Gestational Trophoblastic Disease (GTD)

Types of GTD
Benign
•    Hydatidiform mole/molar pregnancy (complete or incomplete)
malignant
•    Invasive mole 
•    Choriocarcinoma (chorioepithelioma)
•    Placental site trophoblastic tumor

    The term Gestational Trophoblastic Tumors  has been applied the latter three conditions
    Arise from the trophoblastic elements
    Retain the invasive tendencies of the normal placenta or  metastasis
    Keep secretion of the human chorionic gonadotropin (hCG).

Hydatidiform Mole

 (molar pregnancy)

Definition and Etiology 
     Hydatidiform mole is a pregnancy characterized by vesicular swelling of placental villi and usually the absence of an intact fetus.
     The etiology of hydatidiform mole remains unclear, but it appears to be due to abnormal gametogenesis and fertilization 
    In a ‘complete mole’ the mass of tissue is completely made up of abnormal cells 
    There is no fetus and nothing can be found at the time of the first scan. 

    In a ‘partial mole’, the mass may contain both these abnormal cells and often a fetus that has severe defects. 
    In this case the fetus will be consumed ( destroyed) by the growing abnormal mass very quickly.  (shrink)

Incidence 

•    1 out of 1500-2000 pregnancies in the U.S. and Europe
•    1 out of 500-600 (another report 1%) pregnancies in  some Asian countries. 
•    Complete > incomplete
    Repeat hydatidiform moles occure in 0.5-2.6% of patients, and these patiens have a subsequent greater risk of developing invasive mole or choriocarcinoma
    There is an increased risk of molar pregnancy for women over the age 40
    Approximately 10-17% of hydatidiform moles will result in invasive mole
    Approximately 2-3% of hydatidiform moles progress to choriocarcinoma ( most of them are curable) 

Clinical risk factors for molar pregnancy

• Age (extremes of reproductive years)
                  <15
                  >40
• Reproductive history
                  prior hydatidiform mole
                  prior spontaneous abortion
• Diet
                  Vitamin A deficiency
• Birthplace 
                  Outside North America( occasionally has this disease).

Cytogenetics 

• Complete molar pregnancy 
  Chromosomes are paternal , diploid
      46,XX in 90% cases
      46,XY in a small part
• Partial molar pregnancy 
  Chromosomes are paternal and maternal, triploid. 
      69,XXY   80%
      69,XXX or 69,XYY  10-20%

Comparative Pathologic Features of Complete and Partial Hydatidiform Mole

Signs and Symptoms of Complete Hydatidiform Mole

• Vaginal bleeding
• Hyperemesis ( severe vomit)
• Size inconsistent with gestational age( with no fetal heart beating and fetal movement)
• Preeclampsia
• Theca lutein ovarian cysts

Signs and Symptoms of Partial Hydatidiform Mole

• Vaginal bleeding
• Absence of fetal heart tones
• Uterine enlargement and preeclampsia is reported in only 3% of patients.
• Theca lutein cysts, hyperemesis is rare.

Diagnosis of hydatidiform mole

Quantitative beta-HCG
Ultrasound is the criterion standard for identifying both complete and partial molar pregnancies. The classic image is of a “snowstorm” pattern
    The most common symptom of a mole is vaginal bleeding during the first trimester 
    however very often no signs of a problem appear and the mole can only be diagnosed by use of ultrasound scanning. (rutting check)
    Occasionally, a uterus that is too large for the stage of the pregnancy can be an indication.   
    NOTE:  Vaginal bleeding does not always indicate a problem!


Differential diagnosis 
•    Abortion
•    Multiple pregnancy 
•    Polyhydramnios

Treatment 

 Suction dilation and curettage :to remove benign hydatidiform moles
   When the diagnosis of hydatidiform mole is established, the molar pregnancy should be evacuated. 
    An oxytocic agent should be infused intravenously  after the start of evacuation and continued for several hours to enhance uterine contractility
•    
•    Removal of the uterus (hysterectomy) : used rarely to treat hydatidiform moles if future pregnancy is no longer desired.  

Chemotherapy with a single-agent drug
     Prophylactic (for prevention) chemotherapy at the time of or immediately following molar evacuation may be considered for the high-risk patients( to prevent spread of disease )



High-risk postmolar trophoblastic tumor
    Pre-evacuation uterine size larger than expected for gestational duration
    Bilateral ovarian enlargement (> 9 cm theca lutein cysts) 
    Age greater than 40 years
    Very high hCG levels(>100,000 m IU/ml)
    Medical complications of molar pregnancy such as toxemia, hyperthyrodism and trophoblastic embolization (villi come out of placenta )
     repeat hydatidiform mole 


Follow-up
    Patients with hudatidiform mole are curative over 80% by treatment of evacuation. 
    The follow-up after evacuation is key necessary 
    uterine involution, ovarian cyst regression and cessation of bleeding
    Quantitative serum hCG levels should be obtained every 1-2 weeks until negative for three consecutive determinations, 
    Followed by every 3 months for 1 years. 
    Contraception should be practiced during this follow-up period

Systemic Sclerosis (scleroderma)

Systemic sclerosis is an autoimmune connective tissue disorder. Other similar diseases include SLE, RA, Sjogren’s syndrome and mixed connective tissue disease. There is a lot of overlap in the symptoms of these diseases. Many will require immunosuppressive therapy.

-          You should always consider connective tissue diseases in ill patients with multisystem involvement, when there is no infection present.

-          Also remember that, even though the common presentations are discussed below, connective tissue disorders can present with strange symptoms, that can be just about anything!

Systemic sclerosis is sometimes referred to as CREST. This is a mnemonic you can use to remember some of the main symptoms of the disorder:

-          C – Calcinosis – calcium deposits, usually seen in the fingers

-          R – Raynaud’s phenomenon

-          E – Esophogeal Dysmotility

-          S – Scleodactyly – thickening of the skin

-          T – Telangiectasia – red spots on the skin

You might also here systemic sclerosis referred to ‘scleroderma’.

There are two main types of systemic sclerosis:

-          Limited cutaneous scleroderma – aka scleroderma – in this variation, the signs are mostly confined to the hands, arms and face – i.e. mostly to the skin. In 80% there is also pulmonary hypertension.

o   5 year survival is >90%

o   10 year survival is >75%

o   Generally only those with pulmonary involvement with have life threatening illness

o   Usually skin changes on the upper limb are distal to the elbow.

-          Diffuse cutaneous scleroderma – aka systemic sclerosis – tends to be more rapidly progressing and severe. Affects larger areas of the skin, and there is multi-systemic involvement. Can be life-threatening, e.g. if the heart/lungs/liver/kidneys become involved.

o   5 year survival is 70%

o   10 year survival is 55%

o   Skin changes can occur anywhere, and in advanced cases, may cover the whole body!

o   Patches typically appear on the trunk

Epidemiology / Aetiology

-          4x as common in women

-          Prevalence is about 1 per 1000

-          Peak incidence is between 30-50

-          Children sometimes affected in localised patches

Pathology

-          The disease is the result of vascular damage within the skin and organs.

-          Organ damage is usually the result of fibrosis.

-          Renal and pulmonary complications are the most life-threatening

-          In normal disease progression, there can be some element of disease regression. This might include periods, perhaps a few weeks long, where the patient says their symptoms feel much less severe –although they are usually still apparent.

Clinical features

-          Sclerodactyly – thickening of the skin

-          Skin pigmentation changes – commonly a loss of pigment around the affected areas, but there may also be patches of hyperpigmentation.

-          Calcinosis of the fingertips – calcium deposits at the fingertips. You may see these at little pits near the finger tips (digital pitting), and they are often visible as white dots around the distal phalanges on radiograph.

-          Reynaud’s phenomenon – the result of vascular spasms that reduce the blood supply to the fingers, usually when the hands get cold. The phenomenon may also be triggered by emotional stress. There is a classic pattern of colour change – the fingers will go white, then blue, then as they warm up, or the episode passes, they will become red. The red part of the cycle is the result of hyperaemia that occurs after a period of reduced blood flow. The episodes are often painful.

o   Sometimes also occurs in the tongue, toes, nose and ears.

o   Occurs in 4-30% of all women. Rarer in men

o   Can be divided into primary and secondary disease. In primary disease, it is often symmetrical, and will usually not result in any complications (e.g. ulceration, tissue necrosis, gangrene).

o   Secondary disease is what we see when it is related to connective tissue disease. This is often asymmetrical, and extremely painful. There may be associated ulceration, tissue necrosis, and gangrene.

§ Smoking is a big risk factor!

o   It is important to remember when asking about this in the history that everybody’s fingers will turn white/blue if they are cold for long enough! You need to find out if they think these changes are abnormal, and often there may be a clear horizontal line across the fingers where the colour changes appear.

o   It commonly occurs in association with connective tissue disorders, but it can be idiopathic, and occur in isolation, or in association with other disorders, or as the result of medications (e.g. β-blockers). It also occurs in pregnancy.

o   Treatment

§ Avoid sudden changes in temperature / low temperature. This might involve wearing gloves in moderate weather

§ Stop smoking

§ Try medications

·         Calcium channel blockers

·         Angiotensin-II agonsits

·         SSRI’s may also be useful

-          Oesophageal Complications

-          Telangactasia

-          Pulmonary complications

-          Reduced movements of the fingers/wrists – due to the swelling and skin thickening involved in the disease

General features of connective tissue disease

-          Mouth ulcers

-          Dry eyes

-          Dry mouth

-          Hair loss – mostly associated with SLE – but remember there is a lot of overlap! If symptoms of more than one connective tissue disorder are present, we would probably call it mixed connective tissue disease.

-          Hand, foot and leg ulcers – particularly when Reynaud’s phenomenon is present.

If you are a bit stuck when taking a history, going through a systems review is likely to yield lots of useful information in a patient with connective tissue disease

Investigations

-          Anti-centromere antibodies – associated with limited cutaneous scleroderma. Foud in 70% of cases.

-          Anti-Scl-antibodies – associated with Diffuse cutaneous scleroderma. Found in 40% of cases.

Treatment

Organ complications are managed individually. Treatment for the organ involvement has come a long way in the last 20 years, and has dramatically improved survival. However, scleroderma is still one of the least treatable rheumatological conditions.

Specific organ treatments, e.g.

-          Renal crisis – ACE inhibitors often used

-          Oesophageal involvement – PPI’s widely used

-          Pulmonary Hypertension – usually treated with calcium channel blockers. However, in many patients this is not sufficient. Other drugs can be used IV, e.g. prostacyclin.

o   In very severe cases, patients may be considered for lung transplant.

-          Interstitial lung disease – occurs in many patients, and restrictive lung disease will occur in about20% of patients, and many of these will die as a result. This may be treated with low dose long term corticosteroid therapy (e.g. 7mg daily of prednisolone), and can also be treated withcyclophosphamide. However, it is often resistant to treatment.

You should also monitor annually, e.g. with:

-          ECG

-          Spirometry

Immunosuppressive therapy

This may be used in those with more aggressive disease. This may involve therapies such as IV cyclophosphamide during flare-ups, to try and induce remission.

Osteomalacia and Rickets

These are essentially the same disorder. In children, the disease is rickets but after fusion of the epiphyseal plates it is known as osteomalacia.

The most common cause is vitamin D deficiency.

The condition is characterised by normal bone formation with abnormal bone mineralisation, thus there isexcess osteoid and cartilage, and insufficient bone.

Causes

-          Vitamin D deficiency – due to lack of sunlight ± insufficient dietary intake. Both often occur simultaneously. Common in the elderly (e.g. often indoors for long periods) and also in dark skinned populations residing in non-native climes (e.g. in the UK) – particularly if they cover up their skin (e.g. common in Inidan Pakistani women and girls in the UK. As a result, chapatti flour is fortified with vitamin D).

-          Renal osteomalacia – resulting in vitamin D deficiency. Often occurs in patients with long-term renal pathologies.

-          Drug Induced – particularly with anticonvulsants

-          Vitamin D resistant rickets / osteomalacia – a collection of inherited diseases, including familial hypophosphataemia, and a disorder where the vitamin D receptor is defective.

o   Type I hereditary vitamin D-dependent rickets – caused by ineffective conversion of vitamin D precursors in the kidneys (25()H)D to 1,25(OH)D. Autosomal recessive

o   Type II hereditary vitamin D-dependent rickets – due to mutations in the 1,25(OH)D receptor, causes end-organ resistance to vitamin D

o   Both are treated with high levels of calcitriol  ( 1,25()H)2vitamin D )

-          Hypoparathyroidism

-          Low dietary calcium / phosphate (rare)

Clinical Features

-          Muscle aches

-          Muscle weakness

-          Bone Pain / pain on walking

-          Predisposition to fractures – especially in the elderly

-          Tetany – parasthesia of the lips, tongue and face, sometimes facial and carpopedal spasm, rarely seizures. May be hard to distinguish from other causes of seizure.

-          In children

o   Generally unwell

o   Delayed walking / crawling / sitting

o   In pregnancy, amy affect the foetus, especially the skull of the newborn (pingpong ball like skull - craniotabes)

§ Craniotabes is also seen in syphilis, and neonates with this are often tested for the disease.

o   Rachitic Rosary – bead like nodules on the ribs

o   Kyphoscoliosis

o   Bowed legs and ‘knock knees’ only occur in severe cases in older children.

Investigations

-          Vit D – often ↓

-          Alkaline phosphate: may be ↑ or ↔

-          Parathyroid hormone ↑

-          ↓Calcium

o   Low vitamin D results in low absorption of calcium in the diet, which inturn stimulates increased PTH production. High levels of PTH also increase phosphate excretion, but may normalise serum calcium levels.

-          ↓Phosphate

-          Renal failure (in renal osteomalacia)

-          X-ray – usually of radius / ulnar

o   Diagnosis cannot be made with X-ray alone – also need PHT and 25(OH)D level to rule out other causes of demineralisation.

o    Rickets

§ Changes most easily seen at the ends of the radius and ulnar

§ Ragged bone edges

§ Apparent increased distance from arm bones to carpal bones (Due to demineralisation of this area).

§ Fuzzy, cup-shaped diaphyses (ends of the bone)

§ General increase in radiolucency of the bone

o   Osteomalacia

§ Reduced amount of cortical bone

§ Partial fractures

Treatment

-          Vitamin D supplements + calcium  are first line – 400U tablets, 1-2 times/day

o   After 3 weeks, x-ray improvements can be seen. Typically starting at the very tip of the bone, and continuing down through the affected segment

o   Malapborption might require calciferol (1,25(OH)2D) - 1mg/day (equivalent to 40,000 units of Vit D!)

o   Vit-D resistant rickets should be treated with calciferol 10,000 unites/day

o   Renal osteomalacia is best treated with alfacalcidol

o   Hypercalcaemia is common with all vit D treatments, especially alfacalcidol.

Osteoporosis

Osteoporosis is the most common bone disorder. It is a reduction in bone mass and alteration of bone structure, not just a reduction in bone density. The easiest way to measure the extent of the disease is withbone density scans.

The condition in itself is clinically silent, however, it massively increases the risk of fractures, which increases the risk of mortality.

Epidemiology

-          Most common bone disorder

-          Genetic factors are very important – in twins, concordance is 60-90%. Many genes have been implicated, and it is likely that numerous genes are involved.

o   Osterogenesis imperfecta is a type of monogenic osteoporosis that has been well described, but is rare compared to multigenic and multifactorial causes. OI actually comprises of 4 subtypes, which are classified by the presence of a blue sclera. In some cases, this is apparent in childhood, but may resolve with age. In some cases, affected children are born with multiple fractures. There is also often joint hypermobility, aortic root dilation (causing aortic regurg) and hearing loss. These secondary features are related to defects in collagen.

-          More common in women (4:1)

-          More common in Caucasian population than in other races

-          Affects 35% of the over 50’s in the UK

Causes

-          Post menopausal bone loss is the most common cause – this is related to oestrogen deficiency

-          Hyperparathyroidism

-          Malabsroption (e.g. coeliac’s disease)

-          Osteomalacia

o   Most commonly the result of vitamin D deficiency

-          Multiple myeloma

-          Hypopituitarism

Aetiology

-          Family history

-          Alcohol excess

-          Smoking

-          Amenorrhoea

-          Late menarche

-          Early menopause – including surgical menopause

-          Lack of weight bearing exercise

-          Drugs:

o   Corticosteroids

§ Including Cushing’s disease

o   Anticonvulsants

o   Heparin

o   Thyroxine

o   Extreme alcohol excess

-          Low calcium and/or vitamin D intake

Clinical features

-          Fracture

-          Reduced height (vertebral fracture)

-          Stooping posture – kyphosis, aka dowager’s hump – as a result of wedge shaped fractures of the vertebral bodies.

Pathology

Essentially, there is loss of bone mass, despite normal mineralisation.

-          As opposed to osteomalacia – which occurs when bone is not being properly mineralised, despite the normal production of bone matrix.

Caused by a loss of coupling between bone deposition and bone absorption mechanisms. This can result in excess osetoclast activity, decreased osteoblast activity, or both. The process of mineralisation of new bone matrix remains normal.

Osteoporosis affects both trabecular (long thick bones, e.g. femur) and cortical bone (high surface area, think bones, e.g. spine). When it affects trabecular bones, reabsoprtion of bone is the main mechanism.

Post menopausal osteoporosis

This is the most common type of osteoporosis. Bone mass naturally declines with age. Peak bone mass occurs several years after puberty, and then steadily declines. In women, this decline is increased during and after menopause. This, coupled with the fact that women have a lower peak bone mass than men, means post-menopausal women are at particularly high risk.

Reduced levels of oestrogen mean that normal osteoclast and osteoblast activity is no longer in conjunction,and osteoclast activity slightly exceeds osteoblast activity, so that over time, bone mass is reduced.

Corticosteroid induced osteoporosis

Steroids affect bone density regulatory mechanisms at several places:

-          Decreased absorption of calcium from the gut

-          Decrease muscle mass – which can affect bone remodelling by altering the normal weight bearing stressors normally exerted on bone

-          Increasing osteoclast activity

Diagnosis

-          Bone mineral density two standard deviation BELOW the mean value for young adults of the same sex. This is assessed using a DEXA scan.

o   More mild reduction in bone density are classed as osteopenia. This is likely to progress toosteoporosis, so preventative measures may be initiated at this stage.

o   The BMD is assessed on a scale relative to 0.

§ >0 – better BMD than the reference

§ 0 to -1 – in the top 84% of the population

§ -1 to -2.5 – osteopenia

§ <-2.g - osteoporosis

-          Thyroid Function Test

-          Vitamin D levels

-          Myeloma screen

o   ESR

o   Serum immunoglobulins / electrophoresis

o   Urinary Bence Jones Protein

-          X-ray – not very sensitive or specific. Often osteoporosis only presents with a fracture, so you will end up doing one anyway!

-          Screening programs are not widely undertaken, as their efficacy is not proven

Complications

Fractures mainly depend on the type of bone affected by the osteoporosis. The lumbar vertebrae, wrist and thehip are the most commonly affected bones.

-          Vertebral fractures.

o   This can present ‘silently’, perhaps as an exaggerated kyphosis – Dowager’s Hump. This is particularly common in elderly women, and can also cause a reduction in height.

§ Only 30% of vertebral fractures are symptomatic

o   It may also present as acutely, especially when the nerves and nerve roots are involved.

§ Thoracic spine – pain radiates around the front of the torso

§ Lumbar spine – sciatic and femoral nerves may be involved.

§ Sudden onset back pain

§ 25% may feel nauseous and/or vomit

§ Localised tenderness

o   Management

§ Bed rest (1-2 weeks) may be helpful

§ TENS can relieve pain

§ Diazepam (muscle relaxant) may also be helpful

§ Initiate preventative treatments (calcitonin, bisphosphonates)

§ Physiotherapy

-          Non-spinal fractures

o   Managed in the standard way

Treatment

The aim of treatment is to reduce the risk of fracture.

Lifestyle changes

May be sufficient for some patients. Measures include:

-          Sufficient daily calcium intake – the equivalent to 1 pink of milk per day (1200-1500mg)

-          Smoking cessation

-          Reduction in alcohol intake

-          Increase weight bearing exercise

o   Not only increases bone density, but also helps to prevent falls.

o   At least 30 minutes weight bearing exercise 3x per week is needed to increase bone density

Drug treatments

-          NICE guidlines:

o   1^st line – use a bisphosphonate

o   2^nd line – if no improvement, try a different bisphosphonate

o   3^rd line – if no improvement, try strontium

Drug treatments can reduce the risk of fracture by up to 50%

Supplements

Many patients also receive dietary supplements as adjuncts to their pharmacological therapy:

-          Calcium

-          Vitamin D

Used alone, they reduce the risk of fracture only by 4%! In very elderly patients, for whom vit D deficiency is the main mechanism of bone density loss, they may be sufficient

  

Bisphosphonates – e.g. risedronate, clodronate, pamidronate, etidronate

The different drugs have similar mechanisms, but different efficacy. The most effective is usually pamidronategiven IV. Etidronate is the least effective, and has to be given in higher doses, which increase the side effects.

The drugs are essentially analogues of pyrophosphate.

Mechanism

-          Bind to hydroxyapatite crystals in the bone, and are then taken up by osteoclasts – resulting in a high concentration of the drugs in these particular cells. Once within the cell they:

o   Cause apoptosis – by acting as analogues to ATP

o   Inhibit cholesterol synthesis mechanisms – which eventually results in apoptosis

o   Inhibit binding of the osteoclasts ruffled border to the bone surface – and thus the osteoclast cannot resorb the bone.

Pharmacokinetics

-          Poorly absorbed from the gut

-          Should be taken on an empty stomach – as they can bind to calcium in food, after which, the drug cannot be absorbed.

o   Only about 10% of the oral dose is absorbed under normal circumstances

o   Usually taken weekly, and with plenty of water.

-          Pamidronate is only available IV, all other agents only available as oral preparations

-          They are rapidly removed from the blood by the kidney, but as they bind to salts, they stay deposited in bone for long periods

Unwanted effects

-          GI upset – which can be severe!

-          Bone pain

-          Oesophagitis – to reduce the risk, the patient should take the drug:

o   With a full glass of water

o   At least 30 minutes before food

o   And stay stood or sat upright for at least 30 minutes after the tablet is taken

-          Headache

Uses

As well as osteoporosis, bisphosphonates are used in Paget’s disease, and sometimes used against bone metastases.

HRT

No longer used as mainstream treatment, but if other treatments are not tolerated or effective, then it may be useful in women in post-menopausal osteoporosis.

-          Most effective when started early in menopause, and continued for >5 years

-          Bone loss continues, and is possibly increased upon stopping HRT

-          Also increases the risks of cardiovascular disease and stroke

Strontium

Sometimes used as an alternative to bisphosphonates

Calcitonin

Sometimes used in those for whom bisphosphonates are not very effective