Gestational Trophoblastic Neoplasia: In a Tertiary Care Hospital
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Gestational trophoblastic disease constitutes a spectrum of tumors and tumor like conditions characterized by proliferation of placental tissue, either villous or trophoblastic. The study was conducted in the Department of Pathology, Goa Medical College, as a retrospective study. A total of 24 cases were studied over a period from January 2014 to March 2017. The parameters which were studied included age group, obstetric history, beta-hCG values and histopathological types. Of the 24 cases, 87% were in the age group of 20-35 years. The spectrum of disorders that were studied comprised of 79% of complete mole, 8% partial mole, 1 case of placental site trophoblastic tumor and 1 case of choriocarcinoma.
These are a group of disorders related to normal or abnormal gestation that have a common denominator, i.e., the proliferation of trophoblasts.
It is characterized by proliferation of placental tissue, either villous or trophoblastic. The major disorders of this type are hydatiform mole (complete, partial, invasive), choriocarcinoma and placental site trophoblastic tumor (PSTT).
Survival rates depend on several factors. Nearly all women with molar pregnancy or low risk GTN can be cured, often with fertility sparing surgery alone. A placental site trophoblastic tumor can often be cured, particularly if it is found before it spreads outside the uterus. Even with faster growing GTN, cure rates are as high as 80-90% with intensive treatment.
Overall, GTT is rare but often curable. Out of this, molar pregnancy is the most common GTD.
Surgery and/or chemotherapy may be used to treat women with GTD. Treatment options and recommendation depend on several factors including the type, stage, risk grouping of GTD, the patients’ preferences and overall health.
Commonly used drugs for chemotherapy for GTD include: methotrexate, dactinomycin, etoposide, vincristine and cisplatin.
The present study was undertaken with the aim:
1) To find out which was the most commonly occurring GTD in Goa.
2) To find out which was the most common age group for the occurrence of GTD.
This retrospective study was done in the Department of Pathology, Goa Medical College. For this study, 24 cases of histologically diagnosed gestational trophoblastic disease from January 2014 to March 2017 were selected and data was collected from their case records.
Baseline β–hCG values were available in 12 of the cases, follow-up values were taken and noted. The treatment given was noted.
Twenty-four cases of persistent gestational trophoblastic disease were studied. Of these, the majority (87.5%) occurred in the 20-35 years age group with the mean age being 26.7 years (Figure1). The most common complaints with which the patients presented were abdominal pain and bleeding per vaginum.
Histopathologically, complete mole constituted the major proportion (79%) of the group (Figure 2), followed by partial mole (8%). One case was diagnosed as placental site trophoblastic tumor and one case was diagnosed as choriocarcinoma. The case of choriocarcinoma and invasive mole had previous history of molar pregnancy. Metastasis was recorded in 2 of the cases (1 case of choriocarcinoma and 1 case of invasive mole). Both had metastasis to the lung which was detected by computed tomography (CT) scan.
Baseline β–hCG values were available for 23 cases (Figure 3) out of which 12 had values more than 1,00,000 milli international units per milliliter (m IU/ml).
Suction curettage was performed in all hydatidiform moles. Follow-up β-hCG values were available in 12 cases, which showed normalization of values within 6 months. One case of hydatidiform mole was given methotrexate injection. Hysterectomy was performed and chemotherapy was given in the case of invasive mole. The case of choriocarcinoma was treated with chemotherapy (methotrexate, actinomycin, leucovorin and cyclophosphamide).
Gestational trophoblastic disease (GTD) is a spectrum of cellular proliferations arising from the placental villous trophoblasts encompassing four main clinicopathologic forms: hydatidi form mole (complete and partial), invasive mole, choriocarcinoma, and placental site trophoblastic tumor (PSTT). The term “gestational trophoblastic neoplasia” (GTN) has been applied collectively to the latter three conditions, which can progress, invade, metastasize, and lead to death if left untreated. The incidence in the United Kingdom is estimated at 1-3 per 1000 pregnancies for complete hydatidiform mole and 3 per 1000 pregnancies for partial hydatidiform mole respectively, with other western countries reporting similar data.
Hippocrates was probably the first to describe gestational trophoblastic disease around 400 BC in his description of ‘dropsy of the uterus’. GTDs are classified as at least five distinct groups on the basis of histopathology, cytogenetic, and clinical features: hydatidiform mole (HM) which includes complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM), invasive mole, choriocarcinoma (CCA), placental site trophoblastic tumor (PSTT), and miscellaneous trophoblastic lesions. However, current WHO classification 3 of GTD is presented as follows:
CLASSIFICATION OF GESTATIONAL TROPHOBLASTIC DISEASES:
1. Hydatidiform moles
a. Complete hydatidiform mole (CHM)
b. Partial hydatidiform mole (PHM)
2. Invasive hydatidiform mole
3. Gestational choriocarcinoma (CC)
4. Placental site trophoblastic tumor (PSTT)
5. Epithelioid trophoblastic tumor (ETT)
6. Tumor-like conditions:
a. Exaggerated placental site reaction (EPS)
b. Placental site nodule (PSN)
7. Unclassified trophoblastic lesions.
Some of these lesions are true neoplasms, whereas others represent abnormally formed placentas with a predisposition for neoplastic transformation of the trophoblast. Two benign entities, the exaggerated placental site reaction and the placental site nodule, are included because they are trophoblastic lesions that must be distinguished from other entities with malignant potential.
In hydatidiform mole, the trophoblastic proliferation is associated with swelling of the villi.
Complete mole is caused by abnormal gametogenesis and fertilization. The nuclei of the trophoblastic cells contain only paternal chromosomes, being androgenetic in origin, whereas all cytoplasmic DNA is maternally derived. Eighty-five percent of the cases are 46 XX and 15% are 46 XY. It has been hypothesized that in 46 XX cases, the process is fertilization of an empty ovum with no effective genome by a haploid sperm that duplicates without cytokinesis. Whereas in 46 XY cases there might be fertilization of the empty ovum by two haploid sperms with subsequent fusion and replication. In a few cases, DNA is tetraploid, these occurring in an older age group.
Patients with complete mole tend to be older than 30 years of age and more likely to have diets deficient in vitamin A precursors. A history of previous term birth reduces the risk of molar pregnancy, whereas a history of a previous mole greatly increases the probability of having another. Most repetitive moles are of the complete type, but can also be of the partial type or a complete mole can be followed by a partial mole.
On examination, the uterus is disproportionately larger than period of gestation. Serum hCG levels continue to rise after 14th week of pregnancy, unlike the drop seen in case of a normal pregnancy. At the time of presentation, there may be vaginal bleeding indicating the mole has begun to abort spontaneously.
Grossly, complete mole appears like a bunch of grapes, with most villi showing hydropic degeneration. In hysterectomy specimens, these swollen villi are shown to fill and distend the uterus. There are no identifiable embryo, amniotic membranes and umbilical cord. Cases showing presence of embryo represents a twin gestation(Figure 4).
Microscopically, the two features of complete mole are variable degrees of vesicular swelling and trophoblastic proliferation. Immunohistochemically, hCG is widely distributed and placental alkaline phosphatase (PLAP) is patchily distributed in the molar trophoblasts. By flow cytometry, 50% of complete moles are diploid, 43% are tetraploid, 3.6% are polyploid and 1.7% are triploid (Figure 5).
Ovarian changes: Bilateral theca lutein cysts are present in 50% of cases due to excessive hCG levels.
Around 15-35% of all moles are partial type. An embryo is often found, although this is usually abnormal(blighted ovum).The volume of placental tissue is relatively normal. Grossly, there are vesicles admixed with normal sized ones. Lesser degree of trophoblastic proliferation is noted. Clinically, the uterine size is nearly always small or appropriate for gestational age. Serum hCG levels tend to be relatively low.
Initial management of partial mole is suction evacuation of the uterus followed by sequential quantitative estimation of the beta subunit of hCG for at least a year. Initially the checkup is done at an intervals of one week till the serum hCG level becomes negative, followed by monthly interval for 6 months.
Refers to a hydatidiform mole (almost always of complete type but occasionally of partial type) in which the villi penetrate deeply the myometrium and/or its blood vessel causing perforation in some cases (Figure 6). It represents an exaggerated expression for capacity of invasion.
The vascular invasion may result in trophoblastic nodules in sites outside uterus, such as vagina, lung, brain and spinal cord (Figures 7 & 8). These patients are primarily treated with chemotherapy, hysterectomy is only indicated in certain circumstances.[12,13] (Figure 9)
It is a malignant neoplasm of trophoblastic cells derived from a previously normal or abnormal pregnancy, such as, an extrauterine ectopic pregnancy. It is rapidly invasive and metastasizes widely but once identified, it responds well to chemotherapy.
Grossly, choriocarcinoma has a soft, dark red, hemorrhagic, round, nodular appearance. Microscopically, the tumor has a dimorphic plexiform admixture of cytotrophoblast and syncytiotrophoblast (Figure10).
Immunohistochemically, choriocarcinoma cells are positive for hCG and keratin. There may also be reactivity for human placental lactogen (hPL), pregnancy-specific beta-1 glycoprotein (SP1) and carcinoembryonic antigen (CEA).
With the use of chemotherapy namely chlorambucil, methotrexate, and actinomycin D, the survival rate is close to 100% for tumors restricted to uterus, and 83% for patients with metastatic disease.
PLACENTAL SITE TROPHOBLASTIC TUMOR (PSTT):
PSTTs comprise less than 2% of gestational trophoblastic neoplasms. They are neoplastic proliferations of extra villous trophoblasts (intermediate trophoblasts).
The frequency of GTN was comparable to that of other studies from the Indian subcontinent. Majority of GTN cases were in the younger age group, and in multiparous women. The most common presenting complaint was vaginal bleeding. Few cases were detected on ultrasound. Complete mole was the commonest trophoblastic disease in these patients. GTN has an excellent prognosis even in those with invasive mole and choriocarcinoma as it responds extremely well to chemotherapy and a surgical (suction & evacuation) line of management. Beta-hCG plays an significant role in pretreatment evaluation and as an important prognostic marker for follow up.
- Berkonitz RS, Goldstein DP. Chorionic tumors. N. Engl J. Med 1996; 335:1740-1748.
- Shin IM, Kurman RJ. Molecular basis of gestational trophoblastic disease. Curr Mol Med 2002;2:1-12
- Brewer JI, Gerbie AB, Dolkart ER, et al. Chemotherapy in trophoblastic disease. AmJ gynecol. 1964; 90:566.4.
- Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet. 2010; 376 (9742): 717–729.
- Ober WB FR. The early history of choriocarcinoma. Ann NY Acad Sci 1961;172:299-426
- Scully RE, Bonfiglio TA, Kurman RJ, Silverberg SG. Histological typing of female genital tract tumors. WHO International Histological Classification of Tumors, 2nd Edition. New York: Springer Verlag:1994.
- Tse KY, Chan KKL, Tam KF, Ngan HYS. An update on gestational trophoblastic disease. Obstetrics, Gynaecology & Reproductive Medicine. 2012;22(1):7-15
- Shih M, Mazur MT, Kurman RJ. Gestational Trophoblastic Tumors and Related Tumor-Like Lesions-Email author. In: Kurman RJ, Ellenson H, Ronnett L, editors:’Blausteins Pathology of the Female Genital Tract. 6th Edition. Springer, 2011;p 1075-1135
- Rosai J. Rosai and Ackerman’s textbook of surgical pathology. 10th Edition.Volume 2.Mosby, 2011; p. 1639-1646
- Rice LW, Lage JM, Berkowitz RS, Goldstein DP, Bernstein MR. Repetitive Complete and Partial Hydatidiform Mole. Obstetrics & Gynecology. August 1989; 74(2)
- Hiralal K. D.C. Dutta’s Textbook of Obstetrics. 7th Edition (revised). Haemorrhage in early pregnancy. p. 194-199. New Central Book Agency. 2001.
- Lurain JR, Brewer JI. Invasive mole. Semin Oncol. 1982; 9:174-180
- Takeuchi S. Nature of invasive mole and its rational management. Semin Oncol. 1982; 9:181-186.
- Kumar V, Abbas A, Aster JC. Robbins and Cotran Pathologic Basis of Disease. Volume 2. Elsevier, 2014;p.1041-1042.