Current Diagnostic Pathology (2002) 8, 50d59^ 2002 Elsevier Science Ltddoi:10.1054/cdip.2001.0088, available online at http://www.idealibrary.com on

REVIEW

The pathology of cystic fibrosisM. N. Sheppard and A. G. Nicholson

Royal Brompton Hospital, Sydney St. London SW3 6NP, UK

KEYWORDScystic fibrosis, pathology,gene therapy

Summary Cystic fibrosis (CF) is one of the commonest lethal inherited conditionsamong Caucasians. It affects multiple organ systems and exhibits a range of clinicalproblems of varying severity. Life expectancy has improved in recent years as treatmentregimes have become more intensive, but current treatments are expensive, often timeconsuming and may affect quality of life. New treatments for the pulmonary disease areunder clinical trial and include antiproteases, amiloride, a sodium channel blocker, DNaseand gene therapy. The gene for cystic fibrosis was identified in 1989 and this together withthe emerging technology of gene therapy heralded a new dawn for the treatment ofgenetic disease. The lung is considered an ideal organ to target due to ease of access, butsubsequent research has shown that the airway surface provides an efficient barrier totopically applied gene transfer agents. A number of Phase I clinical safety trials werecarried out through the 1990s and provided proof of concept evidence that delivery ofDNA by either viral or non-viral means was safe though not clinically efficacious. Currentresearch is now focusing more on the barriers faced by delivery agents, with the aim thatmore efficient gene delivery will lead to a gene therapy for cystic fibrosis. The histopathol-ogist is rarely called upon to make the initial diagnosis as cystic fibrosis is usually diagnosedclinically, being characterized by chronic bronchopulmonary infection, malabsorption dueto pancreatic insufficiency and a high sweat-sodium concentration on sweat testing. Mostinformation concerning both macroscopic and microscopic findings in cystic fibrosis hascome from autopsy studies, so the pathological features are often extreme. However,with increasing survival of patients with cystic fibrosis, we are seeing more subtle changesin other organs and in addition, more aggressive drug therapy, gene therapy and lungtransplantation are bringing with them new disease entities and complications. ^ 2002

Elsevier Science Ltd

INTRODUCTION

Cystic fibrosis (CF), an autosomal recessive disorder, isthe most common genetic disease of Caucasians. One in25 Caucasians are carriers of the gene, although this israrer in other races. There are over 230 different allelesof the gene, located on the long arm of chromosome 7.The gene encodes for a membrane protein, the cysticfibrosis transmembrane conductance regulator (CFTR),which functions as an ion channel. CF is caused bymutations in this gene. The mutations affect CFTRthrough a variety of molecular mechanisms, which leadsto little or no functional CFTR at the apical membrane inepithelial cells. The basic defect in ion transport results

Correspondence to: MNS. E-mail: m.sheppard@rbh.nthames.nhs.uk

in the accumulation of sticky tenacious mucus in rela-tion to epithelial surfaces in many organs, including thelungs, sinuses, pancreas, gastrointestinal tract, andhepatobiliary system, sweat glands and reproductivetract.

GENETICS

More than 900 mutations in the CFTR gene have beenreported but diagnosis is based on the occurrence of twomutations and on assays that measure the basic defect ofabnormal chloride transport in the affected organs. Thisgene encodes a protein expressed in the apicalmembrane of exocrine epithelial cells, which functionsprincipally as a cAMP-induced chloride channel but alsoappears capable of regulating other ion channels. The

THE PATHOLOGY OF CYSTIC FIBROSIS 51

commonest mutation is a deletion of phenylalanine atposition 508 (deltaF508), which accounts for 70% ofcases.1 However, genetic tests can lead to confusion.Genetic analysis has shown that a symptomatic patientcan be a heterozygote, indicating that one lesion in theCFTR gene may be sufficient to cause CF-like lungdisease.2 Asymptomatic normal patients with two mutantalleles, deltaF508 and R117H, have also been reported.Although genotype analysis can be a useful adjunct, itshould not be the sole diagnostic criterion for CF.3

Assessment of molecular genotypes has showncorrelation with the severity of pancreatic insufficiencybut generally not with the severity of pulmonary disease,4

the exception being the A455E CFTR mutant which isassociated with mild lung disease.5 The poor correlationbetween CFTR genotype and severity of lung diseasestrongly suggests an influence of environmental andsecondary genetic factors (the so-called CF modifiers)and several candidate genes related to innate andadaptive immune response, have been implicated. Inaddition, the presence of a genetic CF modifier formeconium ileus has been demonstrated on humanchromosome 19q13.2.

It is now clear that the pathophysiology of CF airwaysdisease is far more complex than can be solely attributedto altered chloride transport. For example, in addition tofunctioning as a chloride channel, CFTR has also beenimplicated in the regulation of other apical membraneconductance pathways through interactions with theamiloride-sensitive epithelial sodium channel (ENaC) andthe outwardly rectifying chloride channel (ORCC).Superimposed on this functional diversity of CFTR isa highly regulated pattern of CFTR expression in thelung. This heterogeneity occurs at both the level of CFTRprotein expression within different cell types in theairway and the anatomical location of these cells in thelung.

Evolution of lung damage is highly variable in CF evenin patients with the same CFTR mutations, and it islikely that human leukocyte antigen (HLA) class IIpolymorphism contributes to CF-associated pulmonaryinflammation. Among 98 adult CF patients tested, thegenotypic frequencies of DR4 and DR7 alleles (serologicgroup DR53) and DR7/DQA*0201 haplotype werehigher than in 39 selected control subjects withoutatopy, although these did not significantly relate tospecific CFTR genotypes. In the CF patients, the DR7allele was significantly associated with an increase intotal IgE and with chronic Pseudomonas aeruginosacolonization.6

The phenotypic spectrum associated with mutationsin the CFTR gene extends beyond the classically de-fined cases of CF. For example, there are large numbersof the so-called monosymptomatic diseases, such asvarious forms of obstructive azoospermia, idiopathicpancreatitis and disseminated bronchiectasis, that are

associated with CFTR mutations uncharacteristicfor CF. The composition, frequency and type ofCFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mildmonosymptomatic presentations, and this expansion ofthe spectrum of disease associated with the CFTRmutant genes perhaps creates a need for revision ofdiagnostic criteria and a dilemma for setting nosologicalboundaries between CF and other diseases with CFTRaetiology.7

RESPIRATORY TRACT

Upper respiratory tract

The upper airway is often involved in cystic fibrosis withnasal polyps found at all ages, their incidence in childrenranging from 6.7% to 20%.8 Nasal polyps are very rare innormal children, so their presence strongly pointstowards the diagnosis in this age group. Histologically,they contain mucous cysts and hyperplastic mucousglands. The polyps are often multiple and may cause nasalobstruction with depression and widening of the nasalbridge. In adults up to 40% of patients develop polyps,a considerably higher incidence than in children. Thepresence of nasal polyps bears no relation to the severityof pulmonary involvement in either children or adults.

Lower respiratory tract

The majority of patients die of pulmonary disease. Theabnormal chloride transfer across epithelial membranescauses an excessively viscid mucus lining of the airways,and bacterial infection, particularly with Staphylococcusaureus, Haemophilus influenzae and Pseudomonasaeruginosa, stimulates a vigorous and excessive primarilyneutrophil-driven inflammatory response, whicheventually damages host tissue. The airways typicallybecome chronically colonized with bacteria that cannotbe eradicated, leading to bronchitis, bronchiectasis, andfinally, pulmonary fibrosis with respiratory failure. Allthese pathologies may be complicated by massivehaemoptysis and pneumothorax.9

Bacterial infection

The main infective agents are bacteria, withStaphylococcus aureus, Haemophilus influenzae andPseudomonas aeruginosa being the chief pathogens.S. aureus is associated with infection in the first few yearsof life. It can be seen in almost 40% of infants within thefirst 3 months of life.10 Chronic S. aureus infection usuallyprecedes P. aeruginosa infection, and a deterioration inlung function with chronic S. aureus infection beforecolonization by P. aeruginosa indicates that it is the

Figure 1 Bronchial wall showing inspissated mucus in thelumen with papillary proliferation of the surface epithelium anddense underlying chronic inflammation in cystic fibrosis.

52 CURRENT DIAGNOSTIC PATHOLOGY

S. aureus infection that often initiates lung injury.11

However, it is chronic P. aeruginosa infection that isassociated with chronic lung injury and reducedsurvival,12 with P. aeruginosa being rarely eradicated.Burkholderia cepacia, formerly known as Pseudomonascepacia, has been isolated in older cystic fibrosis patientsand its isolation has been causally associated with a rapiddecline in pulmonary function.13 The role of non-tuberculous mycobacteria in causing infection anddamage in the lungs of patients with cystic fibrosis hasalso recently been highlighted,14 as has chlamydialinfection.15

Fungal infection

Between 50% and 60% of patients have fungi, usuallyAspergillus fumigatus, in their sputum and an equalproportion may develop fungal precipitating antibodiesin their serum.16 Patients with cystic fibrosis arepredisposed to pulmonary fungal colonization because ofextensive lung damage and long-term antibiotic therapy,usually within airways but occasionally as intra-cavityfungal balls.17

Allergic bronchopulmonary aspergillosis (ABPA) wasfirst associated with cystic fibrosis in 1965. Asthma,mucoid impaction, bronchiectasis, bronchocentric granu-lomatosis and eosinophilic pneumonia have all beendescribed as part of the spectrum of ABPA.18

Microscopically, there may be eosinophilic infiltrationof the bronchial wall, desquamation of epithelium,thickening of the basement membrane and plugging withmucus, containing large numbers of eosinophils andCharcotdLeyden crystals. As an allergic response toinhaled Aspergillus spores, fungal elements may be sparsein the mucus plugs. These plugs can have a characteristicappearance. Bands of agglutinated eosinophils alternatewith layers of mucus. In cases with co-existentbronchiectasis, there are the characteristic plugs as wellas inflammation and destruction of the bronchial wallswith a prominent eosinophilic infiltrate. Bronchocentricgranulomatosis represents a more profound hyper-sensitivity reaction with palisading epitheloid cells,Langhans giant cells and many eosinophils surroundingand infiltrating bronchi. When the inflammatorypattern extends into the small airways and alveoli it givesa similar pattern to eosinophilic pneumonia. Theincreasing use of immuno-suppressive strategies andaggressive antipseudomonal therapy in CF has led to anincrease in Aspergillus lung disease, including invasiveaspergillosis.19

Autopsy reports on 156 patients with cystic fibrosisfrom 1964 to 1982 disclosed only one with disseminatedfungal infection, but a more recent study in the 1980sshowed an increased incidence (21%) of invasivedisease.20 It should be noted that the cellular reaction tofungal infection in cystic fibrosis may be acute, with little

or no granuloma formation. Therefore, special stains forfungi should be done routinely in any study of cysticfibrosis pathology in the lung.20

Viral infection

The place of viral infection in initiating or promoting lungdamage remains controversial. Viral infections candamage mucociliary clearance and encourage secondarybacterial infection, but their role in cystic fibrosis is notfirmly established.

Bronchi and bronchioles

Several authors have shown that the lungs are normal atbirth,21 although one study in fetal lungs during thesecond trimester of pregnancy showed accumulation ofmucin in the tracheobronchial glands as compared withcontrols.22 Even before infection becomes clinically de-tected, there is submucosal gland hypertrophy, duct ob-struction and mucous cell hyperplasia of the trachea andmajor bronchi with mucus hypersecretion. The bronchialseromucous glands are increased in volume with anelevated gland-to-wall ratio and dilated ducts filled withinspissated secretions.

Once infection sets in, the airways are filled with thickmucopurulent material containing bacterial colonies,neutrophils and thick mucus, and there is often papillaryproliferation of the overlying epithelium (Fig. 1). Repeat-ed pulmonary infections cause acute bronchitis, and thisis found at autopsy in patients with cystic fibrosis dyingat more than 1 month of age.23 The bronchitis andbronchiolitis are associated with a mixed cellular infil-trate of acute and chronic inflammatory cells includingneutrophils, histiocytes, lymphocytes and plasma cellswith no difference in the lesions produced by differentbacteria. Prominent follicular hyperplasia is alsofrequently seen.

Figure 2 Cystic fibrosis postmortem lung with bronchiectasisin the upper lobe. Note dilated thickened bronchi, which extendto the periphery of the lung and contain pus.

Figure 3 Cystic fibrosis postmortem lung with the bronchiec-tatic cavities filled with fresh blood.

THE PATHOLOGY OF CYSTIC FIBROSIS 53

Bronchiectasis increases in severity with age.Bedrossian et al.23 showed that bronchial changes andbronchiectasis could be seen from birth and becamemore common with advancing age and universal by thetime the patients reached their twenties. This processaffects the proximal airways and the distribution isusually most marked in the upper lobes, right middlelobe, lingula and superior segments of the lower lobes(Fig. 2). Parenchymal changes with pneumonia were alsoseen from birth and were present in up to 82% of casesby age 24. Formation of endobronchial abscessesproduces saccular spaces within the lung parenchyma.Collapse can result from mucus plugging and by enlargedlymph nodes impinging on the bronchi and is verycommon in infants.24 Emphysema is much less common,being present only from 2 years upwards and reaching41% in the 10d24-year age group.

As with the bronchi, bronchiolitis is almost universal ininfants with florid mucosal and luminal inflammation andulceration. Follicular bronchiolitis with hyperplasia of themucosa-associated lymphoid tissue is also common.

Lung parenchyma

Pneumonia is seen at all stages in the evolution of thedisease23 with alveoli filled with neutrophils and/or fociof organization. Although these changes can revert tonormal, parenchymal destruction often occurs withrepeated infection, and S. aureus infection is particularlyassociated with pneumatocoeles resulting frompulmonary parenchymal necrosis. There is often achronic inflammatory interstitial infiltrate with lympho-cytes, plasma cells and fibrosis of the interstitium.Histologically proven bronchiolitis obliterans organizing

pneumonia, with clinical improvement with cortico-steroid therapy has been reported.25

Cysts can occur within the lung, which may beseparate from the bronchial tree or communicate viaa small channel. Four types are described. The firstand most common is bronchiectatic with directcommunication with bronchi. The second is interstitialwith a cystic space located in the visceral pleura orinterlobular septae lined by fibrous tissue, which isassociated with pneumothoraces. The third is thepneumocoele already described and the fourth and leastcommon is the emphysematous type.23

Pulmonary vasculature

Pulmonary hypertension leads to medial hypertrophyand intimal fibrosis of the pulmonary arterial branches.Haemoptysis is common and is the result of rupture ofdilated bronchial arteries or veins in the walls of airwaysor bronchiectatic cavities, as well as direct injury tovessels by infection, an increase in bronchopulmonaryarterial anastomoses and loss of elasticity of vessels dueto pulmonary hypertension.26 Massive haemoptysis is theterminal event in many patients (Fig. 3).

Complication of improved survival in the lungs

The survival of cystic fibrosis patients has been graduallyincreasing, with a mean survival in 2001 of 35 years.Patient survival rates have increased because of antibiotictherapy and improved nutrition with pancreatic enzymereplacements. The severity of the lung disease increaseswith age with eventual respiratory failure. Haemoptysiswith fatal outcome, emphysema and pneumothoraxbecome more common.27 Pulmonary hypertension andcor pulmonale develops. Pulmonary amyloidosis can alsopresent with a diffuse interstitial pattern in long-termsurvivors.28

54 CURRENT DIAGNOSTIC PATHOLOGY

Complications of lung transplantation

Heart}lung transplantation is now well established in themanagement of end-stage respiratory disease in bothchildren and adults with cystic fibrosis.29 Children withcystic fibrosis have an increased incidence of lungrejection compared with cystic fibrosis adults. There isalso a higher incidence of tracheal stenosis in children,which could be explained by a less well-developedcollateral circulation. Bilateral (sequential) cadaverdonor transplantation is the usual procedure of choice.The 4-year survival rate for adult, all-disease, double-bilateral lung transplantation has improved to 53%. Issuesof diabetes mellitus, mechanical ventilation, osteo-porosis, malnutrition, fungi and drug-resistant bacteria,pleural fibrosis and sinusitis in relation to transplantationcan adversely affect outcome.30 However, due to lack oforgan donation, over 50% of patients die on the waitinglist for transplantation. The lungs after transplantationare also prone to infection with common bacterialpathogens and pulmonary infection often co-existing withrejection. P. aeruginosa is the most common isolate.31

PLEURA

With increased survival, pneumothorax has emerged asan increasingly common complication. This is related tothe spontaneous rupture of apical bullae (subpleural cysts'1 cm in diameter), pneumatocoeles or subpleuralabscesses. There is little pathological difference betweenthe pleural changes in pneumothorax of non-cysticfibrosis and cystic fibrosis cases. CF is associated withvarying degrees of pleural inflammatory reaction, and theextent of pleural reaction may be associated with surgicaldifficulties at the time of lung transplantation.

HEART

Most changes are secondary to respiratory failure andpulmonary hypertension. As patients survive longer, corpulmonale frequently occurs late in the course of thedisease and carries a poor prognosis.32 Myocardialnecrosis and fibrosis can cause sudden and unexpecteddeath in infancy due to cardiac arrest. Eighteen reportedCF patients with this complication had varied clinicalfeatures including mild pulmonary involvement, earlyonset severe pancreatic insufficiency and profoundelectrocardiogram (ECG) changes. In this group ofpatients, five were deltaF508 homozygotes, one was delta-F508/N1303K and one was a deltaF508/M compoundheterozygote. The co-existence of a genetic predispositionto myocardial lesions, resulting most probably fromsevere cystic fibrosis transmembrane (CFTR) geno-types (such as deltaF508/deltaF508, deltaF508/N1303K)and deficiency of certain trophic factors necessary formetabolism of the myocardium, has been postulated.33

GASTROINTESTINAL TRACT

On occasion the pathologist may make a diagnosis ofcystic fibrosis in fetal autopsy material, the most obviouschanges being found in the gastrointestinal tract wherethick meconium plugs can be present from as early as 17weeks gestation.34 Their presence is highly suggestive ofcystic fibrosis in the fetus and can occur in the absence ofchanges in the lung, pancreas or liver. It is a combinationof reduction in water content, increase in mucoprotein,absence of proteolytic enzymes and increase in albuminthat accounts for the increased viscosity. The pluggingcan progress to meconium ileus in which there ismechanical obstruction of the distal ileum, which affects17% of patients with cystic fibrosis at birth.35 This showsdense meconium adherent to the intestinal mucosa, withdilatation and obstruction of the lumen. Microscopically,there is extensive goblet cell hyperplasia and stronglyalcianophilic mucinous material. Obstruction may lead toischaemic necrosis of the ileal wall with perforation and thedevelopment of meconium peritonitis.36 Other associatedintestinal abnormalities include volvulus and ileal atresias.

Postnatally, pathology can be found throughout the GItract. In adults, lesions in the salivary and labial glands canbe found, with eosinophilic plugs in ducts causingenlargement.37 Upper gastrointestinal problems includereflux and oesophagitis with peptic ulceration. There isalso an increased incidence of Barrett’s oesophagus.Oesophageal varices associated with portal hypertensionoccur with cirrhosis. Patients with cystic fibrosis are atincreased risk of developing gastrointestinal adeno-carcinoma.38

In the small bowel, the characteristic findings ofmeconium ileus can be one of the earliest features ofcystic fibrosis.39 Some infants present with the ‘meconiumplug syndrome’ in which a hard plug of meconium ispresent in the colon with abdominal distension. Theinfant then passes the plug and resumes normal bowelfunction. Intussusception can also develop in up to 1% ofpatients with cystic fibrosis.40 Older patients with cysticfibrosis may develop ‘meconium ileus equivalent’ or‘distal intestinal obstruction syndrome’, especially if oralintake of fluids is inadequate or patients fail to takepancreatic enzyme preparations. Appendiceal abscessshould also be considered as a rare complication of CF.41

Colonic strictures, after the use of high-dosepancreatic enzymes, are being increasingly reported,especially in children. The main histological feature of‘fibrosing colonopathy’ is dense fibrosis of the submucosainvolving long segments. The pathogenesis is uncertain,but a direct toxic effect of the enzymes, a low fibre cysticfibrosis diet, malabsorbed fat, poor blood supply,abnormal motility and use of laxatives and gastrografinhave all been implicated. The affected colon hasa cobblestone appearance and, on microscopy, there isthickening of the muscularis propria, submucosal fibrosis,

Figure 4 Cystic fibrosis pancreas showing dilated ducts filledwith gelatinous material. There is fibrosis and fatty change in theparenchyma.

THE PATHOLOGY OF CYSTIC FIBROSIS 55

widespread interruption of the muscularis mucosae andchronic mucosal inflammation, with active cryptitis.Moderate to severe infiltration by eosinophils, withincrease in the number of mast cells, may be seen.42

Rectal prolapse of mucosa can occur in up to 22% ofpatients with cystic fibrosis43 and may be the firstmanifestation of the disease. It often recurs in the first5 years of life but resolves following treatment forpancreatic insufficiency.

PANCREAS

Pathological changes in the pancreas were amongst thefirst to be recognized, the disease initially being called‘cystic fibrosis of the pancreas’, and from as early as20 weeks gestation an accumulation of eosinophilicsecretions with dilatation of ductules may be seen.44 Inthe postnatal exocrine pancreas, there is tissue damagedue to acinar release of lytic enzymes with loss of acini,fibrosis and fatty replacement. Four histological gradesof severity are described.45 Grade I is accumulation ofsecretion, grade II exocrine atrophy, grade III atrophywith lipomatosis and grade IV fibrosis with totalobliteration of the exocrine glands and ducts withscattered islets of Langerhans. Pancreatic insufficiencymay result and this often causes the prominent clinicalsymptoms of cystic fibrosis in infancy and earlychildhood. About 85% of patients have such severe lossof pancreatic tissue that inadequate secretion of digestiveenzymes leads to malabsorption, which adversely affectssurvival. Pancreatitis can also occur, with the thicksecretions blocking ducts and subsequent autodigestionby pancreatic enzymes,46 and a recent study has shownthat some cases of idiopathic chronic pancreatitis areassociated with mutations in the CFTR gene. Theabnormal CFTR genotypes in these patients withpancreatitis resemble those associated with maleinfertility.47 Patients with pancreatic sufficiency havea better prognosis and do not usually develop thehepatobiliary disease and distal intestinal obstruction.The pancreas at autopsy is typically fibrosed and fatty,with residual dilated ducts filled with secretions (Fig. 4).

In the endocrine pancreas, progressive pancreaticfibrosis ultimately disrupts pancreatic islet function witha decrease in � cells and an increase in non-� cells.Adenocarcinoma of the pancreas has been reported incystic fibrosis.48 Data on 141 cases of CF-related diabetes(CFRD) patients show DeltaF508 as the most frequentmutation and N1303K as the second most frequentmutation, but without significant difference as comparedwith CF patients without diabetes. W1282X is the thirdmost frequent mutation in CFRD patients, morefrequent than in CF patients without diabetes. There isa significant correlation between the W1282X mutationand CFRD.49

LIVER AND BILE DUCTS

Obstructive biliary disease occurs in 15d20% of affectedpatients. Inspissated secretions can be seen in bile ductsprior to birth, along with bile duct proliferation, focalchronic inflammation and fibrosis.34 Due to the presenceof these inspissated secretions, prolonged jaundice withcholestasis may be seen in neonates.50 This accumulationof mucus leads to the formation of intrahepatic andextrahepatic biliary stones which can lead to clinicalobstruction. Gallbladder calculi occur in about 12% of CFpatients due to the production of thick lithogenic bile51

and gallbladder complications are becoming morefrequent with increasing survival.

Within the liver, bile stasis with proliferation of bileducts and periportal inflammation with fibrosis occurs.52

These lesions have been called ‘focal biliary fibrosis’ andare typical of cystic fibrosis hepatic involvement, seenin up to 25% of patients,53 although they may beasymptomatic and have little clinical significance. Bile ductstenosis with development of sclerosing cholangitis isalso common and there is eventual progression tocirrhosis with the formation of multiple regeneratingnodules within the liver (Fig. 5). This occurs in a minorityof patients (2d5%) and seems to increase with age.54

This extensive liver pathology is responsible for thedevelopment of portal hypertension with oesophagealvarices and hypersplenism, seen with similar frequency tocirrhosis from other causes.55 Fatty infiltration of theliver is common in patients with cystic fibrosis.56 Liver aswell as heartdlung transplantation has been successful incystic fibrosis.57 Five sets of cystic fibrosis siblings bearinga strongly discordant liver phenotype, suggests thatmodifier genes, inherited independently of the cysticfibrosis transmembrane regulator gene, could modulatethe liver expression in cystic fibrosis patients.58

Figure 5 Cystic fibrosis liver with macronodular cirrhosis.

Figure 6 Cystic fibrosis testis with no identifiable epididymis.Loose fatty tissue is identified. No vas deferens is present.

56 CURRENT DIAGNOSTIC PATHOLOGY

GENITOURINARY TRACT

Kidneys

In the past, glomerular changes were considered to besecondary to diabetes mellitus and hypertension.However, there is an increase in urinary oxalateexcretion, which is linked to malabsorption, the patientsdeveloping urolithiasis.59 Renal amyloidosis and immunecomplex glomerulonephritis as well as IgA nephropathyhave also been reported in CF,60 as has microscopicnephrocalcinosis. A primary defect of calcium meta-bolism in the kidney has been postulated.61

Female genital tract

Anatomically the female genital tract is normal, but thecervical mucus has reduced water content and may notundergo the normal viscosity change in midcycle thatfavours sperm penetration,62 one factor contributing toinfertility. Chronic pulmonary sepsis may delay menarcheand cause menstrual irregularities, but pregnancy canoccur with normal delivery of an infant, a more frequentfinding with improved pulmonary function intoadulthood. Cervicitis, cervical erosions and mucus glandhyperplasia are common pathological findings in thecervix and vaginitis occurs.63 Multiple follicular cysts canbe found in the ovaries.64 Postpubertal breasts havenormal development with varying degrees of fibrosisaffecting lobular units and ducts, but proliferative lesionsand carcinoma can occur.65

Male genital tract

Like females, males enter puberty and develop all thesecondary sexual characteristics and sexual function isnormal. However, there is an anatomical abnormality of

the genital tract in nearly all males with CF. The vasadeferentia are atretic or completely absent,66 with thebody and tail of the epididymes and seminal vesiclesabnormally dilated or absent (Fig. 6).67 Theseabnormalities cannot be explained simply by obstructionor infection alone, and a primarily genital phenotype hasbeen described in otherwise healthy males who havecongenital absence of the vas deferens and areheterozygous for deltaF508 CFTR mutation.68 It has beensuggested that the CFTR gene plays a role beyond thenormal development of the vas deferens, perhaps beingrelated to spermatogenesis as well. Forty-two differentCFTR mutations have been identified. The prevalence ofcryptorchidism and inguinal hernia is increased inpatients with absence of the vas deferens, as well as nasalpathology and frequent respiratory infections.69

MUSCLE, BONE AND JOINTCHANGES

Many patients suffer malnutrition because of theirgastrointestinal pathology with poor weight gain, shortstature and muscle wasting. Clubbing and hypertrophicpulmonary osteoarthropathy with proliferation ofvascular connective tissue beneath the periosteumoccurs.70 Osteoporosis, low bone mass and fractures areincreasingly recognized in children and adults with cysticfibrosis and, compared with a normal control population,CF patients have significantly reduced bone density at thelumbar spine, hip and femoral neck. Despite oralsupplements, vitamin D deficiency is also common and isassociated with more severe demineralization at thelumbar spine and hip.71

THE PATHOLOGY OF CYSTIC FIBROSIS 57

SKIN

Eccrine glands

The eccrine sweat glands, while providing the invaluablediagnostic clue of excess sodium and chloride concen-trations, are usually normal by light microscopy.

Apocrine glands

Dilatation with retained secretions are found in up to33% of postmortem cases. The changes are more severein children over the age of 7 years.72

Other skin lesions

Acrodermatitis is a rare presenting sign of cystic fibrosis.It is an erythematous, desquamating, periorificiallyaccentuated rash seen in association with malnutrition.Pathogenesis of the rash appears to involve a complexinteraction among deficiencies of fatty acids, zinc, proteinand possibly copper, leading to either disorderedprostaglandin metabolism, disordered cytokineproduction or free radical-induced damage to cellularmembranes.73

CENTRAL NERVOUS SYSTEMDISORDERS

Ocular abnormalities such as xerophthalmia, papillo-edema, and optic neuropathy have been described,thought to be due to malnutrition. Neuropathologicalchanges in patients with cystic fibrosis include dystrophicaxons in the nucleus gracilis and demyelination of thefasciculus gracilis, with a direct correlation betweendystrophic change and duration of disease. Theneuropathology of cystic fibrosis resembles that ofvitamin E deficiency in animals and vitamin E replacementmay halt these changes.74

SUMMARY

Cystic fibrosis (CF) is one of the commonest lethalinherited conditions among Caucasians. It affects multipleorgan systems and exhibits a range of clinical problems ofvarying severity. Much of the pathology described is wellcharacterized but life expectancy is increasing withimproved therapy, and potential new treatments, bothpharmalogical and genetic, are continually undergoingtrials. Therefore, the extent and patterns of pathologicalfindings in cystic fibrosis will likely change apace, withgreater association to specific mutations as thesebecome characterized.

PRACTICE POINTS

� Cystic fibrosis is the most common genetic diseasein Caucasians

� It affects lungs, gastrointestinal tract, pancreas,liver, genitourinary system with variable severity

� Mutation in the cystic fibrosis gene is also seen inpatients with isolated pancreatitis and absence ofthe vas deferens

� Patients are at increased risk of gastrointestinal andpancreatic adenocarcinomas

� Patient survival is increasing� With survival to adulthood females can be fertile

but males are infertile due to absence of vasdeferens

� New therapeutic options include gene therapy

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