General Practice: Undifferentiated presentations, red flags and suspected cancer

🩺 Undifferentiated presentations, red flags and suspected cancer. In general practice patients present with symptoms, not diagnoses, often early, when serious and minor illness look alike. Most symptoms are self-limiting, but a few patients have serious disease. The skill is using probability, red flags, time and safety-netting - not testing everyone. This chapter covers common presentations, how to approach them, and the NICE NG12 suspected cancer criteria that are heavily examined.
Your four questions for an undifferentiated symptom: What is most likely? What must not be missed? Which features change the probability (red flags)? Is a test, a referral, or watchful waiting with a safety net the right next step?

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Clinical Reasoning in Primary Care

• Pattern recognition (fast, intuitive) works for common presentations; hypothetico-deductive reasoning (slow, analytical) for complex or atypical ones. Experts use both and switch when something does not fit.
• Murtagh's diagnostic strategy: What is the probable diagnosis? What serious disorders must not be missed? What conditions are often missed? Could this be one of the "masquerades" (depression, diabetes, drugs, anaemia, thyroid disease, spinal dysfunction, UTI)? Is the patient trying to tell me something?
• Gut feeling - a sense that something is wrong despite reassuring findings - is an independent predictor of serious illness in children and should prompt review or referral.
• Cognitive biases: anchoring, premature closure, availability, confirmation bias, and diagnostic overshadowing (attributing new symptoms to known mental illness or learning disability).
• Time as a diagnostic tool - planned review allows a self-limiting illness to resolve or a serious one to declare itself, provided there is a safety net.

Low Prevalence and the Predictive Value of Tests

• The positive predictive value (PPV) of a symptom or test depends on prevalence. Serious disease is rare in primary care, so most positive findings are false positives.
• NICE NG12 uses a PPV threshold of 3% for cancer - referral is recommended when a symptom combination carries ≥3% risk of cancer in that age group.
• Example: rectal bleeding in a 40-year-old has a low PPV for colorectal cancer; with change in bowel habit at 65, the PPV is much higher.
• Over-investigation harms: false positives, incidental findings ("incidentalomas"), anxiety, cost and overdiagnosis. See the Statistics chapters on Bayes' theorem.

Red Flags - Principles

• A red flag is a feature that raises the probability of serious disease enough to change management.
• Common general red flags: unexplained weight loss, night sweats, fever, age over 50 with new symptoms, persistent or progressive symptoms, bleeding, new neurology, severe pain that wakes the patient, immunosuppression, history of cancer.
• Absence of red flags does not exclude serious disease - safety-net and review.
• "Yellow flags" (psychosocial factors predicting chronicity) matter in back pain and other persistent symptoms.

Tiredness (TATT)

• One of the commonest presentations; often multifactorial.
• Causes: psychological (depression, anxiety, stress) - the most common; sleep problems (insomnia, obstructive sleep apnoea, shift work); physiological (overwork, new baby); drugs (beta-blockers, antihistamines, opioids, alcohol); anaemia; hypothyroidism; diabetes; CKD; liver disease; coeliac disease; infection (EBV, hepatitis, HIV); malignancy; heart failure; pregnancy; long COVID; ME/CFS.
• History: onset, sleep, mood (PHQ-9), weight, snoring (Epworth score), alcohol, menstrual loss, drugs, systemic symptoms.
• Baseline tests (if no obvious cause): FBC, ferritin, U&E, LFT, TFT, HbA1c, calcium, CRP/ESR, coeliac serology; consider vitamin D, B12/folate, CK, pregnancy test, HIV.
• Red flags: weight loss, night sweats, lymphadenopathy, bleeding, persistent fever, new neurology, abnormal blood count.
• ME/CFS (NICE NG206): suspect if debilitating fatigue, post-exertional malaise, unrefreshing sleep and cognitive difficulties for ≥6 weeks (adults) - diagnose at 3 months; graded exercise therapy is not recommended.

Unintentional Weight Loss

• Significant: >5% body weight over 6–12 months.
• Causes: cancer (GI, lung, pancreatic, haematological), depression, dementia, thyrotoxicosis, diabetes, malabsorption (coeliac, IBD), chronic disease (heart failure, COPD, CKD), infection (TB, HIV), alcohol, drugs, dental/swallowing problems, social isolation and poverty.
• Initial tests: FBC, U&E, LFT, calcium, TFT, HbA1c, CRP, coeliac serology, urinalysis, CXR; FIT; consider HIV, PSA (men), CA125 (women).
• NG12: unexplained weight loss triggers specific pathways (e.g. CXR if 40+, CT if 60+ for pancreatic cancer, FIT for colorectal, urgent OGD at 55+ with upper abdominal symptoms). A non-site-specific (NSS) symptoms pathway exists for vague symptoms suggestive of cancer.

Headache

• Primary headaches (tension-type, migraine, cluster, medication overuse) account for >90%.
• Medication overuse headache: headache on ≥15 days a month with simple analgesics on ≥15 days or triptans/opioids/combinations on ≥10 days for >3 months - withdraw the overused drug.
• Red flags (refer urgently/same day): thunderclap onset (peak within 1 minute - subarachnoid haemorrhage), fever with neck stiffness or rash, new neurological deficit, papilloedema, new headache with cognitive or personality change, headache worse on lying/coughing/straining with vomiting, age >50 with jaw claudication or scalp tenderness (giant cell arteritis - start prednisolone and refer same day), new headache in immunosuppression or cancer, headache after head injury on anticoagulants, pregnancy/postpartum (pre-eclampsia, venous sinus thrombosis), carbon monoxide exposure (several household members).
• Migraine (NICE CG150): acute - NSAID or aspirin + triptan ± antiemetic; prophylaxis if frequent - propranolol, topiramate (avoid in pregnancy; Pregnancy Prevention Programme), amitriptyline; candesartan off-label; CGRP antibodies in specialist care. Avoid combined hormonal contraception in migraine with aura.

Low Back Pain

• Most is non-specific and improves within 6 weeks.
• Red flags for serious pathology:
  • Cauda equina syndrome - bilateral sciatica, saddle anaesthesia, new urinary retention or incontinence, faecal incontinence, sexual dysfunction → immediate same-day referral for emergency MRI.
  • Malignancy - history of cancer (breast, lung, prostate, kidney, thyroid), age >50, weight loss, night pain, thoracic pain → urgent imaging; consider metastatic spinal cord compression (refer immediately if neurological signs).
  • Infection - fever, IV drug use, immunosuppression, recent infection (discitis, epidural abscess).
  • Fracture - trauma, osteoporosis, long-term steroids.
  • Inflammatory - age <40, morning stiffness >30 minutes, improves with exercise, night waking in second half of night (axial spondyloarthritis).
• Management (NICE NG59): stay active, reassurance, risk stratification (STarT Back tool), exercise programmes, NSAIDs at lowest dose for shortest time; avoid paracetamol alone, opioids for chronic pain, and routine imaging. Do not offer gabapentinoids or antidepressants for sciatica (unlicensed for this and limited benefit).

Dizziness

• Clarify the meaning: vertigo (spinning), presyncope (light-headed, about to faint), disequilibrium (unsteady on feet), or non-specific light-headedness (often anxiety, hyperventilation).
• Vertigo: BPPV (brief, positional - Dix–Hallpike positive; treat with Epley manoeuvre), vestibular neuritis (prolonged, no hearing loss), Ménière's (episodic with hearing loss, tinnitus and aural fullness), vestibular migraine, and posterior circulation stroke (red flags: new headache, neurological signs, inability to walk, vascular risk factors - use HINTS in specialist settings).
• Presyncope: postural hypotension (drugs, dehydration, autonomic), arrhythmia, aortic stenosis, anaemia - ECG and lying/standing BP.
• Older people: usually multifactorial - drugs, vision, neuropathy, cervical spondylosis, deconditioning.

Abdominal Symptoms and Change in Bowel Habit

• Dyspepsia (NICE CG184): lifestyle, review drugs (NSAIDs, bisphosphonates, CCBs), test for H. pylori (stool antigen or breath test, off PPI for 2 weeks) or a 1-month full-dose PPI.
• IBS: diagnose positively if abdominal pain relieved by defecation or associated with altered stool frequency/form for 6 months, with bloating, straining, urgency or mucus; exclude red flags; test FBC, CRP/ESR, coeliac serology, and faecal calprotectin (age <40 to distinguish IBD), CA125 in women with symptoms suggestive of ovarian cancer.
• Red flags: age >50/new symptoms, rectal bleeding, weight loss, iron deficiency anaemia, abdominal or rectal mass, family history of bowel or ovarian cancer, nocturnal symptoms, persistent vomiting, dysphagia.
• Constipation in older people: drugs (opioids, anticholinergics, iron, calcium), dehydration, hypercalcaemia, hypothyroidism, immobility; new constipation at 60+ needs FIT.

Cough and Breathlessness

• Acute cough (<3 weeks) - usually viral URTI; safety-net for pneumonia (CRB-65 in primary care; CRB-65 0 - home, 1–2 consider hospital, 3–4 urgent admission).
• Chronic cough (>8 weeks) - smoking, asthma, GORD, upper airway cough syndrome (postnasal drip), ACE inhibitors, COPD, bronchiectasis, TB, lung cancer, interstitial lung disease, heart failure.
• CXR: offer for persistent cough or other unexplained symptoms (see NG12 below); urgent if haemoptysis at 40+.
• Breathlessness: asthma/COPD, heart failure (NT-proBNP - >2,000 ng/L refer for specialist assessment and echo within 2 weeks; 400–2,000 within 6 weeks), anaemia, PE, obesity, deconditioning, ILD, anxiety.

Skin Lesions and Rashes

• Pigmented lesions - weighted 7-point checklist: major (2 points each) - change in size, irregular shape, irregular colour; minor (1 point each) - largest diameter ≥7 mm, inflammation, oozing, change in sensation. Score ≥3 → suspected cancer pathway for melanoma. ABCDE is an alternative aide-memoire.
• SCC - non-healing, keratinising or crusted lesion, especially on sun-exposed skin or in transplant recipients → suspected cancer pathway.
• BCC - usually routine referral (or treatment in primary care where appropriate), unless in a site where delay could have a significant impact (e.g. near the eye).
• Non-blanching rash with fever → meningococcal sepsis until proven otherwise - give IM/IV benzylpenicillin if there will be a delay and transfer as an emergency.
• Urticaria with angio-oedema - assess for anaphylaxis (airway, breathing, circulation) - give IM adrenaline if present.

NICE NG12 - Key Referral Criteria

Cancer	Refer on suspected cancer pathway (selected key criteria)
Lung	CXR suggests lung cancer; or age 40+ with unexplained haemoptysis. Offer urgent CXR (within 2 weeks) if 40+ with 2 or more unexplained symptoms (or 1 if ever smoked): cough, fatigue, breathlessness, chest pain, weight loss, appetite loss
Upper GI	Dysphagia (any age); age 55+ with weight loss plus upper abdominal pain, reflux or dyspepsia → urgent direct-access OGD
Pancreatic	Age 40+ with jaundice; urgent CT if 60+ with weight loss plus diarrhoea, back pain, abdominal pain, nausea, vomiting, constipation or new-onset diabetes
Colorectal	Offer FIT to adults with symptoms (e.g. change in bowel habit, abdominal pain, weight loss, iron deficiency anaemia, rectal bleeding in specified groups); refer if FIT ≥10 µg Hb/g faeces; rectal or abdominal mass
Breast	Age 30+ with unexplained breast lump; age 50+ with unilateral nipple discharge, retraction or other concerning change; skin changes suggestive of breast cancer; consider if axillary lump in 30+
Ovarian	Persistent abdominal distension/bloating, early satiety, pelvic/abdominal pain, urinary urgency/frequency (especially 50+) → CA125; if ≥35 IU/mL → urgent pelvic ultrasound; refer if ultrasound suggests cancer. Ascites or pelvic/abdominal mass (not fibroids) → refer
Endometrial	Postmenopausal bleeding in women aged 55+ (consider if under 55)
Cervical	Appearance of the cervix consistent with cervical cancer
Prostate	PSA above the age-specific reference range, or a prostate that feels malignant on DRE
Bladder	Age 45+ with unexplained visible haematuria without UTI, or persisting/recurring after successful UTI treatment; age 60+ with unexplained non-visible haematuria plus dysuria or raised WCC
Renal	Age 45+ with unexplained visible haematuria without UTI (as bladder)
Testicular	Non-painful enlargement or change in shape or texture of the testis
Haematological	Very urgent FBC for pallor, persistent fatigue, unexplained fever, infections, generalised lymphadenopathy, bruising/bleeding, hepatosplenomegaly; leukaemia in children/young people - very urgent FBC within 48 hours; refer immediately if petechiae or hepatosplenomegaly in a child
Myeloma	Age 60+ with persistent bone pain (especially back) or unexplained fracture → FBC, calcium, plasma viscosity/ESR, serum protein electrophoresis and serum free light chains
Head and neck	Persistent unexplained neck lump at 45+; unexplained oral ulceration >3 weeks; persistent unexplained hoarseness at 45+ (consider CXR as well)
Brain/CNS	Progressive, subacute loss of central neurological function → urgent direct-access MRI (within 2 weeks)

• Always check the current NG12 - criteria and test thresholds are updated in stages.

FIT, CA125, PSA and Other Primary Care Tests

• FIT (faecal immunochemical test) detects human haemoglobin; in symptomatic patients a threshold of 10 µg Hb/g is used. A negative FIT does not exclude cancer if symptoms persist or there is iron deficiency anaemia - safety-net and consider referral on clinical grounds. Screening (asymptomatic) programmes use higher thresholds.
• CA125 - raised by many benign conditions (endometriosis, menstruation, ascites, pregnancy, liver disease); low specificity in premenopausal women.
• PSA - raised by BPH, prostatitis, UTI, recent ejaculation, vigorous exercise and catheterisation; avoid testing within 6 weeks of UTI. Counsel before testing (the Prostate Cancer Risk Management Programme): risk of false positives, biopsy complications and overdiagnosis.
• Iron deficiency anaemia - in men of any age and postmenopausal women, investigate the GI tract (FIT, OGD and colonoscopy per pathway); check coeliac serology.
• Calcium - hypercalcaemia may indicate myeloma or metastatic cancer (or primary hyperparathyroidism - check PTH).

Cancer in Children and Young People

• Rare (about 1 in 500 by age 15) - symptoms are non-specific and parents often notice first; listen to parental concern.
• Very urgent referral (within 48 hours): unexplained petechiae or hepatosplenomegaly (leukaemia) → immediate; unexplained palpable abdominal mass or organomegaly (neuroblastoma, Wilms' tumour); absent red reflex or new squint (retinoblastoma - urgent referral); unexplained bone swelling or persistent bone pain → X-ray within 48 hours (osteosarcoma, Ewing's).
• Brain tumours - persistent headache, vomiting, visual disturbance, behavioural change, abnormal growth or puberty, unsteadiness; HeadSmart awareness.
• Lymphoma - unexplained lymphadenopathy, especially with fever, weight loss, night sweats or splenomegaly.

Red Flags at a Glance

Presentation	Red flags needing urgent action
Headache	Thunderclap; fever + neck stiffness; papilloedema; new deficit; GCA features
Back pain	Saddle anaesthesia, bladder/bowel change (cauda equina); cancer history; fever; trauma
Dyspepsia	Dysphagia; 55+ with weight loss; GI bleeding; iron deficiency anaemia
Cough	Haemoptysis at 40+; weight loss; persistent >3 weeks in smoker
Bowel	Rectal bleeding with change in habit; FIT ≥10; mass; anaemia
Skin	7-point score ≥3; non-healing lesion; non-blanching rash with fever
Children	Petechiae, hepatosplenomegaly, abdominal mass, absent red reflex

Spot the Diagnosis

• A 64-year-old with new constipation and iron deficiency anaemia; FIT 45 µg/g. → Suspected colorectal cancer - refer on the lower GI pathway.
• A 72-year-old with new headache, jaw pain on chewing and ESR 80. → Giant cell arteritis - start prednisolone 40–60 mg today and refer same day.
• Sudden severe headache "like being hit with a bat" during sex. → Subarachnoid haemorrhage until proven otherwise - emergency admission.
• A 3-year-old with a white pupil on a family photo. → Leukocoria - urgent ophthalmology referral for possible retinoblastoma.
• A 42-year-old with low back pain, bilateral leg pain and numbness "where she sits on a bike". → Cauda equina syndrome - emergency MRI today.
• Pigmented lesion that has grown and has an irregular border; 6 mm. → 7-point score 4 (2 + 2) - suspected melanoma pathway.

Exam-style Scenarios

• Scenario. A 52-year-old woman has bloating most days for 2 months and early satiety. Abdomen is soft. What is the first test?
  Answer: Serum CA125. If ≥35 IU/mL arrange urgent pelvic and abdominal ultrasound; if normal but symptoms persist, reassess and consider other causes (including IBS only after excluding ovarian cancer in this age group).
• Scenario. A 48-year-old smoker has had a cough for 4 weeks and has lost 3 kg. Examination is normal.
  Answer: Offer an urgent CXR (within 2 weeks) - 40+, ever smoked, with unexplained cough and weight loss; refer on the suspected lung cancer pathway if CXR suggests cancer, and safety-net if normal (persistent symptoms need re-evaluation).
• Scenario. A 30-year-old with 8 months of fatigue, worse for days after exertion, unrefreshing sleep and "brain fog"; blood tests normal.
  Answer: Suspected ME/CFS - validate, give energy management advice (pacing), avoid graded exercise therapy, refer to a specialist ME/CFS service to confirm and plan care, screen for depression and sleep disorders.
• Scenario. A 67-year-old man has back pain for 6 weeks, now waking him at night. He had prostate cancer treated 4 years ago.
  Answer: Red flags for spinal metastases - urgent MRI (within 1 week per local pathway); if any neurological symptoms or signs (radicular pain, weakness, sensory level, sphincter problems), contact the MSCC coordinator immediately for emergency MRI within 24 hours.

Key Points

• Serious disease is uncommon in primary care, so predictive values are low - use red flags and time wisely.
• Specific safety-netting is a clinical intervention.
• Know the NG12 criteria for the common cancers, and the FIT threshold of 10 µg/g.
• Parental concern and clinician gut feeling are important warning signs.
• Avoid diagnostic overshadowing and premature closure.

Guidelines and Further Reading

• NICE NG12: Suspected cancer - recognition and referral; NICE DG56: FIT to guide colorectal cancer pathway referral
• NICE NG59: Low back pain and sciatica in over 16s
• NICE CG150: Headaches in over 12s; NICE CG184: Dyspepsia and GORD
• NICE NG206: ME/CFS
• NICE NG106: Chronic heart failure (NT-proBNP thresholds)
• Murtagh J. General Practice (diagnostic strategy)
• Cancer Research UK: Safety netting resources for primary care