ENFERMEDAD TROFOBLASTICA GESTACIONALEspectro de condiciones neoplsicas derivadas de la placenta. La mola hidatidiforme completa y parcial, la mola invasora, coriocarcinoma gestacional y el tumor trofoblstico placentario son diagnsticos histopatolgicos mientras que la neoplasia trofoblstica gestacional postmolar es definida por criterios clnicos y de laboratorio. Las 3 primeras en general tienen un curso relativamente autolimitado El coriocarcinoma tiene un curso fulminante marcado por un extremadamente corto tiempo de duplicacin y ser propensa a metstasis El trmino enfermedad trofoblstica gestacional (ETG) se refiere a todas stas entidades El trmino neoplasia trofoblstica gestacional (NTG) se refiere especficamente a las formas con el potencial de invasin de tejidos y metstasis. Al coriocarcinoma y las formas malignas de la enfermedad (neoplasia trofoblstica gestacional, mola invasora, tumor trofoblstico placentario) que son localmente proliferativas pero con la capacidad de invadir tejidos y potencialmente metastatisar fuera del tero.

La neoplasia trofoblstica gestacional se reconoce hoy como la malignidad ginecolgica ms curable, debido a que los estudios para medir GCH (el prototipo de los marcadores tumorales) en suero o en orina, muestra niveles que son proporcionales al nmero de clulas tumorales viables, adems es extremadamente sensible a mltiples quimioterpicos y la identificacin de factores de alto riesgo de la enfermedad permite la individualizacin del tratamiento; por otra parte mltiples quimioterpicos pueden ser combinados o bien hacerlo con radioterapia o ciruga en algunos casos.

MOLA HIDATIDIFORME Incidencia de 1 en 1500 embarazos Dos tipos, completa y parcial. El manejo de ambas es similar. Y la creencia antigua de que se dividan de acuerdo o no a la presencia de tejido fetal o su ausencia es errnea, ya que existen otras diferencias citogenticas, patolgicas y clnicas.

Influyen: Raza Edad: Los extremos de la edad reproductiva son de mayor riesgo en especial mayores de 40 (pero tambin 15 o menores; la menor incidencia de 20-29). Se ha asociado con la edad de ambos padres avanzada y en especial asociado con molas completas. Estado socioeconmico Dieta (baja en protena, grasas animales vitamina A y caroteno) Historia reproductiva como factores de riesgo: mujeres con historia de mola previa tienen 10 veces ms riesgo y an mayor si ha sido ms de una. Citogentica y patologa: La molas completas son totalmente derivadas de genoma paterno (tabla 7.1) ms frecuente tienen un genoma diploide 46 XX exclusivamente con marcadores andrognicos en los cromosomas implicando la duplicacin del complemento cromosmico haploide del esperma (solo 5% tienen genoma 46XY, no hay 46YY). El feto se reabsorbe antes de que se desarrolle el sistema circulatorio, no hay evidencia de feto o de clulas rojas fetales. Las parciales tienen genoma paterno y materno. Usualmente dos sets haploides paternos se combinan con uno materno resultando en una triploidia y el genoma ms comn es 69XXX. Hay evidencia gruesa o histolgica de desarrollo fetal tales como clulas rojas, esto es una figura prominente en las molas parciales. Histopatologa: Los cambios en la mola parcial son sutiles o aun no diagnosticados Grados variables o focales de vellosidades hidrpicas y la proliferacin trofoblstica habitualmente es ligera comparado con la mola completa En la parcial existen clulas rojas fetales dentro de los vasos de la vellosidad En la completa hay edema velloso difuso, proliferacin trofoblstica difusa y carencia de tejido fetal. Los niveles de GCH son mayores en las molas completas.Aunque algunas molas completas se diagnostican como aborto diferido en ultrasonidos tempranos la gran mayora tienen hallazgos ultrasonogrficos de mola hidatidiforme. Sntomas. La mayora tiene retraso menstrual y se consideran embarazadas Sangrado transvaginal en primer trimestre, puede ser desde un manchado caf a hemorragia que incluso puede llevar a anemia o a necesitar transfusin. El sangrado se presenta en 84 a 97% de las molas completas Puede haber con el sangrado expulsin de vesculas Nausea y vmito se presenta en un tercio de pacientes La mayora de las pacientes con mola completa tienen diagnstico por los hallazgos ultrasonogrficos caractersticos Crecimiento uterino mayor al esperado para edad gestacional se observa en 28 a 50% de las pacientes con mola completa La mayora de las pacientes con mola parcial y algunas completas son diagnosticadas clnicamente como aborto diferido o retenido. Las complicaciones del embarazo molar incluyen: hipertensin inducida por el embarazo, hipertiroidismo, anemia e hiperemesis, y son ms comunes en completas. Preeclampsia en primer trimestre es casi patognomnico de mola (12% de pacientes) El hipertiroidismo es raro, menos de 1% pero cuando existe representa una emergencia, y hasta 10% tienen datos por laboratorio, es debido a elevados niveles de GCH y produccin de sustancias tirotrpicas. Desaparece una vez que se trata la mola. El dato ms severo puede ser insuficiencia respiratoria debido a embolizacin de tejido trofoblstico y ocurre con teros que tengan un tamao mayor al de 16 semanas 15 a 25% tienen quistes taca lutenicos y crecimiento del ovario >6cm debido a la hiperestimulacin de los ovarios por la excesiva produccin de GCH. Se resuelven despus de la evacuacin molar y solo requieren ciruga en caso de torsin. Las pacientes con estos quistes tienen mayor riesgo de enfermedad maligna despus de la evacuacin molar. Ms an si se combinan ovarios con crecimiento ms tero con tamao mayor al esperado para edad el riesgo es an mayor, hasta el 57% con sta combinacin requieren un tratamiento posterior por neoplasia trofoblstica gestacional (NTG). Secuelas malignas ocurren en 2.5 a 7.5% de las pacientes con molas parciales contra 6.8 a 20% despus de la evacuacin de una mola completa. Todos los sntomas anteriores son en general para molas completas ya que las parciales no presentan en general toxemia, tero de mayor tamao, quistes teca lutenicos, hipertiroidismo o problemas respiratorios. Y en las parciales la mayora de las veces son diagnosticadas como aborto diferido en ultrasonido. Diagnstico. En algunas pacientes la expulsin de vesculas puede ser la primera evidencia que sugiere mola Una prueba cuantitativa de GCH > 1,000,000 UI, tero aumentado de tamao, ausencia de latido cardiaco y sangrado vaginal sugiere el diagnstico. Una determinacin nica de GCH no es diagnstica (puede verse en embarazo mltiple) El ultrasonido es el principal medio de diagnstico, se identifica como un tejido ecognico, difuso, mixto, que reemplaza a la placenta producidos por cogulos vellosos e intrauterinos. Esos hallazgos pueden no existir en la mola parcial. Evacuacin. Con frecuencia el diagnstico el diagnstico de mola completa o parcial solo puede ser hecho posterior al estudio histopatolgico al haber realizado dilatacin y legrado por sospecha de un aborto incompleto. En estos casos se recomiendan cuantificaciones seriales de GCH y quiz una radiografa de trax basal post evacuacin. Para las pacientes en que se sospecha mola antes de la evacuacin se sugieren los siguientes exmenes; BH completa con cuantificacin de plaquetas, pruebas de coagulacin, pruebas de funcin heptica y renal, grupo sanguneo y Rh, cuantificacin de GCH, radiografa de trax. Las complicaciones de la mola se observan en 25% de las pacientes con crecimiento uterino mayor al que correspondera a un embarazo de 14 a 16 semanas El mtodo preferido de evacuacin es la succin La induccin con oxitocina o prostaglandinas o la histerotoma deben evitarse pues aumentan el riesgo de secuelas malignas comparado con la succin Durante la aspiracin y posterior a la evacuacin se sugiere oxitocina para evitar sangrado Terminada la evacuacin por succin se sugiere un legrado suave con legra La histerectoma es un mtodo alternativo a la succin en pacientes seleccionadas que no desean ya procrear, se conservan anexos, los quistes teca lutenicos solo se extirpan en caso de ruptura, sangrado activo o torsin. ste mtodo reduce pero no elimina el riesgo de NGT postmolar y an as se presenta en 3 a 5% de pacientes. Factores de riesgo para neoplasia trofoblstica gestacional postmolar. Niveles altos de GCH antes de la evacuacin Tamao uterino mayor al esperado para la edad gestacional Quistes teca lutenicos Edad materna avanzada Muchos de ellos interactan pero la presencia al mismo tiempo de quistes y el tamao uterino aumentan el riesgo de NTG postmolar hasta 57% Independientemente del nmero de factores de riesgo se considera que hasta 23% de las pacientes requerirn tratamiento por NTG postmolar.Vigilancia postmolar. Despus de una evacuacin molar es importante vigilar a todas las pacientes cuidadosamente para poder diagnosticar y tratar oportunamente las secuelas malignas Se debe determinar GCH con pruebas capaces de detectar bGCH hasta niveles 6 months as recog-nized risk factors. These risk factors were used to generatesubstages within each anatomic stage. While this revisedstaging system did correlate with outcome, it resulted in aproliferation of substages with questionable importance.

In 2000, FIGO revised its staging system for GTNagain. The original anatomic stages were retained but the 1992 risk factors were replaced by a risk factor scoregenerated by a standardized modication of the WHOprognostic index score (Table 78). Patients with histo-logically diagnosed PSTT were to be reported separately,reflecting the distinct tumor biology of these lesions.Changes to the WHO classication included eliminationof ABO blood group risk factors and a change in the riskscore for liver metastasis from 2 to 4, reflecting high riskfor patients with liver metastasis reported in many series.Chest X-ray rather than chest CT would be used to assessthe number of metastatic lesions. Abdominal CT and brainMRI were recommended for the evaluation for liver andbrain metastases, respectively. Finally, the three risk groupsof the WHO prognostic index score were consolidatedinto two groups: Low Risk with a score of 6 or less andHigh Risk with a score of 7 or greater. Hancock et al retrospectively compared the outcomes of patients accordingto the risk score categories generated by modied WHOprognostic index score and the proposed FIGO score. Theconsolidated risk categories generated by the FIGO scorecorrelated better with outcome than did the modiedWHO prognostic index score.

Under the new FIGO system, reporting of patients willinclude both anatomic stage and FIGO risk score. Forexample: a 30-year-old patient with non-metastatic GTDdiagnosed 5 months after molar evacuation with an hCGlevel of 8000 mIU/mL would be recorded as a FIGOStage I: 2. Likewise, a 40-year-old with prior term pregnancy7 months previously, hCG of 200,000 mIU/mL, brain

metastases, 10 lung lesions, and uterine tumor measuring6 centimeters would be FIGO Stage IV: 17.

It is anticipated that adoption of the newest revision ofFIGO staging for GTN will allow uniformity for evalua-tion and reporting of outcomes. With accumulation ofdata through FIGO, it is hoped that multivariate analysiscan conrm or refute the prognostic importance of indi-vidual factors used to generate the risk scores. While thesechanges are important on an international scale and thestandard for reporting results of treatment, they are oflesser importance for the practicing general obstetrician-gynecologist initially encountering patients with malignantGTN. For these clinicians, the most important decisionsrevolve around identication of patients who should bereferred out of the community to a specialist for treatmentof high-risk disease. Because the clinical classication system(Table 75) is relatively simple, correlating well with failureof initial single agent chemotherapy, and also identiespatients who fail treatment with the greatest sensitivity, itmay be the best system for use by the generalist for thepurpose of appropriate triage for referral.

Treatment of non-metastatic GTN

Primary remission rates of patients treated for non-metastaticGTN are similar using a variety of chemotherapy regimens(Table 76). Essentially all patients with this condition canbe cured, usually without the need for hysterectomy.Randomized comparisons of the regimens detailed in Table79 have not been completed, and comparison of resultsdiscussed below may not be valid because of slightly dif-ferent criteria used to make the diagnosis of non-metastatic GTN by different investigators.

Methotrexate 0.4 mg/kg/day given by intramuscular(IM) injection for 5 days, with cycles repeated every 12 to14 days was the regimen originally used to treat GTN atthe NIH. Hammond and colleagues reported the NIHexperience treating 58 patients with non-metastatic GTN.Only four (7%) patients had disease resistant to this regimen and three of these were salvaged with single-agent dactinomycin. In Lurains series from the Brewer

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Table 78 THE REVISED FIGO 2000 SCORING SYSTEM FOR GTN

FIGO score 0 1 2 4

Age (years) < 39 > 39Antecedent pregnancy Hydatidiform mole Abortion Term pregnancyInterval from index pregnancy (months) < 4 46 612 > 12Pretreatment hCG (mIU/mL) < 1000 100010,000 10,000100,000 >100,000Largest tumor size including uterus (cm) 34 5Site of metastases Spleen Kidney Gastrointestinal Brain LiverNumber of metastases identied 0 14 48 > 8Previous failed chemotherapy Single drug > 2 drugs

The total score for a patient is obtained by adding the individual scores for each prognostic factor. Total score 06 = low risk; 7 = high risk.From Kohorn EI: The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment.Int J Gynecol Cancer 11:73, 2000.

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Trophoblastic Disease Center, all 337 patients with non-metastatic GTN were cured. Only 10.7% of 253 patientsinitially treated with 5-day intramuscular (IM) methotrexatetherapy required a second agent (dactinomycin), only 1.2%multiple agent chemotherapy, and in only 0.8% was a hys-terectomy needed to achieve a complete remission. Factorssignicantly associated with the development of methotrexateresistance included pretreatment serum hCG in excess of50,000 mIU/mL, non-molar antecedent pregnancy, andhistopathologic diagnosis of choriocarcinoma. For years,5-day IM methotrexate was the primary treatment of choiceat the Southeastern Regional Center for TrophoblasticDisease, with similar results. If patients have abnormal liverfunction, methotrexate should not be used, because thisagent is metabolized in the liver. Furthermore, signicanthematologic suppression, cutaneous toxicity, mucositis,alopecia, gastrointestinal toxicity, and serositis are fre-quently seen in patients receiving this regimen.

Bagshawe and Wilde rst reported the use of alternatingdaily doses of IM methotrexate (1 mg/kg) and leukovorinfactor or folinic acid (0.1 mg/kg) for four doses of eachagent, in an attempt to reduce the toxicity of dailymethotrexate regimens. Folinic acid is a reduced form offolate that rescues cells from the dihydrofolate reductaseblock in the purine synthetic pathway produced bymethotrexate. While this may be true for high doses ofmethotrexate, Rotmensch and associates evaluatedmethotrexate levels in patients after daily methotrexatetherapy compared to levels in patients receiving alternatingdaily doses of methotrexate and folinic acid, with a higherdaily dose of methotrexate given in the methotrexate/folinic acid regimen. They noted that while patients on themethotrexate/folinic acid regimen had higher peakmethotrexate levels after treatment with a higher dose thanthose on single agent methotrexate, trough levels wereboth subtoxic and subtherapeutic 24 hours aftermethotrexate administration. This nding alone mightexplain therapeutic and toxicity benet described for the

low dose IM methotrexate/folinic acid regimen used fortreatment in GTN.

Berkowitz and associates, at the New EnglandTrophoblastic Center, have used methotrexate with folinicacid rescue in 185 patients with GTN. Ninety percent of163 patients with non-metastatic disease and 68% of 22patients with low-risk metastatic disease were placed intocomplete remission with methotrexate and folinic acid.Rather than recycling treatment at xed intervals, theytreated patients based on hCG level regression afterchemotherapy. More than 80% were placed into remissionwith only one course of chemotherapy. All patients withmethotrexate resistance achieved remission with otheragents.

At Charing Cross Hospital in London, 347 of 348(99.7%) low-risk patients treated with methotrexate andfolinic acid survived; however, 69 (20%) had to changetreatment because of drug resistance and 23 (6%) addi-tional patients needed to change treatment because ofdrug-induced toxicity. An analysis of the data from theSoutheastern Trophoblastic Disease Center at DukeUniversity indicated that 8 (27.5%) of 29 patients devel-oped resistance to methotrexate with folinic acid given at14 day intervals, compared to 3 (7.7%) of 39 treated withstandard 5-day methotrexate for non-metastatic disease.Although this difference was statistically signicant,because a larger number of patients receiving standardmethotrexate changed to another agent because of toxi-city, a similar proportion of patients were changed to asecond agent in each group. Wong and associates alsocompared 5-day methotrexate to methotrexate with folinicacid, resulting in comparable sustained biochemical remis-sion rates. In their series, however, patients who receivedmethotrexate/folinic acid achieved remission earlier butexperienced a higher incidence of hepatic toxicity com-pared with patients receiving the 5-day regimen.

Other investigators have used higher doses of intra-venous (IV) methotrexate (300500 mg/m2) followed by

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Table 79 CHEMOTHERAPY REGIMENS FOR NON-METASTATIC AND LOW-RISK METASTATIC GTN

Agent/Schedule Dosage

Methotrexate (1)Weekly 30 mg/m2 IM5 day/every 2 weeks 0.4 mg/kg IM (maximum 25 mg/d total dose)

Methotrexate/folinic acid rescue Methotrexate 1 mg/kg IM, days 1, 3, 5, 7; andEvery 2 weeks Folinic acid 0.1 mg/kg IM, days 2, 4, 6, 8

Methotrexate infusion/folinic acid Methotrexate 100mg/m2 IV bolus; andEvery 2 weeks Folinic acid 200mg/m2 12 hr infusion 15 mg p.o. every 6 hr for four doses

Dactinomycin (2) 5 day/every 2 weeks 913 mcg/kg/d IV (maximum dose 500 mcg/day)bolus, every 2 weeks 1.25 mg/m2 IV bolus

Etoposide (3) 200mg/m2 /day p.o.5 day/every 2 weeks

(1) Dose based on ideal body weight, maximum 2 m2; (2) Potential extravasation injury, gastrointestinal toxicity common; (3) Alopecia, smallleukemogenic risk.IM, intramuscular, IV, intravenous, p.o., oral.

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is repeated until hCG levels normalize and at least on cycleof chemotherapy is given as maintenance chemotherapy toprevent recurrence. Reliable contraception, preferably oralcontraceptives, should be used to prevent an intercurrentpregnancy during chemotherapy or monitoring afterremission is achieved.

Patients in whom the rate of fall of hCG levels hasplateaued or in whom values are rising during therapyshould be switched to an alternative single-agent regimenafter radiographic restaging. If there is appearance of new metastases or failure of the alternative single-agentchemotherapy, the patient should be treated with multi-agent regimens. Hysterectomy should be considered forthe treatment of non-metastatic disease that is refractoryto chemotherapy and remains conned to the uterus.

The overall cure rate for patients with non-metastaticGTN approaches 100%, and the majority of women whowish to preserve fertility can be cured without undergoing

hysterectomy. When chemotherapy is given for an addi-tional 12 cycles after the rst normal hCG value, recur-rence rates are < 5%.

Low-risk metastatic GTN

Patients with metastatic GTN who lack any of the clinicalhigh risk factors or have a total FIGO risk score of 6 or lesshave low-risk disease. They can be treated successfully withinitial single-agent regimens similar to non-metastaticGTN (Table 79). Most often, this has consisted of 5-daytreatment using intramuscular methotrexate or intravenousdactinomycin recycled at 14-day intervals. DuBeshter andassociates used single-agent methotrexate or dactinomycinto treat 48 patients with low-risk metastatic GTN at theNew England Trophoblastic Disease Center. All patientsachieved sustained remission but 51% required a seconddrug, 14% needed combination chemotherapy and 12%required surgery to remove drug-resistant disease. Among52 patients with low-risk metastatic GTN treated initiallywith the 5-day methotrexate regimen at Duke UniversityMedical Center, 60% achieved primary remission within amedian 3 cycles of methotrexate chemotherapy. Patientswere treated with dactinomycin for documented metho-trexate resistance or toxicity with equal frequency. Allpatients achieved remission with only 4% requiring multi-agent regimens. Likewise, Roberts and Lurain reviewed 92patients treated for low-risk metastatic GTN at the BrewerTrophoblastic Disease Center. Among their 70 patientswho were initially treated with chemotherapy alone, 24.6%developed chemoresistant disease and 9.8% had therapychanged to an alternative single-agent regimen because oftoxicity. Overall, 78% achieved remission using the primary

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Table 710 MANAGEMENT OF LOW-RISK NON-METASTATIC OR LOW-RISK METASTATIC GTN

Initiate single-agent methotrexate or dactinomycin regimen(Table 79)

1. Consider hysterectomy if fertility not desired

Monitor hematologic, renal, and hepatic indices before eachcycle of chemotherapyMonitor serum hCG levels weekly during therapyChange to alternative single-agent if resistance or severetoxicity to rst agentIf resistance to alternative agent:

1. Repeat metastatic evaluation2. Consider hysterectomy if no extrauterine metastases3. Multiagent therapy (MAC or EMA/CO, see text)

Remission: three consecutive weekly hCG values in thenormal range12 cycles of maintenance/consolidation chemotherapy

MAC, methotrexate, adriamycin, and cyclophosphamide; EMA/CO,etoposide, methotrexate, actinomycin D, cyclophosphamide andvincristine

Figure 715 Hysterectomy specimen in a 39-year-old womanwith nonmetastatic GTN who underwent surgery during herrst course of methotrexate. She entered complete remission 4 weeks after initial therapy (Courtesy of John Soper, M.D.).

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regimen with or without hysterectomy; all eventuallyachieved remission and only one (1.1%) required multi-agent chemotherapy.

McNeish and associates, reporting from the CharingCross system, reviewed the results of 485 patients withlow-risk GTN (prognostic index score