June 24, 2009 — The management of the extremely rare placental-site trophoblastic tumor (PSTT) is discussed in a paper, published online June 23 in the Lancet, that the journal describes as "landmark."
Peter Schmid, MD, and colleagues from Imperial College London in the United Kingsom, describe the treatment and outcomes for 62 patients with this rare tumor; they collected these patients from throughout the United Kingdom over the past 30 years. This represents "the world's largest series," according to a Lancet press release highlighting the report.
"In view of the extreme rarity of placental-site trophoblastic tumors, substantially increased datasets are unlikely to be obtained in the near future," Dr. Schmid and colleagues comment.
Unclear Why Some Cells Become Cancerous
PSTTs are slow-growing malignant tumors that present months or even years after a normal pregnancy, abortion, miscarriage, or abnormal pregnancy, such as hydatidiform moles. The researchers note that PSTT was diagnosed in 1 in 20,000 women in the United Kingdom between 2003 and 2007.
Trophoblasts are formed during the first stage of pregnancy. They are the first cells to differentiate from the fertilized egg, supplying nutrients to the embryo and then developing into a large part of the placenta. "Exactly why some of these cells in some pregnancies should acquire changes that make them become a cancer is unclear," senior author Michael Seckl, PhD, FRCP, told Medscape Oncology .
PSTT can occur after any type of pregnancy, but it occurs most commonly after a normal pregnancy, Dr. Seckl continued. "Presumably, some placental cells are left behind. . . . We know this can happen in normal pregnancy and while in most cases these cells die off, in some they persist and can eventually turn into this type of cancer."
Rarest Form of Disease, and Biologically Different
PSTT is the rarest form of gestational trophoblastic disease, accounting for only 0.2% of the total of these disorders, and it is biologically different from the other forms, the researchers explain.
In an accompanying editorial, Ernest Kohorn, MD, from the Department of Gynecology at Yale University in New Haven, Connecticut, explains that in other forms of trophoblastic neoplasia, human chorionic gonadotrophin (hCG) is a reliable marker of the persistence of trophoblast cells, and the concentration of hCG correlates precisely with the tumor load. "Single-agent chemotherapy cures 99.9% of such patients, provided that the treating physician is familiar with the management of gestational trophoblastic disease and the patient is compliant," he writes.
However, PSTT is different in that the tumor load is not accurately correlated with the concentration of hCG, Dr. Kohorn notes. It also appears to be less sensitive to chemotherapy, he adds. Unlike other forms of gestational trophoblastic disease, which tend to occur after an abnormal pregnancy, PSTT can follow any type of pregnancy event, and "not infrequently" becomes clinically apparent even years later. In addition, there is great variability in its malignant aggressiveness, he writes.
Commenting on the paper, the editorialist writes: ""What Schmid and colleagues show more convincingly than was previously evident is that the greater the interval between the index pregnancy and the appearance of overt neoplasia, the more likely the disease will be aggressive."
Patients Treated With Surgery, Chemo, or Both
Dr. Schmid and colleagues report on the outcomes of 62 women with PSTT, who were diagnosed from among a series of 35,550 women registered with gestational trophoblastic disease in the United Kingdom between 1976 and 2006.
More than half of these patients (39 of 62; 63%) had locoregional disease, and the remaining 23 (37%) had distant metastases, the majority in the lung, but also at various other sites. Six patients had distant metastases at 2 or more sites. Nearly all of them (59 patients; 95%) had raised concentrations of hCG, but in most of them (41 patients; 69%), the levels were only moderately increased.
Most of the patients (53 patients; 85%) had surgery, either as initial treatment or after chemotherapy. All of the women had an abdominal hysterectomy, and some also had their ovaries removed or lymph nodes sampled.
Most of them (42 patients; 68%) also received chemotherapy, either as initial treatment or after surgery. This comprised various combinations of drugs, including dactinomycin, etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide, and/or cisplatin.
Median follow-up was 6.3 years (range, 2.3 to 10 years). Overall, 14 patients (23%) died. From these figures, the researchers calculated a probability of overall survival of 73% at 5 years and 70% at 10 years.
When they applied univariate analyses to these data, the researchers found that the only significant association that predicted overall survival was time from antecedent pregnancy. There appeared to be a cutoff of 48 months from the antecedent pregnancy that could differentiate between a patients' probability of overall survival and death. Of the 14 patients who died, 13 patients had experienced the antecedent pregnancy more than 4 years previously, and only 1 patient had experienced it more recently (hazard ratio, 93.1; P < .0001).
However, the authors urge caution in interpreting these results, which they describe as "exploratory."
"Why the optimum discriminator for survival was 48 months from antecedent pregnancy is as yet unclear," Dr. Schmid and colleagues comment. But they add that "consideration of the time since antecedent pregnancy in the diagnosis of PSTT could help to direct development of effective treatment strategies."
Surgery Sufficient in Early-Stage Disease
The researchers also present details of outcomes for the various stages of the disease.
Just over half of the group (34 patients) had stage 1 disease, and almost equal numbers were treated with surgery alone (n = 17) or combined surgery and chemotherapy (n = 16). One patient refused to have a hysterectomy and was treated with chemotherapy alone. The outcomes were similar for the 2 treatment options, with the probability of overall survival at 10 years of 93% for combined surgery and chemotherapy and 91% for surgery alone.
Only 5 patients had stage 2 disease. Two were treated with surgery alone, and both have had disease recurrence. The other 3 patients were treated with combined surgery and chemotherapy, and none has had a recurrence so far. The 10-year probability of overall survival in this group was 52%.
The remaining 23 patients had stage 3 or 4 disease, and most were treated with combined surgery and chemotherapy. The 10-year probability of overall survival in this group was 49%.
Dr. Seckl told Medscape Oncology that from his group's experience, he believes that patients who have disease confined to the uterus may need only surgery, whereas those with more advanced disease will need both surgery and chemotherapy.
He also recommends that the treatment of these rare tumors be left to specialists with experience in such cases. Physicians who find patients with this tumor should seek advice from a specialist center, and should refer the patients to the specialist centre, he said.
The researchers have disclosed no relevant financial relationships.
Lancet. Published online before print June 23, 2009.
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