Gestational trophoblastic disease

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Gestational trophoblastic disease
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Intermediate trophoblast 3 - low mag.jpg
Micrograph of intermediate trophoblast, decidua and a hydatidiform mole (bottom of image). H&E stain.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Gestational trophoblastic disease (GTD) is a term used for a group of pregnancy-related tumours. These tumours are rare, and they appear when cells in the womb start to proliferate uncontrollably. The cells that form gestational trophoblastic tumours are called trophoblasts and come from tissue that grows to form the placenta during pregnancy.

There are several different types of GTD. Hydatidiform moles are, in most cases, benign, but may, sometimes, develop into invasive moles, or, in rare cases, into choriocarcinoma, which is likely to spread quickly,[1][2] but which is very sensitive to chemotherapy, and has a very good prognosis. Gestational trophoblasts are of particular interest to cell biologists because, like cancer, these cells invade tissue (the uterus), but unlike cancer, they sometimes "know" when to stop.

GTD can simulate pregnancy, because the uterus may contain fetal tissue, albeit abnormal. This tissue may grow at the same rate as a normal pregnancy, and produces chorionic gonadotropin, a hormone which is measured to monitor fetal well-being.[3]

While GTD overwhelmingly affects women of child-bearing age, it may rarely occur in postmenopausal women.[4]

Classification

Gestational trophoblastic disease (GTD) may be classified as follows:

  • Complete HM.
  • Partial HM.
  • Gestational trophoblastic neoplasia.

Incidence and Mortality

The reported incidence of GTD varies widely worldwide, from a low of 23 per 100,000 pregnancies (Paraguay) to a high of 1,299 per 100,000 pregnancies (Indonesia). However, at least part of this variability is caused by differences in diagnostic criteria and reporting. The reported incidence in the United States is about 110 to 120 per 100,000 pregnancies. The reported incidence of choriocarcinoma, the most aggressive form of GTD, in the United States is about 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is about 0.18 per 100,000 women between the ages of 15 years and 49 years.

Risk Factors

Two factors have consistently been associated with an increased risk of GTD:

  • Maternal age.
  • History of hydatidiform mole.

If a woman has been previously diagnosed with an hydatidiform mole, she carries a 1% risk of hydatidiform mole in subsequent pregnancies. This increases to approximately 25% with more than one prior hydatidiform mole. The risk associated with maternal age is bimodal, with increased risk both for mothers younger than 20 years and older than 35 years (and particularly for mothers >45 years). Relative risks are in the range of 1.1 to 11 for both the younger and older age ranges compared with ages 20 to 35 years. However, a population-based hydatidiform mole registry study suggests that the age-related patterns of the two major types of complete hydatidiform mole and partial hydatidiform mole are distinct. In that study, the rate of complete HM was highest in women younger than 20 years and then decreased monotonically with age. However, the rates of partial HM increased for the entire age spectrum, suggesting possible differences in etiology. The association with paternal age is inconsistent. A variety of exposures have been examined, with no clear associations found with tobacco smoking, alcohol consumption, diet, and oral contraceptive use.

Clinical Features

GTDs contain paternal chromosomes and are placental, rather than maternal, in origin. The most common presenting symptoms are vaginal bleeding and a rapidly enlarging uterus, and GTD should be considered whenever a premenopausal woman presents with these findings. Because the vast majority of GTD types are associated with elevated human chorionic gonadotropin (hCG) levels, an hCG blood level and pelvic ultrasound are the initial steps in the diagnostic evaluation. In addition to vaginal bleeding and uterine enlargement, other presenting symptoms or signs may include the following:

Pelvic pain or sensation of pressure. Anemia. Hyperemesis gravidarum. Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity). Preeclampsia early in pregnancy.

The most common antecedent pregnancy in GTD is that of an HM.

Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and it should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other possible signs include neurologic symptoms (resulting from brain metastases) in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.

Trophoblastic disease must be differentiated from other causes of hyperthyroidism such as Grave's disease and toxic nodular goiter.

Cause of thyrotoxicosis TSH receptor antibodies Thyroid US Color flow Doppler Radioactive iodine uptake/Scan Other features
Graves' disease + Hypoechoic pattern ? ? Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter - Multiple nodules - Hot nodules at thyroid scan -
Toxic adenoma - Single nodule - Hot nodule -
Subacute thyroiditis - Heterogeneous hypoechoic areas Reduced/absent flow ? Neck pain, fever, and
elevated inflammatory index
Painless thyroiditis - Hypoechoic pattern Reduced/absent flow ? -
Amiodarone induced thyroiditis-Type 1 - Diffuse or nodular goiter ?/Normal/? ? but higher than in Type 2 High urinary iodine
Amiodarone induced thyroiditis-Type 2 - Normal Absent ?/absent High urinary iodine
Central hyperthyroidism - Diffuse or nodular goiter Normal/? ? Inappropriately normal or high TSH
Trophoblastic disease - Diffuse or nodular goiter Normal/? ? -
Factitious thyrotoxicosis - Variable Reduced/absent flow ? ? Serum thyroglobulin
Struma ovarii - Variable Reduced/absent flow ? Abdominal RAIU
Disease Findings
Thyroiditis Direct chemical toxicity with inflammation Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.[5][6]
Radiation thyroiditis Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
Drugs that interfere with the immune system Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.[7]
Lithium Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
Palpation thyroiditis Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism Factitious ingestion of thyroid hormone The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.[8]
Acute hyperthyroidism from a levothyroxine overdose The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.[9]
Struma ovarii Functioning thyroid tissue is present in an ovarian neoplasm.
Functional thyroid cancer metastases Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.[10]
Toxic adenoma and toxic multinodular goiter Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.[11]
Iodine-induced hyperthyroidism It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.[12]

Prognostic Factors and Survivorship

The prognosis for cure of patients with GTDs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value. The probability of cure depends on the following:

  • Histologic type (invasive mole or choriocarcinoma).
  • Extent of spread of the disease/largest tumor size.
  • Level of serum beta-hCG.
  • Duration of disease from the initial pregnancy event to start of treatment.
  • Number and specific sites of metastases.
  • Nature of antecedent pregnancy.
  • Extent of prior treatment.

Selection of treatment depends on these factors plus the patient’s desire for future pregnancies. The beta-hCG is a sensitive marker to indicate the presence or absence of disease before, during, and after treatment. Given the extremely good therapeutic outcomes of most of these tumors, an important goal is to distinguish patients who need less-intensive therapies from those who require more-intensive regimens to achieve a cure.

References

  1. Seckl MJ, Sebire NJ, Berkowitz RS (August 2010). "Gestational trophoblastic disease". Lancet. 376 (9742): 717–29. PMID 20673583. doi:10.1016/S0140-6736(10)60280-2. 
  2. Lurain JR (December 2010). "Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole". Am. J. Obstet. Gynecol. 203 (6): 531–9. PMID 20728069. doi:10.1016/j.ajog.2010.06.073. 
  3. Gestational trophoblastic disease: Epidemiology, clinical manifestations and diagnosis. Chiang JW, Berek JS. In: UpToDate [Textbook of Medicine]. Basow, DS (Ed). Massachusetts Medical Society, Waltham, Massachusetts, USA, and Wolters Kluwer Publishers, Amsterdam, The Netherlands. 2010.
  4. Chittenden B, Ahamed E, Maheshwari A (August 2009). "Choriocarcinoma in a postmenopausal woman". Obstet Gynecol. 114 (2 Pt 2): 462–5. PMID 19622962. doi:10.1097/AOG.0b013e3181aa97e7. 
  5. Lambert M, Unger J, De Nayer P, Brohet C, Gangji D (1990). "Amiodarone-induced thyrotoxicosis suggestive of thyroid damage". J. Endocrinol. Invest. 13 (6): 527–30. PMID 2258582. 
  6. Ahmadieh H, Salti I (2013). "Tyrosine kinase inhibitors induced thyroid dysfunction: a review of its incidence, pathophysiology, clinical relevance, and treatment". Biomed Res Int. 2013: 725410. PMC 3824811Freely accessible. PMID 24282820. doi:10.1155/2013/725410. 
  7. Vialettes B, Guillerand MA, Viens P, Stoppa AM, Baume D, Sauvan R, Pasquier J, San Marco M, Olive D, Maraninchi D (1993). "Incidence rate and risk factors for thyroid dysfunction during recombinant interleukin-2 therapy in advanced malignancies". Acta Endocrinol. 129 (1): 31–8. PMID 8351956. 
  8. Cohen JH, Ingbar SH, Braverman LE (1989). "Thyrotoxicosis due to ingestion of excess thyroid hormone". Endocr. Rev. 10 (2): 113–24. PMID 2666114. doi:10.1210/edrv-10-2-113. 
  9. Jha S, Waghdhare S, Reddi R, Bhattacharya P (2012). "Thyroid storm due to inappropriate administration of a compounded thyroid hormone preparation successfully treated with plasmapheresis". Thyroid. 22 (12): 1283–6. PMID 23067331. doi:10.1089/thy.2011.0353. 
  10. Fatourechi V, McConahey WM, Woolner LB (1971). "Hyperthyroidism associated with histologic Hashimoto's thyroiditis". Mayo Clin. Proc. 46 (10): 682–9. PMID 5171000. 
  11. Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G (1991). "High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland". J. Intern. Med. 229 (5): 415–20. PMID 2040867. 
  12. Oosting SF, de Haas EC, Links TP, de Bruin D, Sluiter WJ, de Jong IJ, Hoekstra HJ, Sleijfer DT, Gietema JA (2010). "Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors". Ann. Oncol. 21 (1): 104–8. PMID 19605510. doi:10.1093/annonc/mdp265. 

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