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99
CASE 36: INCREASED BREATHLESSNESS AND
SUDDEN DEATH
His wife finds her 68-year-old husband dead in his bed. During the last year of his life he
had slept on a bed in the downstairs living room, as he was unable to walk upstairs due to
extreme and worsening breathlessness. As his death is sudden and somewhat unexpected, the
general practitioner discusses the case with the local coroner, who decides that a post-mortem
examination is required.
Examination
At autopsy the most significant feature on external examination is that of an abnormally
shaped chest with an increase in the anteroposterior diameter and mild peripheral oedema.
The most significant abnormality on examination of the organs is seen in the lungs, which
are voluminous and meet in the anterior mediastinum, where they overlap the heart anteri-
orly. There are also large air-filled and intact bullae seen in subpleural positions and more
strikingly at the apex. There is also mild thickening of the right ventricular heart muscle.
QUESTIONS
1.
What is the most likely cause of death?
2. Describe the aetiology and pathogenesis of this condition.
3. How may this condition lead to death?
DOI: 10.1201/9781003242697-38
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100 Cases in Clinical Pathology and Laboratory Medicine
100
ANSWERS
The most likely cause of death is respiratory failure resulting from chronic obstructive pulmo-
nary (or airway) disease (COPD). COPD refers to two separate disorders, chronic bronchitis
and emphysema, which commonly co-exist and are characterised by progressive and irre-
versible damage to the lungs and airways that limits airflow to and from the lungs. Cigarette
smoking is, by far, the most common causative factor of COPD. COPD is a major cause of
morbidity and ranks within the ten most common causes of death worldwide. Although there
are typical clinical and radiological features of COPD, this diagnosis, in life, is made on the
basis of lung function tests (spirometry).
Emphysema is the result of chronic inflammation of the airways and lungs, with release of
inflammatory mediators resulting in destruction of alveolar walls. As a result of this the
alveolar surface area needed for gas exchange is reduced and there is loss of structural sup-
port for intrapulmonary airways, which are then more likely to collapse and trap air within
the lungs. This chronic over-inflation of the lungs leads to the classic barrel-shaped enlarge-
ment of the chest (increased anteroposterior diameter). Typical clinical features of emphy-
sema include progressive dyspnoea (usually a relatively late sign), coughing, wheezing and
weight loss. Patients typically show prolonged expiration due to entrapment of air, tend to sit
hunched forwards, and breathe through pursed lips.
Depending on the predominant distribution of tissue damage, emphysema is classified as cen-
triacinar, panacinar, paraseptal or irregular. In general, centriacinar emphysema is the result of
cigarette smoking, with reactive oxygen free radicals from cigarette smoke causing inactivation
of antiproteases. The resultant functional antiprotease deficiency is responsible for tissue damage.
A further cause of emphysema, more commonly with a panacinar distribution, is α-1 a nti-
trypsin deficiency, a genetic abnormality in which homozygous patients have a congenital
deficiency in α-1 antitrypsin and are therefore unable to counteract the destructive eects of
inflammatory mediators on lung tissue. These patients develop emphysema at an earlier age
and may also develop chronic liver disease.
Chronic bronchitis is the result of chronic irritation of the airways caused by inhaled particles in
cigarette smoke or, less commonly, dust from substances like grain and cotton. Chronic bron-
chitis presents with hypersecretion of mucus in the airways, a persistent cough, and frequent
infective exacerbations. Recurrent infections are a secondary rather than causative feature of
chronic bronchitis but an important factor in the chronic nature of the illness.
Emphysema and long-standing severe chronic bronchitis may lead to respiratory failure or
cause pulmonary hypertension, with the latter leading to increased strain on the right ven-
tricle. This culminates in cor pulmonale (pure right-sided heart failure). Both conditions can
result in sudden death. Rupture of a bulla can result in pneumothorax, which may also result
in sudden death, especially in a patient with already compromised respiratory function.
KEY POINTS
•
COPD encompasses emphysema and chronic bronchitis and is most commonly
caused by cigarette smoking.
•
The predominant abnormality in emphysema is destruction of alveolar walls,
whereas chronic bronchitis is characterised by chronic inflammation of the airways.
•
Complications of COPD include respiratory failure, cor pulmonale with right-sided
heart failure, or pneumothorax, all of which may result in sudden death.
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101
CASE 37: A WORSENING COUGH AND
HAEMOPTYSIS
A 54-year-old male who is a long-term smoker presents with a history of worsening cough
with haemoptysis. He confesses to a poor appetite and weight loss of 5 kg over the past 3
months. He works as a builder and is unable to say whether he may have been exposed to
asbestos.
Examination
The patient appears emaciated. There is conjunctival pallor and digital clubbing.
Examination of the chest reveals reduced breath sounds and a stony dull percussion is noted
in the left lower zone. There is no palpable lymphadenopathy or abdominal organomegaly.
INVESTIGATIONS
•
Hb 11.6, MCV 85, WCC 6.7, PLT 240, Na 135, K 3.8, Ur 4.5, Cr 80, Corr Ca 2.75, Bili
4, AST 20, ALT 15, ALP 85.
•
Chest radiograph: Moderate left pleural effusion with a bulky left hilum.
QUESTIONS
1.
What is the most likely diagnosis in this case?
2. What is the importance of the raised serum calcium?
3. What investigative techniques may be employed in confirming the diagnosis?
DOI: 10.1201/9781003242697-39
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ANSWERS
This presentation is very typical of lung cancer. The patient is a smoker presenting with
worsening cough and haemoptysis, and while these features may be seen in non-neoplastic
lung disease such as chronic obstructive pulmonary disease (COPD) and tuberculosis (TB),
the rapid progression of symptoms is more likely to be associated with malignancy. The find-
ings on the chest radiograph further strengthen the diagnosis. Loss of appetite and weight
loss with associated anaemia are indicative of a wasting process, although not specifically
lung cancer.
The hypercalcaemia observed in this patient likely represents a paraneoplastic syndrome,
which results from ectopic hormone secretion by the tumour. Squamous cell carcinomas in
particular are associated with producing PTH-related proteins, which are responsible for the
hypercalcaemia. Other paraneoplastic syndromes seen with lung cancer include Lambert-
Eaton myasthenic syndrome, which causes muscle weakness as a result of autoantibodies
against calcium channels in neuromuscular junctions. Peripheral neuropathy and acantho-
sis nigricans may also be manifestations of lung carcinoma. Apical lung lesions (Pancoast
tumours) may invade the cervical sympathetic chain and produce Horner’s syndrome with
enophthalmos, ptosis, miosis and anhidrosis.
The diagnosis of lung carcinoma may be made on clinical and radiological findings, but con-
firmation by examination of tumour tissue or cells is essential. This is because the treatment
and prognosis are strongly linked to the histological type of lung carcinoma. Tumour tissue
may be obtained in the following ways:
1. Bronchoscopic biopsy of the lung mass.
2. Bronchoscopic brushing of the lung mass and/or saline washing (lavage) of the bron-
chi and lung for deep-seated tumours. These may be done in combination with
biopsy to increase the chances of obtaining diagnostic material or as an alternative
to biopsy if the tumour is very vascular and therefore likely to bleed excessively.
3. In patients with mediastinal lymphadenopathy, endobronchial ultrasound com-
bined with transbronchial needle aspiration (EBUS TBNA) provides not only the
tissue diagnosis but also establishes the lymph nodal stage of the carcinoma. In addi-
tion, the cells obtained from this procedure may be used for analysis of molecular
markers such as EGFR, KRAS, RET, ALK and ROS1, which predict the respon-
siveness of lung adenocarcinoma to certain groups of chemotherapeutic agents. This
allows the selection of the most appropriate therapy for individual patients (targeted
therapy).
Next-generation sequencing (NGS) may be performed to cover not only the pre-
vious markers but also a number of other genes with the possibility of discovering
future targets.
Patients who are negative for chemotherapeutic targets may be tested for PD-L1
status and considered for immunotherapy.
4. Cells may also be obtained from the pleural fluid for diagnosis, staging and molecu-
lar testing.
The most common histological types of lung cancers are squamous cell carcinoma, adeno-
carcinoma and small cell carcinoma (SCLC). These may be present in variable proportions
within the same tumour. Squamous cell carcinoma and adenocarcinoma are sometimes
referred to as non–small cell lung carcinoma (NSCLC) to distinguish them from SCLC,
which is a form of neuroendocrine carcinoma and is responsive to a dierent group of che-
motherapeutic agents.
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Case 37: A Worsening Cough and Haemoptysis
103
The strong association between smoking and lung carcinoma (SCLC and squamous cell
carcinoma) is well proven. Adenocarcinoma is seen to arise in the vicinity of scars in the
lung secondary to infarcts and inflammatory conditions. Whilst surgery may be eective
for squamous cell carcinoma and adenocarcinoma, chemoradiotherapy is the treatment of
choice for SCLC.
KEY POINTS
•
Lung carcinoma is a common form of carcinoma, which should be readily sus-
pected on its clinical and radiological features.
•
Advances in bronchoscopic techniques in obtaining tumour tissue have made
accurate diagnosis and staging easier.
•
Histological typing and molecular analysis of the tumour are central to tailoring
the appropriate therapy for individual patients (personalised medicine).
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105
CASE 38: A YOUNG MAN WITH SHORTNESS OF
BREATH AND HAEMOPTYSIS
A 22-year-old man is brought into the emergency department complaining of a 1-week his-
tory of shortness of breath and one episode of haemoptysis. He does not report a fever or any
gastrointestinal symptoms. There is no family or medication history of note.
Examination
The patient is tachypnoeic (RR 28) with a blood pressure of 110/70 mmHg. He is afebrile,
and there is no cyanosis or jaundice. A further episode of haemoptysis is observed during
assessment.
INVESTIGATIONS
•
Urine dipstick: 3+ blood
•
Urine cytology: Tubular epithelial casts
•
Chest radiograph: Multiple bilateral lung shadows
•
Bloods: Ur 13.5, Cr 175
QUESTIONS
1.
What are the likely causes of this clinical presentation?
2. What is the best test to confirm the diagnosis?
3. What is the treatment for the underlying condition?
DOI: 10.1201/9781003242697-40
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
The patient’s clinical presentation may be caused by an infection involving the lungs with
systemic spread. In the absence of fever or signs of infection, other possibilities should be
considered, but blood and urine cultures should always be performed to exclude sepsis. The
presence of tubular epithelial urinary casts is indicative of renal parenchymal damage, and
in conjunction with the respiratory symptoms and radiographic findings, the possibility of
Goodpasture’s syndrome should be considered.
Goodpasture’s syndrome is an immunologically mediated disorder (type 2 hypersensitivity)
which aects the lungs and kidney. Antibodies are directed against native tissue antigens
of the glomerular basement membrane (GBM) and lung alveolar septa, accounting for the
renal and pulmonary manifestations seen in the condition. It usually presents in young adults
and teenagers and may be triggered by a viral infection or exposure to chemicals (e.g., dry-
cleaning solvents). Smoking has been implicated as a co-factor, and there is a genetic associa-
tion with the HL-DR2 subtype.
While testing for anti-GMB antibodies is required in the workup for suspected Goodpasture’s
syndrome, the best investigation to confirm the diagnosis is a renal biopsy. This would be
expected to show focal proliferative glomerulonephritis in early cases and crescentic glo-
merulonephritis in rapidly progressive cases. Linear deposits of immunoglobulins (IgG) and
complement (C3) would be seen along the GBM in the kidney and also in alveolar septa in the
lungs. The GBM antigen responsible is a component of the non-collagenous domain (NC1) of
the alpha-3 chain of collagen type 4.
There are other conditions that damage the glomerulus due to an intrinsic tissue antigen
(Heymann’s nephritis) and those due to planted antigens (drugs, infections). In Heymann’s
nephritis, the pattern of deposition of immune complexes in the glomerulus is granular and
interrupted rather than the linear pattern seen with Goodpasture’s syndrome.
The treatment for this condition is plasmapheresis, which clears anti-GBM antibodies and
other chemical mediators circulating in the blood. Immunosuppressive therapy limits further
antibody production and prevents lung and renal bleeding. Some patients may require dialy-
sis or renal transplant if the kidney damage is severe. Goodpasture’s syndrome was a rapidly
fatal disease in the 1970s, but prompt diagnosis and treatment have changed the prognosis
in recent years.
KEY POINTS
•
Goodpasture’s syndrome involves a type 2 hypersensitivity reaction that results in
a combination of renal and pulmonary manifestations.
•
The anti-GBM antibody results in rapid damage to the renal GBM and the lung
alveolar septa.
•
Treatment involves plasmapheresis and immunosuppression, without which the
disease may be fatal.
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CASE 39: SUDDEN-ONSET WEAKNESS AND
DYSPHASIA
A 70-year-old man with a history of type 2 diabetes mellitus, hypertension and hypercholes-
terolaemia is brought into hospital with sudden onset of expressive dysphasia and right arm
and leg weakness.
Examination
On examination, the patient has right hemiparesis with reduced power Medical Research
Council (MRC 3/5) in the right arm and right leg.
INVESTIGATIONS
An urgent computed tomography (CT) scan of the brain is arranged. The images are
reviewed, and an intravenous drug treatment is administered. Within an hour, there is
partial resolution of the symptoms.
QUESTIONS
1.
What is the diagnosis?
2. What treatment is most likely to have been given, and why was the urgent CT
scan required?
3. What risk factors are associated with this condition?
4. What blood vessel and what territory of the brain was involved?
DOI: 10.1201/9781003242697-41
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
The likely diagnosis in this case is an ischaemic stroke. Stroke refers to an acquired focal neu-
rological deficit caused by an acute vascular event. The neurological deficit persists beyond
24 hours, in contrast to a transient ischaemic attack (TIA), where symptoms resolve before
24 hours, although the distinction is now blurred with the advent of thrombolysis. The term
cerebrovascular accident is sometimes used synonymously with stroke, but many dislike the
connotations of inevitability it implies, in conflict with the treatable nature of the predispos-
ing factors and, to an extent, the acute event itself.
Strokes are broadly categorised into ischaemic and haemorrhagic types, with the major-
ity being ischaemic. The pathophysiology in a haemorrhagic stroke is rupture of a blood
vessel causing extravasation of blood into the brain substance with tissue damage and
disruption of neuronal connections. The resulting haematoma also compresses surround-
ing normal tissue.
In most ischaemic strokes, there is thromboembolic occlusion of vessels due to underlying
atherosclerosis of the aortic arch and carotid arteries. In 15–20% of cases, there is atheroscle-
rotic disease of smaller intrinsic blood vessels within the brain, most commonly the lenticu-
lostriate arteries, occlusion of which results in so-called lacunar infarcts. A further 15–20%
are due to emboli from the heart.
Although ostensibly an anastomosing ring connecting the main blood vessels of the brain,
the circle of Willis has limited capacity to provide collateral blood supply in the event of
sudden occlusion of one branch. At certain levels of ischaemia, neurons cease to function
but remain viable and can recover with restoration of blood flow, which is the situation
in a TIA. The area at the periphery of an infarct (penumbra) is therefore potentially
salvageable with thrombolysis. In this case, thrombolytic therapy by means of tissue plas-
minogen activator (t-PA) was given to the patient. A CT scan was required to exclude
conditions such as haemorrhagic stroke or brain tumours, which are contraindications to
thrombolysis.
If the critical ischaemic threshold is crossed, irreversible neuronal damage occurs. Dead
neurons release destructive cellular enzymes and excitatory neurotransmitters into the
extracellular fluid, damaging neighbouring neurons and inciting the release of inflamma-
tory mediators from the surrounding microglia and astrocytes. Infarction and liquefactive
necrosis ensue.
Where atherosclerosis is the main underlying pathological process, other non-modifiable
risk factors include age, gender, race, and genetic factors. In contrast, modifiable risk fac-
tors for atherosclerosis include hypertension, diabetes mellitus, hyperlipidaemia and smok-
ing. For embolic disease, atrial fibrillation, heart failure and endocarditis are known risk
factors.
The blood supply to the brain can be divided into an anterior circulation, supplied by the
anterior and middle cerebral arteries (branches of the internal carotid artery), and a posterior
circulation, consisting of the posterior cerebral arteries, which is fed by the vertebrobasilar
arteries. The territory and the extent of the infarct influence the prognosis; here, expressive
dysphasia and right hemiparesis are attributable to infarcts in Broca’s area and the motor
cortex, both frontal lobe territories supplied by left middle cerebral artery.
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