Recent Advances in Management of Oesophageal Cancer

1. Staging and Diagnosis

• High-resolution endoscopic ultrasound (EUS) with fine-needle aspiration for T/N staging
• 18F-FDG PET-CT for detection of occult metastasis and response assessment
• AI-assisted endoscopy - machine learning algorithms are being validated for early detection and margin delineation in ESCC and Barrett's-related EAC (systematic review, 2025, PMID 40205603)
• Circulating tumour DNA (ctDNA) as a biomarker for treatment response monitoring and minimal residual disease detection - now actively studied in perioperative trials

2. Early-Stage Disease: Expanding Endoscopic Therapies

Treatment algorithm for adenocarcinoma and ESCC in medically fit patients - Current Surgical Therapy 14e (NCCN-based data)

3. Multimodal Therapy for Locally Advanced Disease

CROSS Protocol (still the cornerstone)

Perioperative Chemotherapy for EAC

• FLOT4 regimen (docetaxel, oxaliplatin, leucovorin, 5-FU, 4 pre- and 4 post-operative cycles) is preferred over ECF/ECX for EAC/GEJ adenocarcinoma, with median survival increasing from 35 to 50 months vs. MAGIC ECF
• ESOPEC trial directly compared CROSS vs. FLOT4 and found FLOT4 superior for EAC (5-year OS 50.7% vs. 36.3%)
• Total neoadjuvant therapy (moving all chemoradiation to the preoperative window) is under active investigation with FOLFOX + RT and FLOT4 + RT protocols

Definitive Chemoradiotherapy

4. Immunotherapy - The Major Advance

Adjuvant Immunotherapy

• CheckMate 577: Nivolumab (1 year, adjuvant) after trimodality therapy (CROSS + surgery) in patients with residual pathological disease doubled disease-free survival (DFS 22.4 vs. 11.0 months; HR 0.69). This is now standard of care for residual disease post-trimodality therapy. The treatment algorithm (above) now explicitly includes "adjuvant immunotherapy if evidence of residual disease after esophagectomy."

Perioperative Immunochemotherapy (Neoadjuvant + Surgery ± Adjuvant)

• Camrelizumab + chemotherapy: highest pCR and MPR rates
• Pembrolizumab + chemotherapy: highest ORR and DCR
• No significant increase in grade ≥3 TRAEs vs. chemotherapy alone
• Most common immune-related AEs: rash (4-22%), thyroid dysfunction (6-17%), pneumonitis (4-6%)

First-Line Metastatic/Unresectable

• Nivolumab + chemotherapy (CheckMate 648, 2022): approved for advanced/metastatic ESCC with PD-L1 ≥1% - first-line
• Nivolumab monotherapy (CheckMate 648): approved for tumour mutational burden (TMB)-high ESCC
• Pembrolizumab + chemotherapy (KEYNOTE-590): first-line ESCC and EAC/GEJ with PD-L1 CPS ≥10
• Tislelizumab (Tevimbra): FDA-approved March 2025 for first-line treatment of unresectable/metastatic ESCC with PD-L1 ≥1% (in combination with platinum-based chemotherapy); also approved 2024 as second-line monotherapy post-chemotherapy
• Durvalumab + FLOT: FDA-approved November 2025 for resectable gastric/GEJ adenocarcinoma, increasing pCR rate from 7% to ~19% (MATTERHORN trial) - first FDA-approved perioperative immunotherapy for this setting

New Immunotherapy Formulations (2024-2025)

• Nivolumab + hyaluronidase-nvhy (Opdivo Qvantig): subcutaneous formulation, FDA-approved 2024 - eliminates IV infusion
• Pembrolizumab + berahyaluronidase alfa-pmph (Keytruda Qlex): subcutaneous pembrolizumab, FDA-approved 2025

5. Targeted Therapy

HER2-Positive EAC/GEJ

• Trastuzumab + chemotherapy (ToGA regimen) remains standard for HER2-overexpressing advanced GEJ/EAC
• Trastuzumab deruxtecan (T-DXd): antibody-drug conjugate showing marked activity in HER2+ gastroesophageal cancers in later-line settings; phase 3 data expected
• Zanidatamab (bispecific HER2-targeting antibody) in trials

CLDN18.2-Positive EAC/GEJ

• Zolbetuximab (anti-CLDN18.2 cytolytic antibody): FDA-approved 2024 for first-line HER2-negative, CLDN18.2-positive locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma, in combination with fluoropyrimidine/platinum (SPOTLIGHT and GLOW trials). This is a landmark shift in treatment strategy requiring routine CLDN18.2 testing at diagnosis.

ASCO Guideline Update (2026)

6. Surgical Advances

Minimally Invasive Esophagectomy (MIE) and Robotic-Assisted (RAMIE)

• MIE and RAMIE both reduce pulmonary complications by ~50% vs. open (RR 0.46-0.48) and vs. hybrid esophagectomy (RR 0.54-0.57)
• Reduced intraoperative blood loss and shorter hospital stays
• Equivalent anastomotic leak rates, in-hospital mortality, and oncological radicality vs. open approaches
• Equivalent outcomes between MIE and RAMIE

Prehabilitation

AI in Surgery

7. Oligometastatic and Unresectable Disease

• Conversion surgery (after systemic therapy/immunotherapy leading to tumour downstaging) is increasingly pursued in selected patients with initially unresectable or T4b disease - a strategy borrowed from hepatic metastasis concepts
• Thoracic endovascular aortic repair (TEVAR) combined with resection is being evaluated for T4b tumours abutting the aorta (PMID 39058341)
• Stereotactic ablative body radiotherapy (SABR) for oligometastatic disease

8. Active Areas of Investigation

Summary Table: Key Milestones 2022-2026

Gastro-intestinal Anastomosis

I. Healing of a GI Anastomosis

Layers of the Bowel Wall

Phases of Healing

1. Lag phase (days 0-4) - Inflammatory phase. Collagenase activity predominates; existing collagen is lysed faster than new collagen is synthesised. Anastomotic strength actually decreases in this window. This is the period of maximum vulnerability.
2. Proliferative phase (days 4-14) - Fibroblast proliferation and new collagen synthesis accelerates. Anastomotic strength rises sharply.
3. Remodelling phase (days 14 onwards) - Type III collagen matures to type I; final tensile strength approaches pre-resection levels.

The "weak" period occurs when collagenolysis exceeds collagen synthesis - any factor that upsets this equilibrium prolongs vulnerability. (Schwartz's Principles of Surgery, 11e)

II. Factors Influencing GI Anastomosis

A. Local Technical Factors (Surgeon-Controlled)

B. Patient/Systemic Factors (Definitive)

1. Nutritional status - Protein malnutrition directly impairs collagen synthesis, fibroblast function, and immune response. Hypoalbuminaemia (<3 g/dL) is one of the strongest predictors of anastomotic leak. Preoperative nutritional optimisation (including enteral/parenteral nutrition where needed) is essential.
2. Blood supply and perfusion - Systemic hypotension, shock, and coagulopathy reduce microvascular perfusion at the anastomotic edge. Over-zealous fluid resuscitation causes tissue oedema and third-space losses, also compromising small vessel flow.
3. Sepsis - Systemic sepsis and localised intra-abdominal infection raise collagenase levels, actively degrading newly formed collagen at the suture line.
4. Immunosuppression - Steroids, immunosuppressants (e.g. methotrexate, infliximab), and chemotherapy all impair wound healing.
5. Radiotherapy - Prior irradiation causes obliterative endarteritis and fibrosis in the bowel wall, profoundly impairing healing. Anastomoses in irradiated bowel carry substantially higher leak rates.
6. Smoking - Vasoconstriction and impaired tissue oxygenation.
7. Obesity - Poor tissue quality, difficult mobilisation, increased abdominal pressure.
8. Diabetes - Impairs leucocyte function and microvascular circulation.
9. Anaemia - Reduces oxygen delivery to the healing tissue.
10. Deficiencies - Vitamin C, iron, zinc, and copper are all required for normal collagen synthesis.

C. Local Bowel-Related Factors

• Crohn's disease - Transmural inflammation, dense adhesions, and impaired healing.
• Compromised distal lumen - Anastomosis performed proximal to an unrecognised partial obstruction will fail due to elevated intraluminal pressure.
• Bowel oedema - Reduces suture-holding capacity.
• Radiation damage - As above.

D. Location in the GI Tract

• Oesophageal anastomoses - Highest risk; oesophagus lacks a serosa and has a tenuous blood supply. Cervical oesophageal anastomoses leak more often than thoracic but the consequences are usually less severe.
• Gastroduodenal / gastrojejunal - Good blood supply; generally heal reliably.
• Small bowel - Excellent blood supply, heals well.
• Ileocolic - Good outcomes; side-to-side/functional end-to-end stapled anastomosis has the lowest leak rate.
• Colorectal - Significant risk, especially below the peritoneal reflection.
• Coloanal / low anterior - Highest risk in colorectal surgery. Routine defunctioning proximal stoma is often used as protection.

III. Sites of GI Anastomosis

Upper GI

Biliary/Pancreatic

Small Bowel

Large Bowel / Anorectal

IV. Techniques of GI Anastomosis

A. Configuration (Geometry)

A. Sutured end-to-end colocolic anastomosis. B. Sutured end-to-side ileocolic anastomosis. C. Stapled side-to-side (functional end-to-end) ileocolic anastomosis. (Schwartz's Principles of Surgery, 11e)

• Used when both bowel ends are of roughly equal calibre.
• Most physiological - restores normal anatomical continuity.
• Most common in: rectal resections (circular stapler EEA), small bowel anastomoses, colocolostomy.
• Risk: if there is size disparity, one end can be antimesenteric-ally cut obliquely ("fish-mouthed") to enlarge it.

• One end of bowel is joined to the side of another segment.
• Useful when the proximal bowel is smaller than the distal bowel (e.g. chronic obstruction leads to proximal dilatation and distal collapse).
• Common examples: hepaticojejunostomy, Roux-en-Y jejunojejunostomy, oesophagojejunostomy after total gastrectomy.

• The side of the proximal bowel is joined to the end of the distal bowel.
• Used when the proximal is of smaller calibre than the distal.
• Example: ileorectal anastomosis (small ileum to wider rectum).
• May have a slightly better blood supply than end-to-end.

• Two antimesenteric walls of bowel are joined together using a linear cutting stapler.
• Creates a wide-calibre, well-vascularised anastomosis.
• Widely favoured in ileocolic and small bowel anastomoses.
• In Crohn's disease, a wider side-to-side anastomosis may delay the time to symptomatic re-stricturing.
• The open end after the stapled anastomosis is then closed with a further linear stapler or hand-sutured.

B. Suture Techniques (Hand-Sewn)

1. Single-Layer Anastomosis

• Full-thickness interrupted or continuous sutures, taking a generous bite of submucosa on each side.
• Interrupted single-layer: most commonly 2-0 or 3-0 absorbable sutures (polyglycolic acid, polyglactin). Allows individual knot security.
• Continuous single-layer: faster to construct; slightly higher risk of purse-stringing the anastomosis if overly tightened.
• Used for colonic, ileocolic, small bowel, and oesophageal anastomoses.

2. Double-Layer (Two-Layer) Anastomosis

• Inner layer: continuous all-layers (full-thickness) suture using absorbable material (e.g. 3-0 Vicryl) to achieve mucosal apposition and haemostasis.
• Outer layer: interrupted seromuscular (Lembert) sutures using non-absorbable or slowly absorbable suture (e.g. 3-0 silk or PDS), inverting the inner layer and bringing serosa into apposition (serosa-to-serosa contact aids healing in bowel, unlike the oesophagus which lacks serosa).
• Historically considered more secure; no longer shown to be superior to single-layer in controlled trials.
• More tissue inversion may narrow the anastomotic lumen.

3. Suture Material Considerations

C. Stapled Techniques

1. Linear Cutting Stapler (GIA - Gastrointestinal Anastomosis Stapler)

• Simultaneously cuts and places two rows of B-shaped staples on each side of the cut.
• Used for: bowel transection, side-to-side anastomosis (functional end-to-end), closure of enterotomies.
• Creates the commonest modern anastomosis: the functional end-to-end (side-to-side) ileocolic anastomosis.
• The residual common enterotomy opening is then closed with a further linear stapler or hand-sutured.

2. Linear Non-Cutting Stapler (TA - Thoraco-Abdominal Stapler)

• Places two or three rows of staples without cutting.
• Used for: closure of a bowel stump (e.g. Hartmann's procedure), closing the common enterotomy after a side-to-side anastomosis.

3. Circular Stapler (EEA - End-to-End Anastomosis Stapler)

• An instrument with an anvil and a circular cartridge that simultaneously cuts a ring of tissue and places a double row of circular staples, creating an end-to-end anastomosis.
• The anvil is placed in one bowel end (secured with pursestring suture); the instrument body is inserted per anus or through a stab incision in the other end.
• Key uses:
  • Low anterior resection / colorectal anastomosis - where hand-suturing in the deep pelvis is technically impossible
  • Oesophagogastric anastomosis (Ivor Lewis oesophagectomy) - circular or ORVIL linear stapler
  • Total gastrectomy - oesophagojejunostomy
• Step-by-step: purse-string in each end → insert anvil → dock anvil to instrument body → close and fire → withdraw, inspect two complete "doughnuts" of resected tissue (confirms full-thickness bites taken on both sides) → test with air insufflation under saline.

Patient in modified lithotomy position. After resection and purse-string placement, the circular stapler is inserted through the anal canal. Both purse-strings are tied to secure bowel to anvil and rod. The stapler is closed and fired, leaving a circular end-to-end anastomosis. The two "doughnuts" are inspected for completeness.

4. Comparison: Hand-Sewn vs. Stapled

D. Special Techniques

• Maingot's Abdominal Operations: "A biliary-enteric anastomosis is performed using a mucosa-to-mucosa technique in a tension-free manner."

• Manual mucosectomy of the anal canal
• Coloanal anastomosis created at the dentate line using interrupted absorbable sutures transanally
• Often protected by a proximal defunctioning loop ileostomy

• After proctocolectomy for UC or FAP
• An ileal reservoir (J-, W-, or S-pouch) constructed from terminal ileum using linear staplers
• Pouch-anal anastomosis either hand-sewn (after mucosectomy) or stapled (double-stapled technique, preserving transitional zone)

V. Complications of Anastomosis

VI. Principles to Ensure a Safe Anastomosis (Summary)

1. Adequate blood supply to both ends - healthy pink, pulsating vessels, no blue/dusky bowel.
2. No tension - mobilise both limbs sufficiently before constructing the anastomosis.
3. Submucosa included in every stitch or staple line.
4. Airtight and watertight - test by air insufflation or rectal wash.
5. Well-nourished, optimised patient - correct malnutrition, treat sepsis, stop immunosuppressants where possible.
6. Avoid contaminated fields - in gross faecal peritonitis, consider a temporary stoma rather than a primary anastomosis.
7. Calibre match - choose configuration appropriate to the lumen sizes.
8. Protect if in doubt - a proximal defunctioning stoma (loop ileostomy) for high-risk low rectal or coloanal anastomoses.

"Accurate approximation of two well-vascularised, healthy limbs of bowel without tension in a normotensive, well-nourished patient almost always results in a good outcome."

• Schwartz's Principles of Surgery, 11e, p. 1301

• Schwartz's Principles of Surgery, 11e - Anastomoses, Chapter 29, p. 1301-1303
• Sabiston Textbook of Surgery, The Biological Basis of Modern Surgical Practice - Anastomotic Leak, Chapter 26
• Fischer's Mastery of Surgery, 8e - Anastomosis, Chapter on Oesophagectomy and Gastric Reconstruction
• Maingot's Abdominal Operations - Anastomosis in Crohn's Disease, Chapter on Intestinal Surgery
• Current Surgical Therapy, 14e - Multimodal Therapy and Anastomotic Technique

Blind Loop Syndrome (Stagnant Loop Syndrome / Small Intestinal Bacterial Overgrowth)

Definition

Normal Intestinal Flora

• The upper small intestine (duodenum and proximal jejunum) contains fewer than 10³ bacteria/mL, predominantly gram-positive aerobes and facultative anaerobes (lactobacilli, enterococci, streptococci)
• The distal ileum contains 10⁶-10⁸ organisms/mL - a mix of aerobes and anaerobes
• The colon contains >10¹¹ organisms/mL - predominantly anaerobes (Bacteroides, Clostridium)

1. Gastric acid - bactericidal effect; achlorhydria markedly increases risk of SIBO
2. Intestinal motility (peristalsis) - the "migrating motor complex" (MMC) sweeps bacteria distally
3. Intestinal immunoglobulins (IgA) - mucosal antibacterial defence
4. Ileocaecal valve - prevents retrograde colonic contamination
5. Mucus layer and intact epithelium
6. Bile salts - have direct bacteriostatic properties

Aetiology and Causes

A. Anatomical Blind Loops (Surgical)

B. Anatomical Conditions (Non-Surgical)

C. Motility Disorders

D. Hypochlorhydria / Achlorhydria

• Prolonged PPI use
• Pernicious anaemia / atrophic gastritis
• Post-gastrectomy state

E. Immune Deficiency

• Common variable immunodeficiency (CVID)
• IgA deficiency
• HIV/AIDS

F. Miscellaneous

• Elderly (decreased gastric acid, impaired motility)
• Cirrhosis / portal hypertension (impaired gut immunity)
• Radiation enteritis

Pathophysiology

1. Fat Malabsorption (Steatorrhoea)

• Unconjugated bile salts have a higher pKa and are passively absorbed in the proximal small bowel before they can participate in micelle formation
• The intraluminal concentration of bile salts falls below the critical micellar concentration (2-3 mmol/L)
• Micelle formation fails → impaired absorption of fat and fat-soluble vitamins (A, D, E, K)
• Unabsorbed fatty acids stimulate colonic secretion → watery diarrhoea
• Resulting in: steatorrhoea, osteomalacia (vitamin D), night blindness (vitamin A), coagulopathy (vitamin K), vitamin E deficiency (spinocerebellar degeneration)

2. Vitamin B12 Deficiency (Megaloblastic Anaemia)

• Bacteria, especially anaerobes in the distal small bowel, competitively consume vitamin B12 preferentially before it can be absorbed by the terminal ileum
• Some bacteria also produce proteases that degrade ileal B12-intrinsic factor complexes
• Leads to vitamin B12 deficiency → megaloblastic anaemia and subacute combined degeneration of the spinal cord (posterior and lateral column degeneration)
• Key distinguishing feature: in blind loop syndrome, B12 deficiency is NOT corrected by adding intrinsic factor (unlike pernicious anaemia), but IS corrected by antibiotics

3. Folate - Paradox

• Anaerobic bacteria synthesise folate; therefore serum folate levels are normal or elevated in SIBO
• This is a useful diagnostic distinction from tropical sprue (and pernicious anaemia), where both B12 and folate are low

4. Carbohydrate Malabsorption

• Bacteria release proteases that degrade brush-border disaccharidases (e.g. lactase, sucrase) → impaired carbohydrate digestion → osmotic diarrhoea and gas/bloating
• Fermentation of unabsorbed carbohydrates produces hydrogen and CO₂ → flatulence and abdominal distension

5. Protein Malabsorption

• Relatively uncommon and less severe; bacterial proteases can degrade luminal proteins
• Enterocyte damage from toxic bacterial metabolites contributes

6. Mucosal Damage

• Toxic bacterial metabolites and unconjugated bile salts directly damage the enterocyte brush border → partial villous atrophy → worsens all malabsorption

Clinical Features

Gastrointestinal

• Diarrhoea (watery or fatty/greasy stools)
• Steatorrhoea - pale, bulky, offensive, difficult to flush stools
• Abdominal pain and cramps
• Bloating, flatulence, borborygmi
• Anorexia and weight loss
• Nausea and vomiting

Haematological

• Megaloblastic anaemia - macrocytic anaemia with hypersegmented neutrophils
  • Due to vitamin B12 deficiency
  • Note: folate is usually normal or elevated (anaerobic bacteria synthesise it)

Neurological

• Subacute combined degeneration of the spinal cord (posterior columns + lateral corticospinal tracts)
  • Peripheral neuropathy (paraesthesiae, numbness)
  • Dorsal column loss (proprioception, vibration)
  • Upper motor neuron signs if severe
• Spinocerebellar ataxia (vitamin E deficiency)

Nutritional/Metabolic

• Osteomalacia (vitamin D deficiency) - bone pain, proximal myopathy, pathological fractures
• Coagulopathy (vitamin K deficiency) - easy bruising, prolonged prothrombin time
• Glossitis and angular stomatitis (generalised nutritional deficiency)
• Peripheral oedema (hypoproteinaemia)

Dermatological (Bowel-Associated Dermatitis-Arthritis Syndrome)

• Pustular or vesicopustular skin lesions
• Arthralgia / arthritis (non-destructive, seronegative)
• Dermatology 5e: "In bowel-associated dermatitis-arthritis syndrome, there is usually bacterial overgrowth in a blind loop of bowel."

Investigations

Laboratory Tests

Specific Diagnostic Tests

• Duodenal / jejunal aspirate obtained via endoscope or nasojejunal tube
• Bacterial count >10³ CFU/mL in jejunal aspirate is diagnostic of SIBO
• Allows identification of organisms and antibiotic sensitivity
• Invasive; not widely used in routine practice

• Glucose hydrogen breath test: Glucose is absorbed in the proximal small bowel; if bacteria are present, they ferment glucose and produce an early rise in breath hydrogen
• Lactulose hydrogen breath test: Lactulose is not absorbed; a rise in breath hydrogen within 30 minutes of ingestion suggests early fermentation by small bowel bacteria
• Diagnostic criterion: early rise of ≥20 ppm above baseline within 30 minutes
• Tietz Textbook of Laboratory Medicine: "The early increase is diagnostic when it can be distinguished clearly from the later colonic phase"
• Limitations: poor sensitivity; variations in gastric emptying and transit times affect accuracy; false positives in rapid transit

• Radiolabelled bile salt is administered; if bacteria deconjugate it, the ¹⁴C label is released and detected in breath
• Superseded by non-radioactive alternatives

• Non-radioactive versions; better safety profile

• Radiolabelled (⁵⁷Co) vitamin B12 absorption measured in urine
• In blind loop: urinary excretion is low (0-6% vs. normal 7-25%), resembling pernicious anaemia
• Key distinguishing feature: not corrected by intrinsic factor (unlike pernicious anaemia); IS corrected after a course of broad-spectrum antibiotics - this correction was pathognomonic of blind loop syndrome
• Now replaced by breath tests and direct culture

• Identify structural abnormalities: diverticula, blind loops, strictures, fistulae, "hide-bound" appearance in scleroderma
• Useful for delineating the anatomy before surgical correction

• Identifies: diverticula, loops, strictures, fistulae, associated disease (Crohn's, scleroderma)

Treatment

1. Correction of Underlying Cause (Definitive Treatment)

• Surgical correction of the anatomical abnormality (e.g. take down a blind loop, resect a stricture, repair a fistula) produces a permanent cure and is the treatment of choice when feasible
• Indicated when patients require multiple antibiotic courses or continuous antibiotic therapy
• Sabiston: "Surgical correction of the condition causing stagnation and blind loop syndrome produces a permanent cure and is indicated for patients who require multiple rounds of antibiotics or are receiving continuous therapy"
• Note: in diverticulosis or non-correctable dysmotility, surgery may not be possible; chronic medical management is required

2. Antibiotic Therapy

• A single 7-10 day course is sufficient for most; the patient may remain symptom-free for months thereafter
• If symptoms recur, cyclic/rotating antibiotics (1-3 weeks out of every 4-6 weeks) with different antibiotic classes is used to minimise resistance
• Goldman-Cecil: "Rifaximin is effective, but less so in individuals with an excluded (blind) intestinal loop" - because the drug is non-absorbable and may not reach the excluded loop in adequate concentration

3. Nutritional Supplementation

4. Prokinetic Agents

• Used in dysmotility-associated SIBO to improve intestinal transit and clearance
• Prucalopride (5-HT₄ agonist), metoclopramide, erythromycin (motilin receptor agonist)
• Octreotide (50 μg SC daily) - specifically useful in scleroderma-associated SIBO; stimulates the MMC and reduces bacterial overgrowth
• Generally have modest benefit; prokinetics alone are insufficient to eradicate established overgrowth

5. Stop/Reduce Acid-Suppressing Drugs

• PPIs and H₂ blockers should be withdrawn or reduced where possible, as achlorhydria is a contributing factor

Complications

• Severe malnutrition and cachexia
• Bone disease (osteomalacia, osteoporosis, pathological fractures)
• Irreversible neurological damage (subacute combined degeneration)
• Anaemia and immunosuppression
• In jejunoileal bypass patients - also oxalate nephrolithiasis and bowel-associated dermatitis-arthritis syndrome

Summary

• Sabiston Textbook of Surgery, The Biological Basis of Modern Surgical Practice - Blind Loop Syndrome, Chapter 91, p. 1985
• Goldman-Cecil Medicine - Intestinal Bacterial Overgrowth, Chapter 126
• Bailey and Love's Short Practice of Surgery, 28e - Bacterial Overgrowth, Chapter 74
• Yamada's Textbook of Gastroenterology, 7e - Bacterial Overgrowth Syndrome, Chapters 11 & 25
• Maingot's Abdominal Operations - Jejunoileal Diverticulosis and Bacterial Overgrowth
• Goodman & Gilman's Pharmacological Basis of Therapeutics - SIBO, Table 54-7
• Tietz Textbook of Laboratory Medicine, 7e - Abnormalities of the Small Intestine Associated With Bacterial Overgrowth, Box 52.4

Tumor Markers

Definition

"Tumor markers are indicators of cellular, biochemical, molecular, or genetic alterations by which neoplasia can be recognised. They are surrogate measures of the biology of the cancer, providing insight into the clinical behaviour of the tumor."

• Sabiston Textbook of Surgery

Ideal Characteristics of a Tumor Marker

1. Produced exclusively by the specific tumour (100% specificity - never achieved in practice)
2. Easy specimen collection (blood or urine)
3. Assay is reproducible, rapid, and inexpensive

• Low sensitivity - especially in early-stage disease
• Low specificity - elevated in benign conditions
• Overlapping expression across multiple tumour types

"Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood lack the sensitivity and specificity necessary to diagnose cancer; however, in concert with other tests, they may contribute to detection, and in many instances are useful in following response to therapy and detecting recurrence."

• Robbins & Kumar Pathologic Basis of Disease

Classification of Tumor Markers

1. Proteins
2. Whole cells (circulating tumour cells, CTCs)
3. RNA-based markers (mRNA, miRNA, lncRNA)
4. DNA-based markers (ctDNA, SNPs, gene fusions, methylation)

A. Protein Markers (Classical)

Individual Tumor Markers - Detailed

1. Carcinoembryonic Antigen (CEA)

• Nature: Oncofetal glycoprotein (MW 200 kDa); member of the immunoglobulin gene superfamily; normally present on the luminal surface of foetal intestinal epithelial cells; component of the glycocalyx.
• Normal value: <2.5 ng/mL (non-smokers); <5 ng/mL (smokers)
• Tumours: Colorectal (primary use), pancreatic, gastric, lung, breast carcinomas

2. Alpha-Fetoprotein (AFP)

• Nature: Oncofetal single-chain polypeptide (MW 70 kDa); synthesised by hepatocytes and endoderm-derived GI tissues during foetal life; falls to <10 ng/mL after birth.
• Normal value: <10 ng/mL (non-pregnant adult)
• Tumours: Hepatocellular carcinoma (HCC), nonseminomatous germ cell tumours (yolk sac tumour 90-95%, embryonal carcinoma 10%, teratoma 20%), intrahepatic cholangiocarcinoma (sometimes)

3. Prostate-Specific Antigen (PSA)

• Nature: A serine kallikrein protease; produced by prostatic epithelium and periurethral glands; liquefies seminal fluid.
• Normal value: Varies by age; generally <4.0 ng/mL (though age-specific norms are used)
• Tumour: Prostate adenocarcinoma

4. Cancer Antigen 125 (CA-125)

• Nature: A mucin-type glycoprotein expressed on the surface of epithelial ovarian cancer cells and normal peritoneal, pleural, and pericardial mesothelium.
• Normal value: <35 U/mL
• Tumours: Epithelial ovarian cancer (primary), fallopian tube, endometrial, cervical, pancreatic, colonic

5. Carbohydrate Antigen 19-9 (CA 19-9)

• Nature: A mucin-type glycoprotein expressed on pancreatic cancer cells; epitope is normally present within the biliary tree; requires the Lewis (Lea/Leb) blood group antigen for synthesis.
• Normal value: <37 U/mL
• Tumours: Pancreatic ductal adenocarcinoma (PDAC), biliary tract cancers, stomach, colon

6. Human Chorionic Gonadotropin (hCG / β-hCG)

• Nature: A glycoprotein hormone (heterodimer: α and β subunits); normally produced by trophoblastic cells in pregnancy; β-subunit is measured specifically in oncology.
• Tumours: Gestational trophoblastic tumours (choriocarcinoma, hydatidiform mole), nonseminomatous germ cell tumours (choriocarcinoma >90%, some mixed GCTs), occasionally large cell lung carcinoma

7. Lactate Dehydrogenase (LDH)

• Not tumour-specific but useful as a non-specific marker of tumour burden and tissue destruction.
• Elevated in: lymphomas, leukaemia, testicular germ cell tumours, melanoma, disseminated malignancy.
• In testicular GCT: LDH is the third serum marker (alongside AFP and hCG) used for staging and prognosis.
• Elevated LDH indicates aggressive disease, large tumour bulk, and rapid cell turnover.

8. CA 15-3 / CA 27-29

• Nature: Mucin glycoproteins (products of the MUC-1 gene); CA 27-29 is a more sensitive assay for the same antigen.
• Tumour: Breast cancer
• Used for monitoring response to therapy and detecting recurrence in metastatic breast cancer.
• NOT recommended for screening or primary diagnosis.
• Elevated in: cirrhosis, hepatitis, benign breast/ovarian disease, endometriosis.

9. Calcitonin

• Tumour: Medullary thyroid carcinoma (MTC) - produced by parafollicular C cells
• Elevated calcitonin is both diagnostic and a monitoring marker; stimulated by calcium/pentagastrin in equivocal cases.
• All patients with MTC and their first-degree relatives (MEN 2A, 2B) require calcitonin surveillance.

10. Thyroglobulin (Tg)

• Tumour: Differentiated thyroid carcinoma (papillary and follicular) post-thyroidectomy
• After total thyroidectomy + radioiodine ablation, serum Tg should be undetectable. Any detectable Tg indicates residual/recurrent differentiated thyroid cancer.
• Anti-thyroglobulin antibodies (anti-Tg Ab) can interfere with the assay.

11. Catecholamines and Metabolites

• Tumours: Phaeochromocytoma, paraganglioma, neuroblastoma
• Markers: Urinary vanillylmandelic acid (VMA), urinary metanephrines, plasma metanephrines (most sensitive)
• Plasma metanephrines: sensitivity ~99% for phaeochromocytoma
• 24-hour urinary catecholamines, metanephrines, VMA for neuroblastoma (also: urine homovanillic acid [HVA])

12. Immunoglobulins (M-protein / Paraprotein)

• Tumours: Multiple myeloma, Waldenström macroglobulinaemia, MGUS, plasmacytoma
• Serum protein electrophoresis (SPEP) demonstrates a monoclonal "M-spike"
• Quantification of the specific immunoglobulin (IgG, IgA, IgM) + serum free light chains (kappa/lambda ratio)
• Serum free light chains (FLC) are the most sensitive markers in light-chain only myeloma
• Used for diagnosis, staging, monitoring response, and detecting relapse

13. β-2 Microglobulin

• Non-specific marker of tumour burden
• Elevated in multiple myeloma, lymphoma, leukaemia
• Strong independent prognostic factor in multiple myeloma (forms part of staging systems)

14. Neuron-Specific Enolase (NSE)

• Tumours: Small cell lung cancer (SCLC), neuroblastoma, neuroendocrine tumours (NET), medullary thyroid carcinoma, carcinoid
• Used for monitoring response to treatment in SCLC

15. Chromogranin A (CgA)

• Tumours: Neuroendocrine tumours (functioning and non-functioning), carcinoid tumours, pheochromocytoma, paraganglioma
• Widely used for diagnosis and monitoring of NETs; correlates with tumour burden
• Can be elevated by PPIs (inhibit gastric acid → gastrin-driven CgA rise from ECL cells)

16. 5-HIAA (5-Hydroxyindoleacetic Acid)

• Tumour: Carcinoid tumour (functioning midgut)
• 24-hour urinary 5-HIAA: elevated in carcinoid syndrome
• Confirms carcinoid syndrome and monitors response to octreotide/surgery

Summary Table of Major Tumor Markers

Clinical Uses of Tumor Markers

1. Screening

• AFP + ultrasound for HCC in cirrhotic patients
• β-hCG for gestational trophoblastic disease follow-up
• Calcitonin for MTC in MEN 2 families

2. Diagnosis

3. Staging and Tumour Burden

• Higher levels generally reflect greater tumour bulk
• AFP and hCG are part of the IGCCCG staging system for testicular germ cell tumours (good, intermediate, poor prognosis risk groups)
• β-2 microglobulin is a component of ISS staging for myeloma

4. Prognosis

• Pre-operative CEA: independent predictor of survival in CRC
• AFP level and doubling time: correlate with HCC prognosis
• CA-125 stage correlation in ovarian cancer
• LDH elevation: poor prognostic sign in lymphoma and testicular GCT

5. Monitoring Response to Therapy (Primary Clinical Use)

• After effective treatment, marker levels should fall. The rate of fall and the post-treatment nadir are clinically important.
• Persistent elevation or failure to reach expected nadir = residual disease
• Tietz: "Serial results are nearly always more useful than single isolated results because the main application of tumor markers is in monitoring."

6. Detection of Recurrence

• A rise in marker level (e.g. CEA post-colectomy, PSA post-prostatectomy, CA-125 post-chemotherapy) often precedes clinical or imaging evidence of recurrence by weeks to months
• Allows earlier intervention

Emerging / New Generation Markers

A. Tissue Molecular Markers (Predictive Biomarkers)

B. Circulating Tumor DNA (ctDNA) / Liquid Biopsy

• Tumour-derived cell-free DNA shed into the bloodstream from apoptotic/necrotic cancer cells
• Detects tumour-specific mutations, gene fusions, copy number changes, methylation patterns
• Applications:
  • Early detection: CancerSEEK assay (61-amplicon panel + 39 oncoproteins): sensitivity 69-98% for 5 cancer types, specificity >99%
  • Residual disease detection: Post-surgical ctDNA predicts relapse in CRC
  • Treatment guidance: EGFR T790M detected in plasma → osimertinib eligibility
  • Treatment monitoring: ctDNA falls within 1-2 weeks in responsive tumours
  • Acquired resistance detection: Non-invasive tumour evolution tracking
• FDA-approved applications: Cologuard (stool DNA + FIT for CRC), cobas EGFR Mutation Test (plasma EGFR)

C. Circulating Tumor Cells (CTCs)

• Intact malignant cells shed from the primary or metastatic tumour into blood
• In metastatic cancer, estimated at 1 CTC per billion blood cells
• CellSearch system (FDA-approved): EpCAM-based isolation
• Applications: prognosis in metastatic breast/colorectal/prostate cancer

D. RNA-Based Markers

• MicroRNA (miRNA): Stable in body fluids; differential expression in cancer
• NETest: 51-gene mRNA-based blood test for neuroendocrine tumours

E. Proteomic Profiling

• Mass spectrometry of serum generates complex protein "fingerprints"
• Potential for much higher diagnostic sensitivity/specificity than single markers
• Still largely investigational

Limitations of Tumor Markers

1. Low sensitivity in early disease - the stage where treatment has the greatest impact
2. Non-specificity - elevated in benign conditions (false positives cause anxiety and unnecessary investigation)
3. Heterogeneity - not all tumours of the same type produce the marker (e.g. some CRCs do not produce CEA)
4. No single tumour-specific marker exists for most cancers
5. Assay variation between laboratories - serial measurements should be done on the same platform
6. Rifaximin note: similarly, in oncology, "opportunistic screening with panels of tumor markers is not helpful" (Tietz Laboratory Medicine)
7. Prozone / hook effect - extremely high antigen concentrations may give falsely low immunoassay results (especially β-hCG)

"Opportunistic screening with panels of tumor markers is not helpful. Serial results are nearly always more useful than single isolated results."

• Tietz Textbook of Laboratory Medicine

Conclusion

• Robbins & Kumar Pathologic Basis of Disease (10e) - Tumor Markers, Chapter 7
• Robbins & Kumar Basic Pathology - Tumor Markers, Chapter 7
• Sabiston Textbook of Surgery - Tumor Markers, Chapter 60
• Tietz Textbook of Laboratory Medicine (7e) - Tumor Markers
• Harrison's Principles of Internal Medicine (22e) - Circulating Nucleic Acids as Liquid Biopsies, Chapter 503
• Henry's Clinical Diagnosis and Management by Laboratory Methods - Tumor Markers in Body Fluids

Stereotactic Core Biopsy

Definition

"Stereotactic breast biopsy is the sampling of nonpalpable or indistinct breast lesions through spatial localisation of the lesion within the breast using radiographic imaging."

• Current Surgical Therapy, 14e

Historical Background

• In the late 1980s, Dowlat introduced stereotactic biopsy technology to the United States
• Prior to this, all non-palpable breast lesions required surgical excision after needle localisation - resulting in vast numbers of surgeries for non-malignant mammographic abnormalities
• In the United States, >1 million surgical breast biopsies are performed annually; only 15-30% are malignant - highlighting the importance of a reliable non-surgical diagnostic technique
• Image-guided core biopsy now accounts for more than half of all breast biopsies
• It is endorsed by the American Society of Breast Surgeons and is a quality measure for the National Accreditation Program for Breast Centers

Principle of Stereotactic Localisation

1. A scout (0°) image is obtained with the breast compressed between the paddle and the image receptor
2. Two additional images are then obtained at +15° and -15° (30° apart)
3. The parallax shift of the target lesion between these two angled views allows calculation of its precise X, Y, and Z (depth) coordinates within the compressed breast
4. The computer translates these coordinates to position the needle device accurately at the target

FIG. 1: A. Diagram of breast compression between paddle and image receptor with pre-fire needle targeting the lesion. B. Scout mammogram showing marker and needle hub correctly positioned at the target. (Current Surgical Therapy 14e)

Imaging Modalities Used

1. 2D Digital Mammography (Standard)

• The original and most widely used platform
• Acquires two-dimensional images from which 3D coordinates are calculated
• Best for microcalcifications, focal asymmetries, and densities visible on mammography

2. Digital Breast Tomosynthesis (DBT / 3D Mammography)

• FDA-approved; increasingly available
• The X-ray tube moves in an arc around the breast, taking multiple images at 1 mm slice intervals from many angles within seconds
• Computer generates a highly focused 3D image of the breast
• Particularly valuable in dense breast tissue - can distinguish a true distortion or asymmetry from overlapping breast tissue (which standard 2D mammography cannot)
• Reduces recall rates and improves characterisation of lesions

FIG. 2: Comparison of 2D mammography (single image) vs. 3D tomosynthesis (multiple stacked slices). (Current Surgical Therapy 14e)

3. MRI-Guided Biopsy

• For lesions visible only on MRI (enhancement without a mammographic or sonographic correlate)
• Uses the same stereotactic coordinate principles but within an MRI suite

4. Ultrasound-Guided Biopsy

• Preferred when the lesion is sonographically visible (palpable masses, solid nodules)
• Real-time visualisation of needle within lesion
• More comfortable patient positioning (no prone requirement)
• Stereotactic guidance is used specifically when the lesion is not seen on ultrasound

BI-RADS Classification and Indications

Indications for Stereotactic Core Biopsy (Box 1 - Current Surgical Therapy 14e)

1. BI-RADS 4 - suspicious lesions
2. BI-RADS 5 - highly suspicious lesions (confirms diagnosis and facilitates treatment planning)
3. BI-RADS 3 - probably benign lesions when:
   • Clinical suspicion is elevated
   • Patient or physician preference
   • Short-term imaging follow-up is not practical
4. New suspicious microcalcifications - the classic indication
5. Developing asymmetries or architectural distortions on mammography
6. Non-palpable asymmetry, focal asymmetry, or density not visible on ultrasound
7. Mammographic lesion corresponding to suspicious MRI enhancement
8. New mass or abnormal tissue at a previous surgery site
9. BI-RADS 6 - known malignancy requiring further sampling for treatment planning (e.g. receptor status before neoadjuvant chemotherapy)
10. Multifocal or multicentric lesions - to facilitate treatment planning
11. Discordant imaging-pathology assessment after initial biopsy - repeat biopsy needed

Contraindications

Absolute Contraindications

• Pregnancy (radiation exposure)
• Lesion immediately adjacent to a breast implant (risk of implant perforation)
• Patient unable to cooperate (mental disability)

Relative / Technical Contraindications (Box 2 - Current Surgical Therapy 14e)

Equipment

A. Core Needle Biopsy (CNB) Device

• Spring-loaded automated 14-gauge core needle
• Appropriate for masses >1 cm
• Retrieves multiple tissue cores in separate insertions
• Provides cores for histology (preserves tissue architecture - unlike FNA which provides only cytology)

B. Vacuum-Assisted Biopsy (VAB) Device - Preferred for Microcalcifications

• 7 to 11 gauge rotating cutter with vacuum suction
• Single-insertion device: vacuum suction pulls tissue into the collecting aperture; rotating cutter excises it
• Can perform up to 12 biopsies in 360° around the lesion with a single insertion
• 9-gauge is most popular - can remove up to 1 cm of tissue
• Allows larger volume sampling - reduces sampling error
• Advantages over 14G CNB:
  • Repeat biopsy rate for inadequate microcalcification sampling: 11.6% vs. 23.7% with CNB
  • In diagnosing DCIS: only 6% upgraded to invasive carcinoma at surgery vs. 21% with 14G CNB
  • Nearly 3x more accurate for diagnosing atypical ductal hyperplasia (ADH) - though underestimation still occurs in 18-25%
  • Can completely excise small lesions (<1 cm) percutaneously

C. Marker / Clip Placement

• A radiopaque metallic clip (titanium or other material) should be placed at the biopsy site at the time of the procedure in all suspicious lesions because:
  • The lesion may be partially or completely removed during biopsy
  • Enables accurate surgical localisation at future operations
  • Essential if the patient is expected to undergo neoadjuvant chemotherapy (which causes tumour regression and may eliminate the imaging target)

"A clip or other marking device should be placed at the time of percutaneous biopsy of all suspicious lesions to improve the accuracy of future localisation."

• Current Surgical Therapy 14e

Step-by-Step Procedure

1. Pre-procedure workup: Review complete mammographic examination to confirm the lesion location. Document clinical breast examination. Place radiopaque markers over areas of palpable concern.
2. Informed consent: Discuss the possibility of non-diagnostic results, risks, benefits, and alternatives.
3. Patient positioning:
   • Prone biopsy table: Patient lies prone with the breast hanging through a fenestration in the table; the operator works below the table. Optimal stability and patient comfort.
   • Upright add-on unit: Stereotactic add-on attached to standard mammography equipment; patient sits or stands.
4. Breast compression: Breast compressed and held between the image receptor and the compression plate throughout the procedure.
5. Target confirmation: Imaging performed to confirm the target lesion lies within the accessible area.
6. Coordinate calculation: Computer generates X, Y, Z coordinates of the target and transfers them to the stereotactic targeting device.
7. Skin preparation and local anaesthesia: Sterile technique; local anaesthetic (usually 1% lidocaine) injected into the skin and breast tissue along the planned needle track.
8. Scout images: Scout view obtained; after target identified, two images at ±15° confirm needle position.
9. Pre-fire images: Images obtained with the needle in pre-fire position to confirm alignment with target.
10. Needle firing / tissue acquisition:
    • For CNB: needle is fired and multiple separate passes are made
    • For VAB: single insertion, multiple tissue cores obtained by rotation around the lesion
11. Post-fire confirmation: Images obtained after tissue acquisition to confirm adequate sampling (especially that calcifications are present in the specimen).
12. Specimen radiography: Tissue cores are radiographed to confirm calcifications are present in the specimen - this is the definitive evidence of adequate sampling for microcalcification targets.
13. Clip/marker deployment: Radiopaque clip placed at the biopsy site.
14. Post-procedure imaging: Mammogram obtained to document clip position and confirm satisfactory haemostasis.
15. Wound care: Manual pressure, dressing applied. Most patients are discharged within 30-60 minutes.

Accuracy and Performance

• Sensitivity of core needle biopsy performed stereotactically or with ultrasound: 97-99%
• Accuracy increases with larger needle gauge
• Sensitivity is superior to FNA because tissue architecture is preserved
• Specimen radiograph confirming calcifications in the core is mandatory for microcalcification targets

Advantages Over Surgical Excisional Biopsy

Radiological-Pathological Concordance

• Concordant result: pathology explains the imaging lesion (e.g. calcifications in fibrocystic change explain benign-looking microcalcifications; carcinoma explains a BI-RADS 5 mass)
• Discordant result: pathology does NOT explain the imaging appearance (e.g. normal/benign tissue from a BI-RADS 5 lesion) - this requires repeat biopsy or surgical excision

Indications for Surgical Excision After Stereotactic Core Biopsy (Box 3 - Current Surgical Therapy 14e)

1. Malignancy (invasive carcinoma or DCIS) confirmed - proceed to definitive surgery
2. Discordant radiological-pathological findings - benign/normal result from a suspicious or highly suspicious lesion
3. Atypical Ductal Hyperplasia (ADH) - upgrade risk to DCIS or invasive cancer is 18-25% (VAB) to even higher with CNB; surgical excision is standard
4. Atypical Lobular Hyperplasia (ALH) and Lobular Carcinoma In Situ (LCIS) - upgrade risk warrants excision
5. Flat Epithelial Atypia (FEA) - upgrade risk
6. Radial scar / complex sclerosing lesion - may harbour carcinoma not sampled
7. Mucocele-like lesion with atypia
8. Phyllodes tumour - complete excision needed
9. Non-diagnostic specimen (no calcifications in specimen radiograph) with remaining clinical or imaging suspicion
10. Lesion completely removed on biopsy without prior clip placement (if clip was not placed and no residual lesion remains for localisation)
11. Papillary lesion with atypia or where adequate sampling is uncertain

Complications

Post-Procedure Follow-up

• Most patients: follow-up mammogram at 6-12 months to confirm stability of the biopsy site and any residual abnormality
• Post-DCIS excision: postoperative mammogram to confirm completeness of calcification removal (beyond specimen radiography and margin assessment)
• Age >35 years: unilateral diagnostic mammogram as a new baseline within 4-6 months
• Clip migration: on post-procedure mammogram, the clip should be confirmed at the correct location; migration may require repeat localisation imaging before any planned surgery

Comparison: CNB vs. VAB vs. FNA

Summary

• Current Surgical Therapy, 14e - Stereotactic Core Biopsy of Breast Disease (Pastoriza JM, Mallon WC, Jacobs LK), pp. 767-770