracervical web)
• SLN positions along the LPP are anatomically variable - "anatomically typical positions could not be defined along the LPP" (Lührs et al., 2022, PMID 35437170)
• Drains to internal iliac and presacral nodal groups
• The LPP is less frequently visualized by ICG injection - bilateral display occurs in only ~30% of cases
• When the LPP fails to display, a full presacral lymphadenectomy may be warranted (as per the Geppert 2017 anatomy paper)

3.3 Comparison Table: UPP vs LPP

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4. The PROSACC SLN Algorithm - Step by Step

STEP 1: PATIENT ELIGIBILITY
   ├─ FIGO 2009 stage IA2 - IIA1 cervical cancer
   ├─ Planning robotic radical hysterectomy or trachelectomy
   └─ No prior pelvic surgery/radiation

          ↓

STEP 2: ICG INJECTION (Intraoperative)
   ├─ Cervical injection at 3 and 9 o'clock positions
   ├─ Submucosal + deep stromal injection
   └─ Allow 5-10 minutes for lymphatic uptake

          ↓

STEP 3: SYSTEMATIC PELVIC MAPPING (Near-infrared fluorescence)
   ├─ Retroperitoneal dissection bilaterally
   ├─ Identify lymphatic channels, not just "hot" nodes
   └─ Map BOTH paracervical pathways:
       ├─ UPP: Follow broad ligament → interiliac → proximal obturator fossa
       └─ LPP: Follow cardinal ligament → internal iliac → presacral

          ↓

STEP 4: PULT IDENTIFICATION AND REMOVAL
   ├─ Identify parauterine lymphovascular tissue bilaterally
   ├─ Separate removal as dedicated "SLN-parametrium" specimen
   └─ Submit to ultrastaging separately

          ↓

STEP 5: SLN REMOVAL
   ├─ SLN = juxtauterine mapped nodes within UPP/LPP
   ├─ Remove all ICG-mapped nodes in typical positions
   ├─ Proximal obturator fossa specifically targeted
   └─ LPP nodes removed if visible

          ↓

STEP 6: COMPLETION PELVIC LYMPHADENECTOMY
   └─ Full bilateral pelvic LND after SLN removal
      (for validation - not standard clinical care)

          ↓

STEP 7: ULTRASTAGING + IHC
   ├─ Serial sectioning at 200-250 µm intervals
   ├─ H&E + cytokeratin immunohistochemistry
   └─ Applied to ALL SLN tissue including PULT

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5. Key Results

5.1 Primary Outcomes

5.2 Distribution of SLN Metastases in Node-Positive Women

This means if proximal obturator nodes and PULT were omitted, 50%+ of node-positive women would be missed.

5.3 PULT-Specific Data (from companion paper, PMID 34509298, n=145)

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6. Rationale Behind the Study

6.1 Inadequacy of Previous SLN Algorithms

• Earlier studies (SENTICOL I/II, etc.) reported sensitivity of ~92-96%, with documented false negatives - meaning some node-positive women received no adjuvant treatment
• False negatives were disproportionately in the parametrial and obturator regions - exactly the areas underemphasized in prior algorithms
• No prior study systematically defined SLNs based on lymphatic pathway anatomy rather than tracer uptake alone

6.2 The Parametrial Node Problem

• Classical radical hysterectomy (Wertheim-Meigs/Querleu-Morrow Type C) removes parametrial tissue to achieve oncologic radicality - but this also removes the PULT nodes without specific histologic analysis
• Routine parametrectomy is associated with significant morbidity: ureteral injury, bladder dysfunction, sexual dysfunction, lymphedema
• The question arose: if the PULT nodes could be specifically identified and analyzed, could less radical parametrectomy be justified in node-negative disease?

6.3 The De-escalation Imperative

• The SHAPE trial (2024) demonstrated non-inferiority of simple vs. radical hysterectomy in tumors ≤2 cm - driving interest in less radical parametrial resection
• PROSACC provides the anatomical and oncological framework to identify which patients truly need radical parametrectomy (node-positive PULT → parametrial involvement) vs. those who can safely have limited resection

6.4 Scientific Foundation

1. Geppert 2017 anatomy paper - defined UPP/LPP framework
2. Lührs 2021 (UPLT paper) - proved PULT contains clinically significant nodes
3. Lührs 2022 (cervical vs. endometrial SLN distribution) - confirmed anatomical similarities enabling cross-tumor evidence accumulation

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7. Clinical Implications

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8. Summary Comparison with Other Key Cervical Cancer SLN Trials

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Key References

1. Persson J et al. "A prospective study evaluating an optimized sentinel node algorithm in early stage cervical cancer: The PROSACC-study." Gynecol Oncol. 2024. PMID 38788515
2. Lührs O et al. "Resection of the upper paracervical lymphovascular tissue should be an integral part of a pelvic sentinel lymph node algorithm in early stage cervical cancer." Gynecol Oncol. 2021. PMID 34509298
3. Geppert B et al. "A study on uterine lymphatic anatomy for standardization of pelvic sentinel lymph node detection in endometrial cancer." Gynecol Oncol. 2017. PMID 28196672
4. Lührs O et al. "Similar distribution of pelvic sentinel lymph nodes and nodal metastases in cervical and endometrial cancer." Gynecol Oncol. 2022. PMID 35437170

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Summary

• The proximal obturator fossa (harbors 46% of all SLN metastases and is the sole metastatic site in 40% of node-positive women)
• The PULT/upper paracervical lymphovascular tissue (isolated metastases in 10% of node-positive women)
• Systematic mapping of both the upper paracervical pathway (UPP) - which drains to interiliac and obturator nodes - and the lower paracervical pathway (LPP) - which drains to internal iliac and presacral nodes