Transanal Minimally Invasive Surgery (TAMIS)

Overview and Historical Background

• Fischer's Mastery of Surgery - 8th ed., p. 4362

Indications

• Villous adenoma and tubular adenoma not amenable to simple endoscopic retrieval
• Submucosal lesions of unknown histology requiring excision for diagnosis
• Rectal neuroendocrine tumors ≤1 cm in diameter

• Clinical T1 rectal cancer with all of the following features:
  • Histologically favorable (no lymphovascular invasion, no perineural invasion, no tumor budding, well-differentiated, no mucinous or signet ring features)
  • Tumor occupying <1/3 of the rectal circumference
  • Diameter <3 cm
  • Situated in the distal or mid-third of the rectum (preferably ≤10 cm from the anal verge)
  • Submucosa invasion level: SM1 or SM2 (not SM3)
• Selected T2 cancers after neoadjuvant chemoradiotherapy (watch-and-wait/near-complete response protocols)

• TAMIS is especially valuable for mid-rectal lesions (beyond the reach of conventional Parks' TAE, i.e., above 5–6 cm) where TEM/TEO are not available.

• Transanal total mesorectal excision (TaTME / TAMIS-TME) for rectal cancer requiring radical surgery
• Resection of rectal GISTs and other submucosal tumors
• Fischer's Mastery of Surgery - 8th ed., pp. 4347–4349; Current Surgical Therapy 14e, p. 2807

Contraindications

• T2 or higher rectal cancer (without neoadjuvant therapy protocols) - requires formal segmental resection (SR) with TME
• Any rectal cancer with poor prognostic features (lymphovascular invasion, perineural invasion, tumor budding, poor differentiation, SM3 invasion) - standard recommendation is SR even after LE
• Tumors in the proximal third of the rectum (>10 cm from anal verge), particularly anterior tumors - peritoneal violation is unavoidable and oncologic principles are compromised
• Evidence of lymph node metastasis (N+) on staging MRI or ERUS
• Distant metastatic disease (M1) where cure is not the intent and LE does not change management

• Lesions occupying >1/3 of the rectal circumference (high risk of rectal stenosis and functional compromise)
• Prior pelvic radiotherapy (increased risk of wound breakdown and fistulation)
• Poor anal sphincter tone or significant anal stenosis (platform cannot be safely seated)
• Very distal lesions just at the dentate line (the port sits above the anorectal ring and distal margins may be difficult to achieve; a hybrid conventional TAE/TAMIS approach can be used)
• Immunocompromised patients or those with significant co-morbidity (relative)
• Fischer's Mastery of Surgery - 8th ed., pp. 4349–4352, 4368–4369

Advantages of TAMIS

• Fischer's Mastery of Surgery - 8th ed., pp. 4362–4365; Current Surgical Therapy 14e, p. 2807

Limitations of TAMIS

• Fischer's Mastery of Surgery - 8th ed., pp. 4364, 4368–4370

TAMIS vs. TEM - Key Differences

• Fischer's Mastery of Surgery - 8th ed., pp. 4354–4365; Current Surgical Therapy 14e, p. 2807; Devane LA et al., TAMIS vs. rigid platforms, Clin Colon Rectal Surg 2022 (PMID: 35237103)

Robotic TAMIS (R-TAMIS) - Brief Note

• Fischer's Mastery of Surgery - 8th ed., pp. 4365–4366

Management of Hyperhidrosis

Classification - A Framework for Management

• Most common type; affects palms, soles, axillae, craniofacial region
• Occurs only during waking hours (diurnal); bilateral and symmetric
• Onset in childhood (palmoplantar) or adolescence (axillary)
• Up to 80% have a positive family history
• Not associated with any systemic disease

• Due to underlying systemic cause: endocrine disorders (hyperthyroidism, diabetes, pheochromocytoma, acromegaly, carcinoid, menopause), infections, malignancy (lymphoma), neurologic disorders (Parkinson's disease), or drugs (SSRIs, TCAs, opioids, anticholinesterases)
• Often nocturnal, generalized, or asymmetric
• Management is primarily directed at the underlying cause

Assessment Tools

• Minor's Starch-Iodine Test: Iodine solution is applied to the affected area and dried, then starch powder is dusted over it. Moisture from sweat glands turns the mixture dark blue-purple, mapping the extent and distribution of hyperhidrosis. This guides both diagnosis and treatment (e.g., targeting botulinum toxin injections).

• Hyperhidrosis Disease Severity Scale (HDSS): A 4-point scale rating impact on daily activities (1 = never noticeable; 4 = intolerable and always interferes). Used to grade severity and monitor treatment response.
• Dermatology Life Quality Index (DLQI): Used to quantify quality-of-life impact.
• Gravimetric (weight-based) sweat measurement: accurate but mainly a research tool.

Management - Stepwise Approach

Step 1 - Topical Therapy (First-Line)

• Concentration: 10-35% for axillae; up to 50% (with occlusion under plastic gloves) for palms and soles
• Applied to completely dry skin at bedtime (blow-dry skin first); washed off after 6-8 hours
• Mechanism: precipitates within the eccrine duct lumen causing mechanical obstruction
• If irritation occurs, reduce frequency to every other night or apply over a hydrocortisone cream
• Once effective, frequency can be reduced to 1-2 times per week for maintenance
• Pitfall: Moisture on skin during application generates weak hydrochloric acid, causing burning and desquamation

• An anticholinergic applied topically; especially useful for craniofacial hyperhidrosis
• Can be compounded at specialty pharmacies
• Reduces sweating with less systemic absorption than oral anticholinergics
• Fitzpatrick's Dermatology, 9th ed., p. 1491; Andrews' Diseases of the Skin, p. 892

Step 2 - Physical Therapy Devices

• A low-intensity direct electrical current (15-18 mA) is passed through tap water into the skin surface
• Mechanism not fully established; likely blocks eccrine duct function through pH changes or ion deposition
• Treatment sessions: 20-30 minutes daily or twice daily initially; maintenance once every 1-2 weeks
• Effective for palmar and plantar hyperhidrosis; less commonly used for axillae
• Adding glycopyrrolate 0.01%, botulinum toxin, or aluminum chloride 2% to the iontophoresis medium can accelerate response
• Main advantages: inexpensive, no systemic effects, can be self-administered at home (Drionic device or Fischer unit)
• Limitations: time-consuming, requires regular sessions to maintain effect; cannot be used over broken skin, in pregnancy, or with cardiac pacemakers

• Microwave energy selectively destroys eccrine and apocrine glands in the dermis-hypodermis interface via thermal coagulation
• Primarily used for axillary hyperhidrosis
• High reported patient satisfaction; long-lasting or near-permanent effect
• Side effects: transient edema, erythema, pain; longer-term effects include fibrous bands and possible muscle weakness
• Offers the advantage of also reducing axillary hair and odor

• Fractional laser and microneedle radiofrequency can destroy sweat glands
• Appear effective but require more robust study for response rates and adverse effects
• Andrews' Diseases of the Skin, p. 892; Fitzpatrick's Dermatology, 9th ed., p. 1492

Step 3 - Botulinum Toxin A Injection (Second-Line, Most Evidence)

• Dose: 50-100 U of onabotulinumtoxinA (or up to 200 U of abobotulinumtoxinA / Dysport) per axilla
• Technique: Intradermal injections spaced 1-2 cm apart over the entire hyperhidrotic area (mapped by starch-iodine test); 10-20 injection sites
• Anesthesia: Usually not required (axillary skin relatively insensitive); EMLA cream may be applied
• Onset: Within 72 hours; peak at 5-7 days
• Duration: Anhidrosis lasts 6-12 months (up to 29 months with higher doses)
• Side effects: Minor bruising from needle trauma; no significant compensatory hyperhidrosis (axillary surface area is small compared to the area affected by sympathectomy)
• Repeated injections maintain efficacy and may extend duration over time

• More technically challenging than axillary treatment
• Dose: 100-200 U onabotulinumtoxinA per palm; 50-100 injection sites at 2-3 U each, covering the entire palmar surface including distal wrist crease, thenar and hypothenar eminences
• Anesthesia required: Regional wrist nerve blocks (median, ulnar, and radial nerves) using 1-2% lidocaine without epinephrine, OR ice applied to skin
• Duration: 3-4 months (shorter than axillary)
• Side effect: Temporary hand weakness (especially thumb-index pinch) lasting up to 2 weeks, due to toxin diffusion to intrinsic hand muscles - a predictable and important limitation
• Considered second-line after failure of iontophoresis and topical therapy

• Similar principles to palmar; requires regional nerve blocks
• Doses comparable to palmar treatment
• Response duration similar to palmar

• Botulinum toxin is highly effective for Frey syndrome (auriculotemporal nerve syndrome post-parotidectomy); remission for 1-10 years
• Effective for craniofacial and compensatory hyperhidrosis post-sympathectomy
• Andrews' Diseases of the Skin, p. 892; Fitzpatrick's Dermatology, 9th ed., p. 1491; Dermatology 2-Volume Set 5e, p. 3957

Step 4 - Systemic Pharmacotherapy

• Common anticholinergic side effects: xerostomia, xerophthalmia, constipation, mydriasis, blurred vision, urinary hesitancy/retention, tachycardia (high doses), bradycardia (low doses), mental confusion (especially in children and elderly)
• Contraindications: Myasthenia gravis, paralytic ileus, pyloric stenosis
• Caution: Closed-angle glaucoma, bladder outlet obstruction, GERD, cardiac insufficiency
• Sweating suppression generally lasts 4-6 hours per dose; many patients prefer to use intermittently for social events rather than continuously

• Clonidine (centrally acting α₂-adrenergic agonist): useful for stress-induced and menopausal hyperhidrosis
• Propranolol (β-blocker): particularly useful in stress-induced or anxiety-related hyperhidrosis
• Benzodiazepines: for anxiety-triggered episodes; not recommended long-term
• Diltiazem: occasional reports of benefit in localized hyperhidrosis
• Fitzpatrick's Dermatology, 9th ed., pp. 1491-1492; Andrews' Diseases of the Skin, p. 893

Step 5 - Surgical Treatment

1. Excision of axillary skin: Elliptical excision of the most actively sweating portion of axillary skin, followed by undercutting and subcutaneous resection of sweat glands for 1-2 cm on either side of the incision. Nearly always effective. Preoperative mapping with the starch-iodine test is essential as eccrine gland distribution does not always correlate with hair-bearing areas.
2. Liposuction / subcutaneous curettage (suction-curettage): Tumescent liposuction or surgical ultrasonic aspiration removes the subcutaneous fat containing the sweat glands. Less invasive than excision; avoids skin scarring. Can be combined with direct curettage for higher efficacy.
3. Laser treatments: Nd:YAG laser, diode laser, or fractional CO₂ laser can thermally destroy subdermal sweat glands. Effective for axillary disease with acceptable side effect profiles.

• The definitive, most effective surgical treatment for severe palmar and axillary hyperhidrosis refractory to all other modalities
• Procedure: Thoracoscopic interruption (clipping, cutting, or ablation) of the thoracic sympathetic chain at specific ganglia:
  • T2: Craniofacial/upper limb hyperhidrosis
  • T3-T4: Palmar hyperhidrosis (T3 preferred to reduce compensatory sweating)
  • T4: Axillary hyperhidrosis
• Performed under general anesthesia; bilateral procedure done at the same sitting or in staged fashion
• Immediate and permanent cessation of sweating in the targeted areas

• ETS is considered irreversible; patient selection must be meticulous. Compensatory hyperhidrosis can be more debilitating than the original problem, and patients must be fully informed.
• Sympathectomy clipping (rather than cutting/ablation) allows reversal if compensatory hyperhidrosis becomes intolerable, though reversal is not always successful.
• For axillary hyperhidrosis, local surgical procedures are preferred over ETS due to the high rate of compensatory hyperhidrosis with sympathectomy.
• Fitzpatrick's Dermatology, 9th ed., p. 1492; Andrews' Diseases of the Skin, p. 893; Bailey and Love's Surgery 28e, p. 664

Summary - Treatment Algorithm by Site

Key Points

• The diagnosis of primary focal hyperhidrosis requires at least 6 months of visible focal sweating without apparent cause, plus at least two of: bilateral/symmetric distribution, onset <25 years, cessation during sleep, frequency ≥1 episode/week, positive family history, or impairment of daily activities.
• Secondary hyperhidrosis should always be excluded before treating - it is often nocturnal, asymmetric, and generalized.
• Botulinum toxin remains the most evidence-based non-surgical second-line therapy for focal hyperhidrosis and is the treatment of choice when topicals fail.
• ETS is highly effective but compensatory hyperhidrosis (in up to 30-75% of patients) is a major limitation, and patients must be carefully counselled before surgery.
• A newer FDA-approved oral anticholinergic, sofpironium bromide (a topical glycopyrrolate prodrug), and oxybutynin extended-release are emerging options reviewed in recent literature (Maazi et al., Drugs Context, 2025 - PMID: 40575073).
• Fitzpatrick's Dermatology, 9th ed.; Andrews' Diseases of the Skin; Dermatology 2-Volume Set 5e; Devane et al., Clin Colon Rectal Surg 2022; Maazi M et al., Primary hyperhidrosis: an updated review, Drugs Context 2025 (PMID: 40575073)

Chronic Umbilical Discharge in a 30-Year-Old Woman

Etiology [2 marks]

• Patent vitello-intestinal (omphalomesenteric) duct: Failure of obliteration of the duct connecting the fetal midgut to the yolk sac. Normally obliterates by the 7th week of gestation. Persistence results in a fistula between the ileum and the umbilicus, producing faecal/intestinal discharge. Prolapse of the distal mucosal end produces a raspberry tumour (enteroteratoma / umbilical adenoma) - a red, moist, bleeding nodule at the umbilicus.
• Patent urachus: The urachus connects the fetal bladder to the allantois and normally obliterates to form the median umbilical ligament. Partial or complete failure gives rise to four variants:
  • Patent urachus: Full connection between bladder and umbilicus - urinary discharge from the umbilicus
  • Urachal sinus: Blind-ending tract opening at the umbilicus (no bladder connection) - mucoid/purulent discharge
  • Urachal cyst: Isolated segment that does not drain - presents with infection/mass rather than discharge
  • Urachal diverticulum: Opens only into the bladder - no umbilical discharge

• Umbilical endometrioma: Deposition of ectopic endometrial tissue at the umbilicus. Highly relevant in a 30-year-old woman. Characteristically produces cyclical bleeding/discharge coinciding with menstruation (catamenial). The umbilicus appears as a blue-brown nodule that enlarges and bleeds during periods. Associated with pelvic endometriosis in many cases.
• Umbilical sepsis/abscess: Poor umbilical hygiene leading to accumulation of desquamated epithelium, dirt, and bacteria. Umbilical concretion (calculus) - black/dark compacted debris - may be the nidus. Infection causes abscess formation and purulent discharge. Not the same as omphalitis (which is a neonatal condition).
• Pilonidal sinus of the umbilicus: Rare; hair penetrates the umbilicus in hairy individuals, with sinus formation and discharge.
• Intra-abdominal abscess/fistula: Any deep pelvic or abdominal abscess (e.g., Crohn's disease, appendiceal abscess, ovarian abscess, pelvic actinomycosis) may spontaneously drain through the umbilicus as it is the thinnest and weakest point of the anterior abdominal wall.
• Secondary carcinomatous deposit (Sister Mary Joseph's nodule): Umbilical metastasis from primary gastric, colonic, ovarian, or breast cancer. In a 30-year-old woman, ovarian carcinoma is a relevant concern. Presents as a hard, indurated nodule that may ulcerate and discharge.
• Primary umbilical carcinoma: Rare; involves both axillary and inguinal lymph nodes due to its unique lymphatic drainage.
• S. Das - A Manual on Clinical Surgery, 13th ed., p. 521; Bailey and Love's Surgery 28e, p. 1517

Evaluation [3 marks]

• Character of discharge: faecal (vitello-intestinal fistula), urinary/clear (patent urachus), bloody/cyclical (endometrioma), purulent (sepsis/abscess), mucoid (urachal sinus)
• Timing: cyclical with menstruation strongly suggests endometrioma
• Duration, onset, aggravating factors
• Urinary symptoms (dysuria, frequency, haematuria) - suggest urachal anomaly
• History of abdominal/pelvic surgery, inflammatory bowel disease, pelvic pain (endometriosis)
• Family history of malignancy

• Inspect umbilicus: note appearance of the discharge, colour, associated skin changes (erythema, induration), presence of a nodule or mass
• A red raspberry-like nodule = enteroteratoma/umbilical adenoma
• A blue-brown nodule bleeding cyclically = endometrioma
• A hard, indurated nodule with discharge = malignancy (Sister Mary Joseph's nodule)
• Palpate the abdomen for any deep mass, liver enlargement, ascites
• Pelvic examination: assess for uterine/adnexal pathology, pelvic endometriosis

• Sinogram/fistulogram: Injection of contrast through the distal opening under fluoroscopy - delineates the tract and its connections (with bowel or bladder)
• Ultrasound (abdomen and pelvis): First-line imaging; can identify urachal cyst, pelvic endometriosis, adnexal/pelvic masses; Doppler to assess vascularity of any nodule
• MRI pelvis: Investigation of choice in adults for urachal anomalies (clearly demonstrates the tract and its relationship to the bladder); also excellent for pelvic endometriosis
• Micturating cystourethrogram (MCUG): Demonstrates a patent urachus (contrast fills the tract from the bladder to the umbilicus)
• Cystoscopy: If urachal fistula is suspected; can identify the urachal opening and guide catheter placement
• Biopsy/excision biopsy of any nodule: For tissue diagnosis - especially to exclude malignancy or confirm endometrioma
• Endoscopy (colonoscopy): If enteric fistula is suspected and to exclude IBD
• Tumour markers (CA-125, CEA): If malignancy suspected
• Routine bloods: FBC (infection/anaemia), CRP, serum CA-125 (if ovarian pathology suspected)

Management [5 marks]

• First-line in mild disease: GnRH analogues (leuprorelin) or combined oral contraceptive pill - suppresses menstruation and may shrink the deposit
• Definitive treatment: Wide local excision of the umbilical endometrioma, ensuring clear margins. The umbilicus may need to be sacrificed and reconstructed.
• Concurrent treatment of pelvic endometriosis (laparoscopic ablation/excision) is required if present, as umbilical deposits often recur if pelvic disease is left untreated.

• Surgical excision is the only treatment
• Laparotomy or laparoscopy: The patent duct is traced from the umbilicus down to the ileum; the fistulous tract is excised in continuity with the ileal segment if necessary, with bowel repair or limited resection and anastomosis
• A raspberry tumour (enteroteratoma) at the umbilicus is treated by local excision with obliteration of the underlying duct

• Infected urachal remnants: IV antibiotics first to control sepsis, followed by definitive surgical excision
• Complete surgical excision is recommended for all urachal anomalies - both symptomatic and asymptomatic - because of the risk of malignant transformation to adenocarcinoma (mucinous adenocarcinoma), which carries high mortality
• Technique: Open or laparoscopic/robotic approach; the urachus is excised with a wide bladder cuff (to include any bladder extension); the bladder is closed in two layers; cystoscopy and catheter placement into the urachal tract aids intraoperative identification; the umbilicus can be preserved for cosmesis by circumscribing it during excision

• Conservative initially: Warm compresses, antiseptic soaks, topical antibiotics
• Incision and drainage if an abscess has formed
• Umbilical calculus removal: Under local anaesthesia; the concretion is extracted, the cavity curetted and dressed
• Antibiotics (oral or IV depending on severity): Cover gram-negatives and anaerobes
• Umbilicoplasty may be required if the umbilicus is permanently deformed

• Treatment of the primary intra-abdominal pathology: resection of the affected bowel segment, drainage of abscess
• Umbilical fistula tract excision after eradication of the primary source
• Nutritional optimisation and immunosuppression adjustment (for Crohn's)

• Biopsy to confirm the diagnosis and identify primary site
• Prognosis is generally poor (indicates advanced systemic disease)
• Palliative chemotherapy directed at the primary tumour; surgical excision of the umbilical nodule may be considered for local symptom control
• Multidisciplinary oncology input required

Summary Table

• S. Das - A Manual on Clinical Surgery, 13th ed., p. 521; Bailey and Love's Short Practice of Surgery 28e, p. 1517; Yamada's Textbook of Gastroenterology 7e

Tumor Biomarkers in Clinical Practice

Definition

Classification of Tumor Biomarkers

Ideal Properties of a Tumor Biomarker

• High sensitivity: positive in virtually all patients with the malignancy (few false negatives)
• High specificity: absent in benign conditions and healthy individuals (few false positives)
• Proportional to tumor burden: concentration rises with increasing disease and falls with successful treatment
• Lead time: detectable before clinical recurrence (typically 3-6 months)
• Easily and reproducibly measurable by simple, inexpensive assay
• Available in peripheral blood (non-invasive)

Clinical Uses

1. Screening

• PSA: Used for prostate cancer detection in men >50 years (especially African Americans with higher incidence); combined with digital rectal examination (DRE). Note: PSA is elevated in benign prostatic hyperplasia and prostatitis, making interpretation nuanced. PSA velocity and PSA density improve discrimination.
• AFP: Used for surveillance of hepatocellular carcinoma (HCC) in cirrhotic patients and high-incidence regions (e.g., China); combined with ultrasound every 6 months
• CA-125: Being evaluated for ovarian cancer screening, particularly in high-risk women (BRCA mutation carriers); not yet recommended for general population screening alone
• Calcitonin: Screening for medullary thyroid carcinoma in patients with thyroid nodules and in relatives with familial MTC (MEN2)

2. Diagnosis (Aid to)

• An elevated marker strongly correlates with a specific tumor in the right clinical context
• Multiple markers are used in combination to improve sensitivity and specificity

3. Staging and Prognosis

• Preoperative marker levels reflect tumor burden and correlate with stage
• Pre-operative CEA is an independent predictor of survival in colorectal cancer - higher levels predict worse prognosis even after stratifying for stage and resectability
• AFP and hCG levels in testicular cancer are incorporated into the IGCCCG staging system (good/intermediate/poor prognosis groups) and directly influence treatment intensity
• CA 19-9 in pancreatic cancer: baseline elevation correlates with unresectability and shorter survival
• PSA in prostate cancer: PSA level guides risk stratification (low/intermediate/high risk), treatment decisions, and follow-up intensity
• β₂-microglobulin in myeloma: incorporated into the International Staging System (ISS)

4. Monitoring Treatment Response

• A fall in marker level after surgery, chemotherapy, or radiotherapy indicates effective treatment
• Failure to normalize after surgery suggests residual or metastatic disease
• Important rule: Post-surgical marker levels should not be assessed before 2 weeks (preferably 1 month) to allow pre-existing circulating marker to clear, based on its half-life

• AFP: ~5 days
• hCG: ~24-36 hours
• CEA: ~2-8 days
• PSA: ~2-3 days

• CEA in colorectal cancer: Post-resection CEA should normalize. Failure to do so indicates residual disease. CEA >5 ng/mL post-treatment has sensitivity 71%, specificity 88% for recurrence
• PSA after prostatectomy: Should become undetectable. Rising PSA (biochemical recurrence) precedes clinical recurrence by months
• AFP/hCG in testicular cancer: Return to normal = evidence of complete remission; re-elevation = relapse

5. Detection of Recurrence

• Tumor markers detect recurrence 3-6 months before clinical or radiological evidence - an important lead time that can guide early salvage therapy
• Monitoring CEA 3-monthly for 2 years post-colorectal cancer resection is standard practice - rising levels prompt CT chest/abdomen/pelvis to identify resectable metastases
• Rising PSA post-prostatectomy/radiotherapy triggers bone scan, PSMA PET, or biopsy

6. Selecting and Guiding Targeted Therapy (Molecular / Tissue Biomarkers)

7. Emerging: Liquid Biopsy and Circulating Tumor DNA (ctDNA)

• ctDNA refers to cell-free DNA shed from tumor cells into blood, carrying tumor-specific mutations
• Liquid biopsy using ctDNA allows:
  • Early cancer detection (pre-symptomatic)
  • Identifying actionable mutations without tissue biopsy
  • Monitoring minimal residual disease (MRD) after treatment
  • Tracking clonal evolution and emergence of resistance mutations
• This is a rapidly evolving field with potential to transform early diagnosis and personalized therapy

Common Tumor Markers - Summary Table

Limitations of Tumor Markers

• Low specificity: Most markers are elevated in benign conditions; cannot diagnose cancer alone
• Low sensitivity for early disease: CEA elevated in only 5-40% of localized colorectal cancer
• Inter-laboratory variability: Different assay platforms give different absolute values; serial monitoring must be done with the same assay at the same laboratory
• Heterogeneous tumors: Not all tumors of the same type produce the same marker
• Post-treatment delay: Must wait 2-4 weeks post-surgery before interpreting marker levels

Key Principle

"Their main uses are in following the effectiveness of treatments and in detecting early recurrences - not in primary diagnosis or population screening."

• Harper's Illustrated Biochemistry, 32nd ed., p. 721; Henry's Clinical Diagnosis and Management by Laboratory Methods

• Harper's Illustrated Biochemistry 32nd ed., p. 720-721; Henry's Clinical Diagnosis and Management by Laboratory Methods; Sabiston Textbook of Surgery, Box 60.2, p. 1221; Bailey and Love's Surgery 28e