Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia: A case report

Abstract

Rationale: Familial hydatidiform mole is extremely rare while familial gestational trophoblastic neoplasia (GTN) has never been reported. Inspired by 2 biological sisters with postmolar GTN and liver toxicity, we reviewed susceptible maternal-effect genes and explored the role of possible drug transporter genes in the development of GTN.

Patient concerns: We reported one Chinese family where the two sisters developed postmolar GTN while experiencing fast remission and significant hepatic toxicity from actinomycin D chemotherapy.

Diagnoses: The index pregnancy was diagnosed with curettage. The following GTN was confirmed when there was a rise in beta-hCG for three consecutive weekly measurements over at least a period of 2 weeks. Computed tomography was used to identify lung metastasis. The elder sister was diagnosed with gestational trophoblastic neoplasia (III: 2) while the younger sister was diagnosed as III: 3 according to WHO scoring system.

Interventions: Patients were treated with actinomycin D of 10 μg/kg intravenously for 5 days every 2 weeks. When hepatic toxicity was indicated, polyene phosphatidyl choline and magnesium isoglycyrrhizinate were prescribed.

Outcomes: Both patients responded extremely well to the 5-day actinomycin D regimen. Beta-hCG remained less than 2 mIU/ml after 5 cycles while computed tomography scan showed downsized pulmonary nodules. Both experienced significant rise in ALT and AST levels that could be ameliorated with corresponding medication. Monthly followed-up showed negative beta-hCG levels and normal liver enzyme levels.

Lessons: We speculated that the known or unknown NLRP7 and KHDC3L mutations might be correlated with drug disposition in liver while liver drug transporters such as P-glycoprotein family that are also expressed in trophoblasts might be correlated to GTN susceptibility. Future genomic profiles of large samples alike using next generation sequencing are needed to confirm our hypothesis and discover yet unknown genes.

Figure 1

Pathologic assessment of the uterus in the index pregnancy after dilation and curettage. (A) For the elder sister, hematoxylin-eosin showed endometrial polyps and proliferative phase endometrium. The absence of fetal parts detected by curettage and laparoscopy might indicate a miscarriage of a hydatidiform mole or other deformed pregnancies. (B) For the younger sister, microscopic examination demonstrated generalized trophoblastic proliferation with hydropic degenerated villi, suggesting complete hydatidiform mole.

Figure 2

Serum beta-hCG and ALT levels during chemotherapy. Both patients responded extremely well to the 5-day actinomycin D regimen (the timing of actinomycin D treatment was shown with black arrow). Beta-hCG dropped to less than 2 mIU/mL after 2 and 3 cycles, respectively (each dot on the red line refers to each hCG value tested during surveillance). Notably, both ALT levels would elevate significantly 3 to 7 days after each cycle's actinomycin injection (each dot on the blue line refers to each ALT value tested during surveillance). Neither organic lesion could be found in ultrasonography nor hepatitis virus infection could be suspected in the serum test. We successfully ameliorated the liver condition before each new cycle by using polyene phosphatidyl choline, magnesium isoglycyrrhizinate, and ademetionine 1,4-butanedisulfonate.

Figure 3

Radiographic and ultrasound images of the younger sister. (A and B) Before treatment, multiple nodules were displayed in both lungs according to the computed tomography and ultrasonography revealed a 2 cm high echo mass with irregular fluid area inside. (C and D) After 5 cycles of actinomycin D chemotherapy, computed tomography showed most of the primary pulmonary nodules were diminished and the remaining were significantly downsized, while ultrasonography detected no mass in uterine cavity.

Figure 4

Discovered drug transporters in liver.^[31] The coordinated expression and activity of uptake and efflux transporters mediates absorption of exogenous (drugs) and endogenous substrates from the bloodstream in the hepatocyte or proximal tubular cell, respectively. Drugs may undergo further biotransformation or be excreted into bile or urine for subsequent elimination from the body. Mutation of drug transporter genes that expressed in both liver and trophoblasts such as MDR1 might inhibit efflux of drug from liver thus cause liver toxicity and increase blood drug concentration.