Flashcards in Disorders of growth, differentiaton and morphogenesis II Deck (46):
Anomalies of organogenesis: Agenesis (aplasia)
The failure of development of an organ or structure is known as agenesis (aplasia). Obviously, agenesis of some structures (such as the heart) is incompatible with life, but agenesis of many individual organs is recorded. These include:
3) Anencephaly (neural tube)
4) Oesophageal atresia
5) Biliary atresia
Renal agenesis: this may be unilateral or bilateral (in which case the affected infant may survive only a few days after birth).
It results from a failure of the mesonephric duct to give rise to the ureteric bud, and consequent failure of metanephric blastema induction.
Anomalies of organogenesis: Thymic agenesis
This is seen in Di George syndrome, where there is failure of development of T lymphocytes, and consequent severe deficiency of cell-mediated immunity.
Anomalies of organogenesis: Anencephaly
Anencephaly is a severe neural tube defect in which the cerebrum, and often the cerebellum, are absent. The condition is lethal.
Atresia: Oesophageal atresia
Atresia is the failure of development of a lumen in a normally tubular epithelial structure. Examples include: Oesophageal atresia: which may be seen in association with tracheo-oesophageal fistulae, as a result of anomalies of development of the two structures, from the primitive foregut.
Atresia: Biliary atresia and Urethral atresia
Biliary atresia: which is an uncommon cause of obstructive jaundice in early childhood (may be extrahepatic or intrahepatic).
Urethral atresia: a very rare anomaly, which maybe associated with recto-urethral or urachal fistula, or congenital absence of the anterior abdominal wall muscles (prune belly syndrome).
A failure in development of the normal size of an organ is termed hypoplasia. It may affect only part of an organ, e.g. segmental hypoplasia of the kidney. A relatively common example of hypoplasia affects the osseous nuclei of the acetabulum, causing congenital dislocation of the hip, due to a flattened roof to the acetabulum.
Maldifferentiation (dysgenesis, dysplasia)
Maldifferentiation is the failure of normal differentiation of an organ, which often retains primitive embryological structures.
The best examples of maldifferentiation are seen in the kidney (renal dysplasia) as a result of anomalous metanephric differentiation.
Here, primitive tubular structures may be admixed with cellular mesenchyme and, occasionally, smooth muscle.
Ectopia, heterotopia and choristomas
Ectopic and heterotopic tissues are usually small areas of mature tissue from one organ which are present within another tissue (e.g. gastric mucosa in a Meckel's diverticulum) as a result of a developmental anomaly.
Another clinically important example is endometriosis, in which endometrial tissue is found around the peritoneum in some women, causing abdominal pain at the time of menstruation.
A choristoma is a related form of heterotopia, where one or more mature differentiated tissues aggregate as a tumour-like mass at an inappropriate site. A good example of this is complex choristomas of the conjunctiva (eye), which have varying proportions of cartilage, adipose tissue, smooth muscle, and lacrimal gland acini. A conjunctival choristoma consisting of lacrimal gland elements alone could also be considered to be an ectopic (heterotopic) lacrimal gland.
Complex disorders of growth and morphogenesis: Neural tube defects
Neural tube malformations are relatively common in the UK and are found in about 1.3% of aborted fetuses and 0.1% of live births. The pathology probably results from complex interactions between multiple genetic and environmental factors.
Some genes, including Pax3, sonic hedgehog and open brain, are essential to the formation of the neural tube.
However, dietary folic acid and cholesterol also appear to be vital, and it has been estimated that around half of neural tube defects can be prevented by supplements of folic acid during pregnancy.
Complex disorders of growth and morphogenesis: Adult polycystic kidney disease
Adult polycystic kidney disease (autosomal dominant polycystic kidney disease: ADPKD)
At least one causative gene (ADPKD-1 gene) is known, located on the short arm of chromosome 6.
Both kidneys are grossly enlarged and distorted by multiple cysts derived from all levels of the nephron. As they enlarge, the cysts compress adjacent functional tissue, which is eventually destroyed.
Presentation is at any age from late childhood, with symptomatology related to renal failure and/or hypertension.
There is also an association of the disease with berry aneurysms of the vascular circle of Willis, which may rupture causing often fatal subarachnoid haemorrhage.
Additional cysts may occur, especially in the:
However these do not affect organ function and are, therefore, clinically insignificant.
Complex disorders of growth and morphogenesis: Childhood polycystic kidney disease
Childhood polycystic kidney disease (autosomal recessive polycystic kidney disease; ARPKD). This is more rare than the adult form with several sub-groups indicating several gene defects may be involved. The baby is either stillborn or dies of renal failure and respiratory distress soon after birth.
The kidneys may be so enlarged and readily palpable, renal enlargement may interfere with delivery. The multiple cysts (derived from collecting ducts) are characteristically elongated and arranged radially in the cortex and medulla.
Children with childhood polycystic disease all have additional liver abnormalities, which are probably due to developmental arrest of bile duct formation.
These liver changes include cysts, secondary bile duct proliferation, and extensive fibrosis, often leading to hepatic failure and portal hypertension.
Disorders of sexual differentiation
Disorders of sexual differentiation are undoubtedly complex, and involve a range of individual chromosomal, enzyme and hormone receptor defects.
The defects may be obvious and severe at birth, or they may be subtle, presenting with infertility in adult life.
Chromosomal abnormalities causing ambiguous or abnormal sexual differentiation have already been discussed.
Disorders of sexual differentiation II
Female pseudohermaphroditism in which the genetic sex is always female (XX), may be due to exposure of the developing fetus to the masculinising effects of excess testosterone or progestogens, causing abnormal differentiation of the external genitalia.
The causes include:
1) An enzyme defect in the fetal adrenal gland, leading to excessive androgen production at the expense of cortisol synthesis (with consequent adrenal hyperplasia due to feedback mechanisms which increase ACTH secretion)
2) Exogenous androgenic steroids from a maternal androgen-secreting tumour
3) Administration of androgens (or progestogens) during pregnancy.
Disorders of sexual differentiation: Male pseudohermaphroditism
Male pseudohermaphroditism in which the genetic sex is male (XY), may be the result of several rare defects:
1) Testicular unresponsiveness to human chorionic gonadotrophin (hCG) or luteinising hormone (LH), by virtue of reduction in receptors to these hormones: this causes failure of testosterone secretion
2) Errors of testosterone biosynthesis in the fetus, due to enzyme defects (may be associated with cortisol deficiency and congenital adrenal hyperplasia)
3) Tissue insensitivity to androgens (androgenreceptor deficiency):
a) Abnormality in testosterone metabolism by peripheral tissues
b) in 5a-reductase deficiency
c) Defects in synthesis, secretion and response to Mullerian duct inhibitory factor
d) Maternal ingestion of oestrogens and progestins.
These defects result in the presence of a testis which is small and atrophic, and a female phenotype.
Cleft palate and related disorders I
Cleft palate (around 1 per 2500 births), and the related cleft (or hare) lip (about 1 per 1000 births), are relatively common.
Cleft palate is more frequent in females (67%) than males, whereas cleft lip is more frequent in males (80%) than females, and its incidence increases slightly with increasing maternal age. Approximately 20% of children with these disorders have associated major malformations.
The important stages of development of the lips, palate, nose and jaws occur in the first nine weeks of embryonic life.
From about five week gestational age the maxillary processes grow anteriorly and medially, and fuse with the developing frontonasal process at two points just below the nostrils, forming the upper lip.
Meanwhile, the palate develops from the palatal processes of the maxillary processes, which grow medially to fuse with the nasal septum in the midline at about nine weeks.
Cleft palate and related disorders II
1) Failure of these complicated processes may occur at any stage, producing small clefts or severe facial deficits. A cleft lip is commonly unilateral but may be bilateral. It may involve the lip alone, or extend into the nostril or involve the bone of the maxilla and the teeth.
2) The mildest palatal clefting may involve the uvula or soft palate alone, but can lead to absence of the roof of the mouth. Cleft lip and palate occur singly or in combination, and severe combined malformations of the lips, maxilla and palate can be very difficult to manage surgically.
3) Recently, lip and palate malformations have been extensively studied as a model of normal and abnormal states of morphogenesis in a complicated developmental system.
4) The control of palatal morphogenesis is particularly sensitive to both genetic and environmental disturbances:
Genetic: E.g. Patau's syndrome (trisomy 13) is associated with severe clefting of the lip and palate
Environmental: E.g. the effects of specific teratogens such as folic acid antagonists or anticonvulsants, causing cleft lip and/or palate.
Cleft palate and related disorders III
Cellular factors are involved in the fusion of the frontonasal and maxillary processes. The differentiation of epithelial cells of the palatal processes is of paramount importance in fusion of the processes.
The most important mechanism is mediated by mesenchymal cells of the palatal processes:
a) These induce differentiation of the epithelial cells, to form either ciliated nasal epithelial cells or squamous buccal epithelial cells.
b) These undergo programmed cell death by apoptosis to allow fusion of underlying mesenchymal cells.
c) Positional information of genetic and chemical (paracrine) nature is important in this differentiation, and mediated via mesenchymal cells (and possibly epithelial cells).
d) Actions of epidermal growth factor (EGF) and other growth factors through autocrine or paracrine mechanisms, and by the endocrine actions of glucocorticoids and their intercellular receptors.
In squamous epithelial cells of light-exposed areas, dysplasia produces actinic keratosis, where there are areas of thickened epithelium, hyperkeratosis (increased keratin production) and cellular atypia, often progressing to squamous carcinoma.
In melanocytes, dysplasia may develop either in areas with increased numbers of confluent melanocytes (lentigo), or within pre-existing, naevi (moles), particularly in dysplastic naevus syndrome.
In this syndrome, some kindreds (families), termed BK mole kindreds (Initials are of first patient treated) have a high frequency of malignant melanomas developing from one or more naevi which are dysplastic histologically.
In the conjunctiva of the eye: Squamous epithelial dysplasia may progress to squamous carcinoma melanocyte dysplasia (in acquired atypical melanosis) may affect wide areas of the conjunctiva, and gradually progress to malignant melanoma.
Dysplasia: Respiratory tract
Respiratory tract In the respiratory tract and especially in the bronchus, (but also in the nasopharynx, sinuses and larynx, dysplasia is most frequently caused by tobacco smoking (see above).
The epithelium has often (but not always) already undergone squamous metaplasia, and superimposed dysplasia often progresses to malignancy (squamous carcinoma).
Dysplasia: Mouth and tongue
In the mouth and tongue, dysplasia produces leukoplakia (a descriptive term only, meaning white patch, which can also be produced by other lesions including carcinoma), and may progress to squamous carcinoma.
In the oesophagus: dysplasia of the squamous oesophageal mucosa may progress to squamous carcinoma; and glandular dysplasia of the lower oesophagus occurs in Barretts oesophagus (see above), in areas of glandular metaplasia (when gastric acid reflux causes the normal squamous epitheliumof the lower oesophagus to change to columnar epithelium).
Under these circumstances, dysplasia accounts for a 100-fold risk of malignancy (adenocarcinoma) when compared with the unaffected population.
In the stomach: Dysplasia frequently develops in association with Helicobacter pylori-associated chronicgastritis, and often progresses over time to gastric adenocarcinoma. Given the good prognosis of early gastric adenocarcinoma confined to mucosa or submucosa (five-year survival of more than 90%), it is important to screen and monitor patients known to be at high risk (e.g. with chronic gastritis and dysplasia), as a means of preventing more advanced gastric cancer which has a poor prognosis. Dysplasia frequently develops in existing adenomatous polyps.
Dysplasia: Large bowel
Large bowel In the large bowel epithelium: Dysplasia and subsequent adenocarcinomaare frequent and important complications of longstanding chronic inflammatory bowel disease (and particularly in ulcerative colitis). The overall risk of colorectal cancer in ulcerative colitis is low (around 2%), but this increases to around 10% in patients affected for 25 years.Most adenomas (adenomatous polyps; see below) of the large bowel progress with time through increasing severity of dysplasia to malignancy (adenocarcinoma). In familial adenomatous polyposis (transmitted as a Mendelian dominant condition), adenomas (mainly of the large bowel, but also of the small bowel) develop during the second and third decades, become dysplastic, and undergo malignant change by the age of 35 years.
Dysplasia: Kidneys, ureters and bladder
Kidney, ureters and bladder In the kidney, ureters and bladder: Dysplasia of the urothelium may arise de novo in transitional epithelium (progressing to transitional carcinoma), as described in rubber factory workers.‰Û¢ It may be superimposed on squamous metaplasia (producing squamous carcinoma), as seen in epithelium in the presence of ova of the trematode Schistosoma haematobium.
Penis Dysplasia of the glans penis appears as a sharply defined, slightly raised erythematous (red) patch, with a moist keratinous surface (erythroplasia of Queyrat), which carries a high risk of progression to squamous carcinoma.
Dysplasia: Female genital tract In the female genital tract:
Female genital tract In the female genital tract: Dysplasia of the cervix uteri and, less commonly, of the vagina or vulva, carry a high risk of progression to invasive squamous carcinoma. These lesions (a spectrum of mild, moderate and severe dysplasia to in-situ squamous carcinoma) are classified as cervical, vaginal and vulval intraepithelial neoplasia (Fig. 4.22), and they can be recognised as microscopic changes in cells from exfoliative cytological and biopsy samples. Around 11% of cervical intraepithelial neoplasia stage 1 (CIN 1) cases progress to CIN 3 within three years, and more than 12% of CIN 3 lesions would progress to invasive squamous carcinoma if untreated (although 30% of CIN 3 lesions would regress spontaneously).
Dysplasia: Dysplasia of the endometrium
Dysplasia of the endometrium (known as atypical hyperplasia) is recognised by microscopic architectural and cytological changes. There is a close correlation between the severity of atypia and subsequent development of adenocarcinoma; thus, in severe cytological atypia there is a 25% risk of malignancy in three years.
Breast In the female breast, dysplasia (again known as atypical hyperplasia) is recognised within breast ducts, which are packed with disoriented epithe- lial cells, which have nuclear pleomorphism and mitotic figures. The risk of developing breast adenocarcinoma is five times higher in women with atypical hyperplasia than in women with non-proliferative ductal lesions, and the risk increases further if the patient has a family history of breast cancer.Note that the term dysplasia‰Ûª is sometimes used misleadingly to denote the failure of differentiation of an organ which may retain primitive embryological structures. To avoid confusion, it is better to substitute the terms maldifferentiation or dysgenesis for this condition
The term polyp is used in medicine to describe the macroscopic appearance of a smooth mass of tissue which projects outwards from the surface of an organ. This organ surface is usually an epithelium (such as the nasal mucosa, or the bowel epithelium), although lesions which could be described as polypoid (polyp-like) might also occur on surfaces such as the peritoneum or synovium. Polyps are also described as sessile when they are flat, and pedunculated when they have a stalk.The term polyposis is used to describe a condition or syndrome where there are multiple polyps in an organ (e.g. polyposis coli, affecting the colon) or an organ system (e.g. hamartomatous polyposis of the gastrointestinal tract in Peutz-Jeghers syndrome).It is important to appreciate that the term polyp, when used alone and without further qualification, is purely descriptive of the shape of a lesion, and does not signify any specific underlying pathological process (such as hyperplasia, metaplasia, dysplasia or neoplasia).
A polyp results from focal tissue expansion at a site at (or near) the organ surface, when the enlarging mass takes the line of least mechanical resistance as it expands outwards rather than into the underlying tissue. The pathological process which causes both the focal tissue expansion and polyp formation may be either non-neoplastic (e.g. inflammation, hyperplasia, metaplasia, dysplasia) or neoplastic (e.g. neoplasms of epithelial, mesenchymal, lymphoid or other cellular origin).
Non-neoplastic polyps and most neoplastic polyps are common and benign, but a small proportion of malignant neoplasms can have a polypoid appearance (e.g. lymphomatous polyposis of the gastrointestinal tract; polypoid adenocarcinoma of the large bowel). Note that some existing benign polyps (such as adenomatous polyps of the bowel) can develop increasingly severe dysplasia over a period of time, and that eventually carcinoma-in-situ and invasive adenocarcinoma may threaten the life of the patient.
Fig. 4.24 illustrates that there is great potential for misdiagnosis of sessile and pedunculated polyps of the large bowel, which may be non-neoplastic or neoplastic; of epithelial, mesenchymal, lymphoid or other cellular origin.
Systemic examples of polyps
Polyps of all types may be asymptomatic, or they may come to the attention of the patient and clinician because of their primary effects or complications; these include haemorrhage (associated with local trauma, torsion, inflammation, or ulceration), anaemia (due to chronic subclinical haemorrhage), and mechanical effects (obstruction or intussusception). Some of the common and important examples of polyps are described.
Aural polyps (Non-neoplastic inflammatory) are a common complication of chronic inflammation in the middle ear, and consist of exuberant granulation tissue (capillary hyperplasia). Nasal polyps (Inflammatory) are very common and also result from chronic infective or allergic inflammation and consist of oedematous masses of connective tissue, with inflammatory cells and some incorporated glands.Laryngeal polyps Also called laryngeal nodules (non-neoplastic; inflammatory/mechanical), also consist of oedematous connective tissue and deposits of fibrinoid (fibrin-like) material, beneath squamous epithelium these are caused by vocal abuse, compounded by inflammation and, probably, by smoking).Oral polyps, arising from minor trauma to the oral (mouth, particularly gingival) mucosa, may cause an excessive repair reaction in some individuals. This produces an epulis, a fibrovascular polyp (non-neoplastic regenerative/hyperplastic), with recognised congenital and giant cell variants. Similar vascular polyps are associated with pregnancy.
The large bowel is by far the most common site of gastrointestinal polyps, followed by the stomach, whilst polyps of the small intestine are rare. The large bowel and stomach have a range of epithelial and non-epithelial, non-neoplastic and neoplastic polyps, involving a range of pathological processes.
Gastrointestinal polyps: Inflammatory polyps
Inflammatory polyps (Non-neoplastic) of the large bowel are seen in the context of inflammatory bowel disease, often with exuberant granulation or fibrov- ascular tissue. Note that pseudopolyps are polypoid areas surviving large bowel mucosa surrounded by deep ulcers, also seen in the context of inflammatory bowel disease.
Gastrointestinal polyps: Regenerative/hyperplastic/metaplastic polyps
Regenerative/hyperplastic/metaplastic polyps (Epithelial; non-neoplastic) are seen with Helicobacter pylori-associated gastritis in the stomach, although the pathogenesis is unknown elsewhere in the large bowel. These polyps are usually sessile, with elongated crypts, and no dysplasia. They have no malignant potential.
Gastrointestinal polyps: Hamartomatous polyps
Hamartomatous polyps May be solitary as in juvenile polyps, or multiple (polyposis, as in Peutz-Jeghers syndrome, where they are associated with lip pigmentation and may occur throughout the alimentary tract. The polyps are adenomyomas (consisting of epithelial and smooth muscle elements). They have no malignant potential.
Gastrointestinal polyps: Heterotopic polyps
Heterotopic polyps (Epithelial non-neoplastic) are rare, and exemplified by a solitary stomach polyp containing heterotopic mature pancreatic tissue.
Gastrointestinal polyps: Adenoma/adenomatous polyps
Adenoma/adenomatous polyps (Epithelial; neo- plastic, with varying degrees of dysplasia) are the most important of the polyps of the large bowel and stomach. Large bowel adenomas are very common (20% of 60-year-olds have adenomas). They may be sessile or pedunculated; 75% are tubular, 10% are vil- lous, and the remaining 15% have intermediate hist- ology. Most adenomas of the large bowel and stomach progress with time through increasing severity of Desplasia to malignancy (adenocarcinoma), eventually with invasion and metastasis.In familial adenomatous polyposis (transmitted as Mendelian dominant condition, involving the apc gene on the long arm of chromosome 5), adenomas (mainly of the large bowel, but also of the small bowel) develop during the second and third decades, and undergo malignant change by the age of 35 years.
Gastrointestinal polyps: Polypoid malignant epithelial neoplasms
Polypoid malignant epithelial neoplasms Are mostly adenocarcinomas of the stomach and large bowel which have developed from adenomatous polyps. Rarely, polypoid squamous carcinomas may occur in the oesophagus. Malignant neuroendocrine neoplasms (carcinoids) may also be polypoid.
Gastrointestinal polyps: Mesenchymal polyps
Mesenchymal polyps (Mesenchymal: neoplastic) are common; the benign forms include fibromas, haeman- giomas, lipomas and lymphangiomas. Smooth muscle neoplasms are less likely to be polypoid, and they have an uncertain malignant potential.
Malignant non-epithelial polyps (Neoplastic) are rare, and include sarcomas (equivalent to their benign mesenchymal counterparts) and malignant lymph- omas (lymphomatous polyps).
Genitourinary polyps: Endometrial polyps
Endometrial polyps (Epithelial, non-neoplastic) are hyperplastic/metaplastic lesions occurring in the uterus of premenopausal women, caused by an inappro- priate response of the endometrium to oestrogenic stimuli. They consist of variably sized and often cystic glands (which may have metaplastic changes) within a cellular stroma containing thick-walled blood vessels. Malignant change is rare.
Genitourinary polyps: Cervical/endocervical polyps
Cervical/endocervical polyps (Epithelial, non- neoplastic) are common and consist of columnar mucus-secreting epithelium within oedematous stroma. They have no malignant potential.Benign vaginal polyps (Epithelial and mesenchymal, non-neoplastic) occur in adult women (around 40% are seen in pregnancy or hormone therapy) and consist of oedematous stromal tissue containing spindle-shaped (and often bizarre) cells covered by squamous epithelium. These benign hyperplastic lesions of adults may be mistaken histologically for the malignant botryoid rhabdomyosarcoma seen in infants (see below).