How is rectal adenocarcinoma classified to guide selection of neoadjuvant therapy?

Classification of Rectal Adenocarcinoma for Planning Neoadjuvant Therapy

Rectal adenocarcinomas are classified into risk-based treatment groups using TNM staging combined with high-resolution pelvic MRI assessment of critical prognostic features—specifically T-stage depth, nodal involvement, extramural vascular invasion (EMVI), tumor deposits, circumferential resection margin (CRM) threat, and tumor height—to determine whether patients require total neoadjuvant therapy, standard chemoradiotherapy, or surgery alone. 1

Anatomic Definition and Initial Staging

• Tumors with distal extension ≤15 cm from the anal verge (measured by rigid sigmoidoscopy) are classified as rectal; more proximal tumors are colonic. 1
• All patients require comprehensive staging with high-resolution pelvic MRI using dedicated rectal sequences, complete colonoscopy, chest/abdominal CT, and carcinoembryonic antigen (CEA) measurement. 1
• Pelvic MRI is the most accurate modality for locoregional staging because it defines extramural spread depth, relationship to the mesorectal fascia, EMVI presence, and tumor deposits—all of which guide neoadjuvant therapy selection. 1
• Endoscopic ultrasound may be used for earliest tumors (cT1-T2), though MRI is recommended for all tumors including the earliest ones. 1

Risk-Based Classification System

The ESMO and ASCO guidelines divide rectal cancers into practical treatment groups based on clinical stage and MRI-defined risk features: 1

Very Early/Early Disease (Local Excision Candidates)

• cT1N0 tumors without adverse features: small (<3 cm), well- to moderately differentiated, within 8 cm of anal verge, limited to <30% circumference, no nodal involvement on imaging. 1
• T1 tumors are further subclassified by depth of submucosal invasion (sm1/sm2/sm3 system or Haggitt levels) because sm3 invasion predicts lymph node metastasis risk and mandates radical resection. 1
• cT2N0 tumors generally require radical surgery due to 10-15% nodal metastasis risk, though highly selected cases may undergo local excision with close surveillance. 1

Intermediate/Standard Risk (Standard Neoadjuvant CRT)

• cT1-2N1 or cT3N0-N1 tumors with favorable features: mid-to-upper rectum location, clear CRM (>1 mm from mesorectal fascia), no EMVI, no tumor deposits, <4 involved nodes. 1
• These patients may receive standard long-course chemoradiotherapy (50.4 Gy with concurrent fluoropyrimidine) followed by surgery 6-8 weeks later, then adjuvant chemotherapy. 1

High Risk/Locally Advanced (Total Neoadjuvant Therapy Candidates)

Total neoadjuvant therapy is indicated for patients with any of the following high-risk features: 1, 2

• Low rectal tumors requiring potential abdominoperineal resection
• T4 tumors (invasion into adjacent organs/structures)
• Threatened or involved CRM (≤1 mm from mesorectal fascia on MRI)
• Extramural vascular invasion (EMVI) detected on MRI
• Tumor deposits identified on MRI (classified as N1c)
• Threatened intersphincteric plane in very low tumors
• cN2 disease (≥4 involved regional nodes)
• Enlarged lateral lymph nodes (short axis >7-10 mm)
• Tumors not eligible for sphincter-sparing surgery at baseline

The presence of EMVI or tumor deposits on MRI is associated with a four-fold increased risk of distant recurrence and significantly impacts local recurrence and mortality. 1

T-Stage Subclassification for Treatment Planning

The ESMO guidelines recommend subclassifying cT3 tumors by extramural invasion depth because this predicts outcome and influences neoadjuvant intensity: 1

• T3a: <1 mm extramural extension
• T3b: 1-5 mm extramural extension
• T3c: 6-15 mm extramural extension
• T3d: >15 mm extramural extension

T3c-d tumors are considered locally advanced and warrant total neoadjuvant therapy, whereas T3a-b with favorable features may receive standard chemoradiotherapy. 1

Nodal Classification

• N0: No regional lymph node metastasis
• N1: 1-3 regional nodes involved (N1a: 1 node; N1b: 2-3 nodes)
• N1c: Tumor deposits in perirectal fat without identifiable lymph node structure
• N2: ≥4 regional nodes involved 1

Clinical nodal staging by MRI has limited accuracy (60-75%), so treatment decisions should incorporate the constellation of MRI risk factors rather than cN stage alone. 1

Practical Treatment Algorithm

For cT1N0 with favorable features: Local excision (transanal excision or TEM) with full-thickness negative margins (>3 mm). If pathology reveals adverse features (sm3 invasion, lymphovascular invasion, poor differentiation, positive margins), proceed to radical TME. 1

For cT2N0 or cT1-2N1 or cT3a-bN0-1 with clear CRM and no EMVI: Standard long-course chemoradiotherapy (50.4 Gy with concurrent fluoropyrimidine) followed by TME at 6-8 weeks, then adjuvant chemotherapy for 3-4 months. 1

For cT3c-dN0-1, cT4, or any T-stage with high-risk MRI features (EMVI, tumor deposits, threatened CRM, low location): Total neoadjuvant therapy with long-course chemoradiotherapy (50.4 Gy with fluoropyrimidine) followed by consolidation chemotherapy (3-4 cycles FOLFOX or CAPOX), then TME at 6-8 weeks after completion. 1, 2

For microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors: Immunotherapy (pembrolizumab or dostarlimab) is the recommended treatment regardless of stage, as these tumors show exceptional response to checkpoint inhibition. 2

Critical Staging Pitfalls to Avoid

• Do not rely on CT alone for local staging—pelvic MRI is mandatory because CT cannot assess CRM status, EMVI, or precise T-stage depth. 1
• Do not use clinical nodal stage (cN) as the sole determinant for neoadjuvant therapy intensity; incorporate all MRI risk features including EMVI and tumor deposits. 1
• Do not omit MSI/MMR testing—these patients require immunotherapy rather than chemoradiotherapy. 2
• Ensure at least 12 lymph nodes are examined pathologically to prevent understaging and inappropriate omission of adjuvant therapy. 1
• Do not perform restaging MRI immediately after neoadjuvant therapy—wait 6-8 weeks to allow maximal tumor regression for accurate response assessment. 1, 2

Restaging After Neoadjuvant Therapy

• Restaging requires pelvic MRI with dedicated rectal sequences plus endoscopic examination (digital rectal exam and proctoscopy) performed 6-8 weeks after completing neoadjuvant therapy. 1, 2
• Patients achieving clinical complete response (cCR) on both MRI and endoscopy may be offered watch-and-wait organ preservation with intensive surveillance (MRI and endoscopy every 3-4 months for 2 years), particularly when surgery would require permanent colostomy. 2, 3
• The OPRA trial demonstrated 3-year TME-free survival of 41-53% with organ preservation approaches, with 94-99% of regrowth occurring within the first 2 years. 2, 3