Achalasia

Background/Epidemiology

• Primary oesophageal motility disorder characterised by the absence of oesophageal peristalsis and impairment of lower oesophageal sphincter relaxation.
• Rare- affects 1 in 100000 per year

• Infection with Trypansoma cruzi which causes Chagas' disease causes a syndrome clinically indistinguishable from achalasia

Pathophysiology

• The lower oesophageal sphincter is regulated by excitatory (e.g. acetylcholine, substance P) and inhibitory (e.g. NO, vasoactive intestinal peptide) neurotransmitters
  • In achalasia, there seems to be a lack of nonadrenergic, noncholinergic, inhibitory ganglion cells (cholinergic activity is preserved), possibly as a result of an inflammatory process
  • the result is a chronically non-relaxing LOS

Presentation

• Most commonly- dysphagia
  • Affecting solid foods more than soft more than liquids
  • Develops gradually, commonly intermittent
  • Can be eased by drinking fluids, by standing up/moving about etc
• Regurgitation and dyspepsia are also common.  Chest pain may occur due to oesophageal spasm, but heartburn is rare (LOS tone is increased so acid is unlikely to reflux)
• Later in the disease, aspiration can be common (nocturnal pulmonary aspiration)

Investigations

• Barium swallow is usually performed before endoscopy (for risk of rupture)
  • Classic dilated oesophagus which is tapered distally (said to resemble a bird’s beak); only a small amount of contrast is able to pass through into the stomach
  • 
• Manometry
  • Gold standard
  • Diagnostic features include high resting pressure of the LOS, incomplete relaxation on swallowing and absent peristalsis
  • Without any features on manometry, diagnosis is instead ‘pseudoachalasia’
    • Consider other causes e.g. malignancy, strictures
• Endoscopy may be useful in evaluating causes of pseudoachalasia but is not necessarily required for true achalasia

Management

• Surgical myotomy is preferred if the patient is fit enough
  • requires fundoplication at the same time to avoid serious reflux disease post-operatively
  • PPIs are often prescribed post-operatively for this reason also
• For older patients/patient not suitable for general anaesthetic etc, endoscopic pneumatic dilation may be used
• Endoscopic botox injection is rarely used.  Other medical options include calcium channel blockers and nitrates but these are rarely successful
• NB Endoscopic myotomy methods are now beginning to be used

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Pharyngeal Pouch (Zenker’s diverticulum)

• Rare- affects 1 in 100000 people, most commonly in middle-old age (>60) and in men (5:1)
• Occurs most commonly as a result of in-coordination of swallowing within the pharynx, most likely due to upper oesophageal sphincter dysfunction
  • this leads to herniation of the oesophagus through the cricopharygeus muscle and formation of a pouch
• Most patients are asymptomatic/minimally symptomatic
  • Dysphagia and regurgitation are the most common symptoms (95%)- patient often feels like food is getting lodged in the throat and food can be regurgitated, particularly on lying down
  • Halitosis is also common, as food can get trapped there
  • Chronic cough, aspiration pneumonia or unexplained weight loss can also feature
    • As such, cancer and strictures cannot be ruled out
• Barium swallow is preferred over endoscopy as this may perforate the pouch
  • Nasopharyngoscopy may show salivary pooling in the piriform fossa
• In patients with troublesome symptoms, surgical myotomy (diverticulotomy) +/- resection (diverticulectomy) can be performed
  • Endoscopic procedures may also be performed for small pouches where there is the clinical expertise

Gastro-oesophageal reflux disease (GORD)

Dyspepsia: upper abdominal discomfort/pain, often described as burning, heaviness or ache, often related to eating and may be accompanied by other symptoms such as nausea, fullness or belching.

GORD: reflux of gastric contents into the oesophagus, causing symptoms such as heartburn and acid regurgitation.

Background/Epidemiology

•  More common in men than in women
• Around 25% of adults experience heartburn and 5% have daily symptoms
  • Around a quarter of these patients will see a doctor.
• More common in patients with asthma and more common in overweight individuals

Aetiology

• Reduced lower oesophageal sphincter tone
• Increase abdominal pressure
• Smoking, alcohol, fatty foods, coffee
• Pregnancy
• Obesity
• Tight clothes/big meals
• Hiatus hernia; systemic sclerosis and post oesophageal surgery for achalasia

Presentation

• Heartburn/dyspepsia
  • Discomfort/pain may be epigastric, retrosternally or in the throat
  • Related to meals, and often made worse by lying down, stooping, straining etc
  • It may be relieved by certain drinks e.g. milk, or by antacids
• Other symptoms include
  • “Acid brash”- acid reflux causing an acidic ‘taste’ in the back of the mouth
  • “Water brash”- essentially excess salivation (response of the salivary glands in response to acid in the gullet)
  • Odynophagia (painful swallowing) or dysphagia (feeling that the food is stuck in the gullet)
  • Food or acid reflux
• Atypical features include
  • Chest pain- may be severe.  GORD can often mimic ACS, particularly in older patients
    • thought to perhaps be due to oesophageal spasm
  • Chronic hoarseness of the voice
  • recurrent chest infections
  • Chronic cough
  • Wheeze/shortness of breath
• Examination is usually normal if symptoms are not present at the time.  They may or may not have a ‘tender’ epigastric area (palpation may worsen symptoms).

Differential Diagnosis

• Peptic ulcer disease
• Drugs e.g. NSAIDs
• Infection (esp immunocompromised patients)
• Oesophageal spasm
• GI cancers

Investigations

• Bloods: FBC (?anaemia – peptic ulcer; leucopenia- infection
• NB Many patients in whom there is a high clinical suspicion of GORD won’t require endoscopy, but for those with severe/problematic disease, or with red flag symptoms e.g. weight loss, dysphagia, anaemia, etc- further investigations may be used
• Endoscopy is investigation of choice (NB can be normal)
  • NB This investigation may not show any abnormality (e.g. oesophagitis).  This DOES NOT exclude GORD as the diagnosis, it is mainly used for treatment planning (see below)
  • Patients should not have been taking any drugs that may contribute to symptoms for two weeks or more prior to endoscopy
• You can also use pH measurements to check the acidity in the oesophagus/mouth
  • 24 hour pH monitoring- where the pH is <4 for >6-7% of the study time- suggestive of GORD
• Urea breath test for H pylori infection can be used if a peptic ulcer is suspected
• Finally, if there is suspicion of a motility disorder (e.g. if the patient is complaining more of dysphagia or odynophagia with reflux), consider imaging/manometry tests

Management

• If there are underlying causes and/or contributing factors, make sure to reverse these where possible e.g.
  • Drugs e.g. NSAIDs, calcium channel blockers, nitrates, theophyllines, bisphophonates, steroids
  • H pylori infection
  • Obesity
  • Diet (fatty food, spicy food, fizzy drinks etc) and eating before bed/large meals
  • Alcohol, smoking
• Antacids/alginates e.g.
• Proton pump inhibitors
  • trial for a minimum of 4 weeks at a reasonable dose then treat at the lowest therapeutic dose thereafter (if successful)
  • If the patient doesn’t have any relief, the dose can be doubled for a further month or an H2-receptor antagonist can tried
• Other drugs that can be tried are prokinetics e.g. metoclopramide
• Surgery may be used for patients with a hiatus hernia.  Occasionally, fundoplication can be performed in other patients with refractory symptoms.  However,

Complications

• Barrett’s Oesophagus and Oesophageal adenocarcinoma
• Oesophageal ulcers and/or haemorrhage
• Oesophageal strictures
• Aspiration pneumonia
• Poor oral health (due to acid) e.g. caries/tooth decay, gingivitis, halitosis

Hyperthyroidism

Primary hyperthyroidism: excess of thyroid hormone due to an abnormality of the thyroid gland.

Secondary hyperthyroidism: excess of thyroid hormone due to abnormal stimulation of a normal thyroid gland.

Thyrotoxicosis (vs hyperthyroidism): thyrotoxicosis can be excess circulating hormone of any source; hyperthyroidism is a result of excess production of new thyroid hormone.

Background and Epidemiology

• Overt (clinical) hyperthyroidism is thought to affect ~1.9% of women (0.8/1000/year) and 0.16% of men (0.14/1000/year)
  • Subclinical hyperthyroidism is likely to be higher

Presentation

There are a wide range of symptoms and signs to possibly find in a patient with thyrotoxicosis:

• Thyroid enlargement
  • Diffuse, unilateral, nodular
• Dyspnoea, palpitations
  • sinus tachycardia, atrial fibrillation, heart failure, resting tachycardia, use-dependent oedema
• Hyperactivity, emotional lability, insomnia, irritability, nervousness, anxiety, agitation
  • tremor
• Exercise intolerance, fatigue, muscle (mainly proximal) weakness
  • Muscle wasting/weakness, proximal myopathy, hyperreflexia
• Change in bowel habit (increased/diarrhoea)
• Heat intolerance, increased sweating
  • Warm, moist skin (excess sweating- diaphoresis)
• Increased appetite, weight change (loss or gain or stable despite intake change)
• Infertility, oligomenorrhoea, amenorrhoea
• Polyuria, thirst, generalised itch
  • Skin changes e.g. onycholysis, urticaria, diffuse pigmentation, diffuse non-scarring alopecia, palmar erythema,
• Reduced libido; Gynaecomastia

NB There are also some symptoms/signs specific to different causes (see below)

Investigations

• FBC, U&Es, LFTs
• TFTs
  • TSH normal- no hyperthyroidism
  • TSH increased- Check free T4
    • Normal/low- consider hypothyroidism
    • Free T4 high- secondary hyperthyroidism (rare)
      • MRI/CT head/pituitary- look for tumour or lesion that might be the cause
    • TSH Low- check free T4
      • Normal- measure free T3
        • Normal- likely transient cause e.g. acute illness
        • High- T3 toxicosis (occurs in 10-15%)- further investigation
  • If TSH is low and free T3/T4 is high, consider a thyroid uptake scan 
    • Low uptake
      • Single cold nodule – consider thyroid cancer
      • Diffusely low uptake- measure thyroglobulin
        • If this is high- possible thyroiditis (ectopic thyroid hormone production or excess iodine also possible)
        • If low, it is likely that exogenous hormone is the cause.
    • High uptake
      • Diffusely hot- Grave’s disease
      • Single hot nodule- Toxic thyroid adenoma
      • Multiple hot nodules- Toxic multinodular goitre
• Thyroid Antibodies
  • 

Causes

• Grave’s disease
• Toxic Thyroid adenoma
  • <5% of all cases of thyrotoxicosis
  • More common in women and >40 years old
  • Solitary adenoma which secretes thyroid hormone (predominantly T3 thyrotoxicosis- and usually mild thyrotoxicosis.)
    • Inhibits TSH secretion and therefore the rest of the thyroid gland shuts down (shrinks/atrophy)
  • Symptoms are usually mild.  The patient may have a palpable nodule or it may only be detected by thyroid scintigraphy (uptake scan)
  • Treatment is usually radioiodine (because the inactive ‘normal’ thyroid fails to take up any radioactive iodine)
    • Risk of post-treatment hypothyroidism is relatively low
    • Surgery is an alternative
• Toxic Multinodular goitre
  • Accounts for about 30-40% of hyperthyroid cases.
  • Also most common in women >40 years.  May develop from a diffuse (and often euthyroid) goitre.
  • In a similar fashion with toxic nodules- multinodular goitre releases thyroid hormone and suppresses TSH secretion
  • Patients can be asymptomatic (free T3/T4 may be within normal levels as well but TSH will always be low)
  • There will usually be a goitre present with palpable nodules
  • Treatment is usually with radioiodine (even if asymptomatic it may be appropriate if TSH is chronically and markedly suppressed as this can be a risk factor for AF and osteoporosis)
    • Risk of post-treatment hypothyroidism is relatively low
    • Surgery is an option for large, problematic (e.g. tracheal compression) goitres
• Thyroiditis
• TSH-secreting tumour
  • Extremely rare
  • Consider if there are features of hyperthyroidism with raised TSH and raised thyroid hormone
  • There may also be clinical signs of tumour (~80% are macroadenomas) e.g. visual disturbance, headaches
  • MRI/CT imaging is the investigation of choice
  • Treatment can be with octreotide and antithyroid drugs (+/- beta-blocker) but the mainstay is surgical resection
• Amiodarone
  • Often causes a thyroiditis type picture

Thyroiditis (Subacute/Transient) or De Quervain’s thyroiditis

Background/Epidemiology

• Self-limiting condition which characteristically has three clinical phases
  1. Hyperthyroidism
  2. Hypothyroidism
  3. Euthyroidism
• May be a cause of up to 15% of patients with thyrotoxicosis and up to 10% of patients with hypothyroidism.
• There are also three different pathological types of subacute thyroiditis
  • Subacute granulomatous thyroiditis (de Quervain’s or subacute painful)
  • Subacute Lymphocytic thyroiditis (painless)
  • Subacute post-partum thyroiditis
• As with other thyroid conditions, women are more at risk than men (3-5:1).  Average age of onset is 30-50 years old.

Aetiology/Risk factors

• Subacute granulomatous
  • Most commonly follows an episode of viral illness
  • There are genetic factors that may predispose e.g. HLA-B35
• Lymphocytic
  • Thought to be, at least in part, an autoimmune process, as antibodies (in particular antimicrosomal antibodies and antithyroid peroxidase antibodies) are often present in these patients
  • Can also occur in patients receiving or having received amiodarone or interferon-α treatment. (can present >2 years later)
• Post-partum
  • Also thought to be autoimmune in nature
  • Much rarer in countries with iodine-rich diets
• Other causes include radiotherapy and infective thyroiditis (rare- only really ever seen in immunodeficient patients)

Pathophysiology

• The inflammatory process occurs.  This causes swelling/enlargement of the thyroid gland.  As the process continues, the thyroid follicles are broken down and thyroid hormone is inadvertently released.
• Hyperthyroid phase occurs at this stage.  As the amount of T3/T4 is depleted, patient typically then become euthyroid and then hypothyroid, before recovering to a euthyroid state.
• Histologically, there is a mixture of acute, subacute and chronic granulomatous, inflammatory change associated with follicle destruction.

Presentation

• Typically, patients present with a prodromal illness or infection
  • May complain of flu-like symptoms e.g. fever, malaise, myalgia, sore-throat, anorexia, fatigue etc
  • May have been diagnosed with infection e.g. pharyngitis, measles, mumps etc
  • NB constitutional symptoms may continue with the thyroiditis (even if symptoms of specific infection had resolved)
• Often the thyroid enlarges (often firm enlargement and diffuse)
  • In painful (granulomatous) thyroiditis, the thyroid is usually acutely painful/tender (gradual/sudden)
    • this can start on one site and spread or begin bilaterally
  • Other local symptoms that can occur include
    • dysphagia
    • hoarseness
• NB in post-partum thyroiditis, there is firm, painless enlargement of the thyroid which can occur up to 6 months after birth
• Symptoms of hyperthyroidism and/or hypothyroidism

Investigations

• FBC
  • WCC may or may not be raised.  CRP can be slightly elevated
• Thyroid function tests
  • NB cf toxic nodular disease, if there is hyperthyroidism- fT4 is usually disproportionately elevated compared to fT3
• Radioiodine scan (decreased uptake can distinguish thyroiditis from Grave’s disease – which may otherwise be indistinguishable from painless thyroiditis)

Management

• Because thyroiditis is often self-limiting, no treatment is routinely required (important to diagnose correctly over Graves regarding unnecessary treatment)
• If the patient remains chronically hypothyroid after the episode, replacement thyroxine can be considered.
• If acute hyperthyroid symptoms are really troublesome, beta-blockers can be used for symptomatic relief

Grave’s Disease

An autoimmune disease characterised by hyperthyroidism due to thyroid-stimulating antibodies.

Background and Epidemiology

• Most common cause of primary hyperthyroidism (60-90%)
• Can be associated with other autoimmune disorders (as part of polyglandular autoimmune syndromes) e.g. pernicious anaemia, type I diabetes, vitiligo, autoimmune adrenal insufficiency, systemic sclerosis, myaesthenia gravis, Sjogren’s syndrome, rheumatoid arthritis and SLE
• More common in women (7.5:1), commonly aged 30-50 but general incidence is around 0.8-2/1000 per year

Pathophysiology/Aetiology

• There is a strong genetic/hereditary component
  • Polymorphisms in MHC (HLA-DRB1 and HLA-DQB1); CTLA4, PTPN22, TSHR1 and FCRL3
• It is hypothesised that susceptible individuals may begin produce autoantibodies after an infection (possible that some bacteria e.g. E coli and Yersinia, may have TSHR-like proteins on their cell wall; antibodies produced to fight off this infection may cross react with TSHRs
• Autoantibodies against the TSH-receptor (TRABs) are produced and stimulate the thyroid gland to produce and release thyroid hormone
  • Not subject to negative feedback
• The goitre seen in Grave’s is caused not just by the action of TRABs but also due to inflammation/lymphocytic infiltration.  Likewise, the ophthalmopathy of thyroid eye disease is due to retro-orbital swelling from lymphocyte and macrophage infiltration (secondary to autoantibody-mediated inflammatory process: orbital fibroblasts are known to express TSHR so this can bind to TRABs)
• NB Smoking is not directly associated with the risk of Grave’s BUT if the patient does have graves, symptoms (particularly eye disease) is worse
  • due to increased inflammatory changes

Presentation

• In addition to symptoms/signs of hyperthyroidism (see here), Graves’ disease also causes a number of other features specific to this diagnosis
  • Diffusely enlarged thyroid gland
    • there may also be a thyroid bruit (vascular bruit)
    • usually soft and symmetrical
  • Ophthalmopathy (thyroid eye disease)
    • Early thyroid eye disease can be misdiagnosed as conjunctivitis
    • Patients may have
      • Tearing, gritty sensation, photophobia, eye pain (particularly on movement but also retro-orbital pain), exophthalmos, diplopia, visual loss, impaired eye movements
  • Thyroid dermopathy
    • inflammatory reaction in the skin can cause non-pitting, pink/purple plaques
    • most commonly over the pretibial region (pretibial myxoedema) and over sites of previous trauma
    • oedema can also present in the eyelid and cause further eyelid retraction and lid lag.
  • Thyroid acropachy
    • Again, inflammatory process of the fingertips/nails (indistinguishable from finger clubbing) 

Diagnosis

• TRAb antibody test positive and clinical features of hyperthyroidism
  • Including low TSH and high free T3/T4
• Thyroid uptake scan
  • Diffuse high-uptake

Management

• In general, younger patients (<40) are prescribed anti-thyroid drugs:
  • Carbimazole

  • Side effects of CARMBIMAZOLE include nausea and GI upset (common).  Rash/Pruritus- allergy is relatively common (change to PTU).  AGRANULOCYTOSIS is a rare but serious side effect.  If the patient develops a severe sore throat, check FBC and stop immediately

  • Propylthiouracil
  • NB Usually start with high doses and titrate down to an appropriate maintenance dose
    • A beta-blocker may help to control symptoms of palpitations and tachycardia in the mean time.
• Older patients with Grave’s tend to have radio-iodine treatment
  • May worsen eye disease
• Occasionally, Grave’s can be treated with surgery, although this isn’t common
• Advise to stop smoking
• Glucocorticoids may improve opthalmopathy symptoms
  • Rarely, radiotherapy can be used to aid opthalmopathy (surgery is last resort)

Follow-up

• The majority of patients who receive surgery/radioiodine will end up with a permanent reduction in thyroid function and so may require thyroid hormone supplementation

Thyroid Physiology and Thyroid Function tests

Thyroid Anatomy

• Two lobes in the anterior neck on either side of the trachea inferior to the thyroid cartilage. About 25-30g.  About 5cm long
  • Joint by the isthmus and may have an additional ‘pyramidal lobe’ (remnant of the hypoglossal tract)
• Lies deep to the sternothyroid and sternohyoid muscles; parathyroid glands usually lie between the posterior border of the thyroid glands and its sheath; internal jugular vein and common carotids lie postero-laterally; the recurrent laryngeal nerve lies between the trachea and the thyroid
• Highly vascular- supplied by the
  • superior thyroid artery
    • first branch of ECA
  • inferior thyroid arterie
    • branch of the thyrocervical trunk of the subclavian
• Venous drainage from the superior, middle (both into the internal jugular) and inferior (drains into the brachio-cephalic veins) thyroid veins

Histology

• Thyroid tissue is subdivided by capsular septa into lobules containing follicles
  • spherical structures filled with colloid of mostly iodinated thyroglobulin
  • surrounded by follicular cells (produce hormone and Tg), between which are parafollicular cells (including C cells- produce calcitonin)
  • Follicles are the functional unit of the thyroid.  Production of thyroglobulin and thyroid hormone occurs.
    • Involves active transportation of iodine into the cells (stimulated by TSH), oxidation of iodine to I- (by thyroid peroxidase), iodination of tyrosine residues on Tg molecule

Thyroid Physiology

• The thyroid produces and secretes 2 metabolic hormones
  • Thyroxin (T4) and triiodothyronine (T3)
    • Act on many different cellular processes- main effect is an increase in metabolism
      • Effects can be split into two groups
        • Those that take minutes to hours after receptor binding (i.e. do not require protein synthesis)
          • e.g. activation of the membrane bound Na/K/ATPase and mitochondrial oxygen consumption
        • Those that take hours and require new protein synthesis.
          • e.g. effects on growth, proliferation, maturation etc
      • In general, in normal, low concentrations, the effect is anabolic i.e. stimulates growth.  In abnormally high concentrations, the effect is catabolic i.e. increased energy expenditure and protein breakdown.
• Under homeostatic control via a negative feedback loop involving the hypothalamic-pituitary-thyroid axis:
  • Thyroid releasing hormone is produced by the hypothalamus
    • Release is pulsatile and circadian
      • Downregulated by free T3 levels
    • Stimulates TSH formation and release
  • Thyroid stimulating hormone is produced by the anterior pituitary by thyrothroph cells
    • Release is
      • upregulated by TRH
      • downregulated by T4 and T3
    • Stimulates thyroid hormone production and release (possibly indirectly via stimulation of iodine uptake, colloid pino/endocytosis and growth of the thyroid gland)
• A note about thyroid hormone in the plasma and action
  • More than 99% of T3 and T4 is bound to plasma carrier proteins (they are both highly water soluble and would otherwise be delivered straight into the tissues)
    • Majority bound to thyroxine binding globulin (TBG) (~75%)
      • Others include thyroxine binding pre-albumin and albumin, as well as HDLs
  • Only unbound (free) hormone has metabolic activity and physiological effects
    • ~0.03% of T4 and 0.3% of T3
    • NB T3 is 3-7 times more potent than T4
  • T4 is the primary secretory product of the thyroid gland (~70-90μg/day).
  • T3 is derived from 2 sources
    • About 20% directly secreted from the thyroid
    • About 80% (of 15-30μg total) is produced via deiodination of T4 in the periphery (mainly liver)
      • NB In the liver, about 40% is converted to T3, another 40% to reverse T3 (metabolically inactive) and 20% is excreted via bile
  • It is important to measure TBG, total bound thyroxine and free thyroxine in order to judge abnormalities of thyroid function (as TBG can be affected by a number of things e.g. drugs (OCP, clofibrate, heroin/methodone, tamoxifen etc) and conditions e.g. liver disease

Thyroid Function tests

• Remember to always base test requests/interpretation of results on the clinical history and examination
• Hyperthyroidism
  • Low TSH and High T3/T4
    • Common causes
      • Primary hyperthyroidism e.g. Graves’; multinodular goitre; toxic nodule
    • Other common causes with low-radio-iodine uptake
      • transient thyroiditis (post-partum, post-viral, DeQuervain’s)
    • Rare
      • Over medication with thyroxine
      • Iodine induced
      • Amiodarone tx
      • Ectopic thyroid tissue
• ‘Normal’ (Investigation for other symptom e.g. AF) or hypothyroidism
  • Low TSH and normal T3/T4
    • Subclinical hyperthyroidism or medication (thyroxine) for hyperthyroidism
    • Rarer causes include steroids, dopamine/dobutamine infusions
    • Acute illness can also cause this picture
  • Low TSH and low T3/T4
    • Treatment for hyperthyroidism or acute illness are most common causes
    • Rarely, pituitary disease or congenital TSH/TRH deficiencies
• Hypothyroidism
  • Raised TSH, Low T3/T4
    • Common
      • Chronic autoimmun thyroiditis
      • Post radio-iodine/thyroidectomy
      • Transient thyroiditis (hypothyroid phase)
    • Other
      • Post radiotherapy
      • Drugs e.g. amiodarone, lithium
      • Iodine deficiency
      • Congenital causes
  • Raised TSH, normal T3/4
    • Subclinical autoimmune hypothyroidism
    • Drugs e.g. amiodarone, sertraline
    • Recovery post acute-illness
  • Raised TSH, raised T3/4
    • Unusual- causes include amiodarone, TSH-secreting tumours (pituitary), interfering antibodies (test picks up mimics of TSH/T3/T4)

Bowen’s disease (SCC in situ)

Background and Epidemiology

• Although commonly called SCC in situ, Bowen’s disease differs slightly in its aetiology and pathophysiology.  (AK is a truer representation of SCC in situ).
• It is estimated to have an incidence of around 15/100000 per year but can be higher.
• Unlike actinic keratosis, it is much more common in women

Pathophysiology/Histopathology

• Similar to that of SCC and AK but (in contrast to AK) there is full thickness epidermal involvement (atypical keratinocytes) and mitotic figures can be present.
  • Bowen’s disease is also thought to have an inflammatory (as well as genetic) component
    • Quite often, there is accompanying inflammatory, mostly lymphocytic, infiltrate in the superficial dermis

Risk factors/Aetiology

• Age
• UV exposure
• Other irradiation damage e.g. radiotherapy, photochemotherapy
• Carcinogens e.g. arsenic (could be used as an ingredient in old ointments for psoriasis/asthma
• There is a significant associated with the HPV virus (typically HPV-16)
• Immunosuppression
• Chronic skin injury/conditions e.g. seborrhoeic keratosis

Presentation

• Slowly growing, usually solitary, patch/plaque with clearly defined borders, scaling/hyperkeratosis, and an erythematous (pink/red) surface.
  • Usually several centimetres in size.
  • Usually otherwise asymptomatic
  • Most commonly found on the lower limbs (shins are common).  Otherwise, the head/neck and upper limbs can be sites.
    • Occasionally, bowen’s disease may be found in areas not exposed to the sun e.g. sub-/peri-ungual, genital (on the penis this is known as Queyrat’s erythroplasia) or perianal
• Under the dermatoscope:
  • Characterised by scaly surface and glomerularly arranged vessels (clustering throughout the lesion)

Investigations

• Skin biopsy should be taken for the definitive diagnosis

Management

• In contract to SCC and AK, topical therapy e.g. topical 5-fluorouracil (first line) or imiquimod treatments are preferred.
• Cryotherapy may be used as an alternative, particularly in smaller lesions
• Other managements e.g. surgery/curettage and PDT can also be used (the latter particularly for immunosuppressed patients; the former may be suitable for small lesions)
• Radiotherapy can be used if the area is unsuitable for other treatment options

Actinic (or Solar) Keratosis

Pre-neoplastic lesion of sun-damaged skin.

Background/Epidemiology

• Caused by abnormal skin development due to UV radiation.
• Considered a precancerous form of SCC
  • Most common precancerous skin lesion
  • It is thought that around 65% of primary SCC and 35% of primary BCC arise from lesions of actinic keratosis.
  • The number of patients that progress from AK to SCC is not fully known but estimated between 1-10% (most do not progress)
• More common in men than women

Pathophysiology

• UV-radiation induced gene mutations in e.g. p53 or p16 tumour regulating genes
• In many ways the histopathology of AK is the same as that of SCC, only milder
  • Atypical, pleaomorphic keratinocytes at the basal layer that can extend into the more superficial layers.  The epidermis is abnormal (acanthosis, parakeratosis and dyskeratosis)- but by definition this is not full thickness abnormality.  Mitotic figures may be present.

Risk factors/Aetiology

• Type I skin type
• Age
• UV exposure (including proximity to the equator)
  • Consider lifestyle e.g. occupation, holidays, tanning booths etc
• Immunosuppression

Presentation

• Multiple flat or thickened, scaly/warty, skin-coloured/erythematous lesion
  • Most <1cm wide
• Commonly on areas of sun exposure e.g. bald scalp, ear, face, nose, back of hands, upper limbs
• Under the dermatoscope actinic keratosis can have the following features
  • Facial
    • erythema, with a marked pink-red ‘pseudonetwork’ surrounding hair follicles
      • fine, linear-wavy vessels surround the hair follicles too
      • the hair-follicle opening itself can be surrounded by a white-yellow halo (keratotic plug)
    • white-yellow surface scale
    • => often described as a ‘strawberry’ appearance
    • NB lesions can also be pigmented and misdiagnosed- presence of the pseudonetwork is often helpful
  • Non-facial
    • dense surface scale with some dot vessels

Differential Diagnosis

• lentigo maligna
• seborrhoeic keratosis
• Basal cell carcinoma
• Bowen’s disease
  • tends to be a large plaque with a sharp outline, most commonly found on the lower limbs

Investigations/Management

• Skin biopsy is only really required if this is suspicious of malignancy.
• Treatment isn’t necessarily required, but options are
  • topical treatment
    • 5-fluorouracil
    • Imiquimod
    • Diclofenac
  • Others
    • Cryosurgery
    • Photodynamic therapy
    • Excision
• Advise the patient about UV protection.

Squamous cell skin cancer

Background/Epidemiology

• Tumour originating from the keratinocytes in the skin
• Second most common skin cancer after BCC (accounts for ~20% of non-melanomatous skin cancer)
• Incidence is rising.  Currently around 17 per 100,000 people per year (around 10,000 cases per year)

Risk Factors

• UV exposure
• Immunosuppression
• Exposure to radiation or carcinogens
• HPV infection (warts)
• Fair (type I) skin
• Chronic inflammation
• Development from pre-malignant disease e.g. Bowen’s disease, actinic keratosis

Pathophysiology

• Loss of function mutations in p53 (e.g. caused by UV-light)
• Other genetic neoplastic changes e.g. mutations in BCL2, RAS and eGFR
• Typical histological features include
  • nuclear atypia, frequent mitotic figures, cellular pleomorphism, hyper- and parakeratosis (retaining the nuclei in the stratum corneum), a disorganised progression of cells from basal to apical layers of the epidermis
  • SCC can be graded based on histology as
    • Well differentiated (normal looking nuclei with abundant cytoplasm and extracellular keratin)
    • Moderately differentiated
    • Poorly differentiated (many atypical nuclei and mitotic figures; >nuclear:cytoplasmic ratio; less keratinisation)

Presentation

• Usually on sun-exposed areas e.g. bald scalp, ears, face and hands
• Variable presentation
  • from rapid development of a painful keratotic nodule
    • may be over an area of pre-existing dysplasia
  • to new, erythematous, infiltrated, warty nodule/plaque that can ulcerate
  • Usually, a slowly-growing, tender, scaly/crusted lump

Diagnosis/Management

• Excisional biopsy is the management of choice for most patients
  • As with BCC, Mohs surgery can be considered for tumours that are high risk or those in difficult areas
  • Radiotherapy may be required in unresectable tumours
  • Cryotherapy is an option for small, well-defined and low risk tumours