Failed Methotrexate-Treated Ectopic Pregnancies: Clinicopathologic Correlations

Abstract

Methotrexate (MTX) administration as an alternative to surgical therapy for unrupured ectopic pregnancies (EPs) has a 5-11% failure rate. The histologic findings in surgical specimens from patients for whom MTX therapy failed have not been exensively described. Review of pathology records from January 1991 through June 1996 revealed 12 MTX-treated tubal EPs that subsequently required surgical interention. Clinical data and histologic findings were compared with those from tubal EPs from maternalagend gestational-age-matched controls. Semiquantitative obervations of chorionic villous morphology were assessed by a senior pathologist unware of the treatment regimens. The average maternal age was 27 years and the mean gestational age was 9 weeks. Patients received one to two intramuscular injecions of MTX (50 mg/M²) and were followed up with serial serum betahuman chorinic gonadotropin (f-hCG) determinations. P-hCG levels fell from presentation to surgical intervention in 36.4% of MTX-treated patients, increased in 9.1%, and rose then fell in 54.5%. Peak r-hCG titers were significantly higher in MTX-exposed paients as compared with controls. There was no correlation between,3-hCG profile and villous morphology. Sixty-seven percent of MTX-treated EPs showed significant trophoblastic atypia as compared with 25% of control cases. Atypical villous trohoblasts had enlarged nuclei with irregular contours, smudged chromatin, and prominent nucleoli. There were no significant differences between failed MTX-exosed EPs and controls in terms of the presence or degree of villous necrosis, trohoblastic vacuolization, or embryonic development. Chorionic villous morphology in failed MTX-treated EPs showed no significant differences from that of nontreated EPs except for a trend toward increased trophoblastic atypia, features that may be confused with early gestational trophoblastic disease. Failed MTX-treated EPs may represent a subset of gestations that are resistant to MTX. As the uses of MTX are exanded to encompass the termination of early intrauterine pregnancies, the recogniion of possible treatmentrelated alterations in the histologic appearance of chorinic villi, trophoblasts, and implantation sites will be pertinent to avoid misdiagnosis.

Keywords

ectopic pregnancy methotrexate failed therapy β-hCG titers

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References

1. Ectopic pregnancy-United States, 1990-1992. Moridity and Mortality Weekly Report 44:46-48, 1995

2. Calabresi P , Chabner BA . Antineoplastic agents. In Gillman AG et al. (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics. Pergaon Press, Inc., New York, pp. 1223-1227, 1990

3. Goldner TE , Lawson HW , Xia Z , Atrash HK . Surveilance for ectopic pregnancy-United States, 1970-1989. MMWR CDC Surveillance Summaries 42(SS-6):73-85, 1993

4. Seifer BD , Gutmann JN , Doyle MB , Jones EE , Diaond MP , DeCherney AH . Persistent ectopic pregancy following laparoscopic linear salpingostomy. Obstet Gynecol 76:1121-1125, 1990

5. Ectopic Pregnancy. Washington, D.C. American Colege of Obstetricians and Gynecologists Tech Bull No.150, December 1990

6. Kenigsberg D , Porte J , Hull M , Spitz IM . Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 47:702-703, 1987

7. Creinin MD , Washington AE . Cost of ectopic pregancy management: Surgery versus methotrexate. Fertil Steril 60:963-969, 1993

8. Slaughter JL , Grimes DA . Methotrexate therapy nonurgical management of ectopic pregnancy. West J Med 162:225-228, 1995

9. Stovall TG . Medical management should be routinely used as primary therapy for ectopic pregnancy. Clin Obstet Gynecol 38:346-352, 1995

10.

10. Stovall TG , Ling FW . Single-dose methotrexate: An expanded clinical trial. Am J Obstet Gynecol 168:1759-1765, 1993

11.

11. Floridon C , Thomsen SG . Methotrexate treatment of ectopic pregnancy. Acta Obstet Gynecol Scand 73:746-752, 1994

12.

12. Corsan GH , Karacan M , Qasim S , Bohrer MK , Ranom MX , Kemmann E . Identification of hormonal parameters for successful systemic singledose methotrexate therapy in ectopic pregnancy. Huan Reprod 10:2719-2722, 1995

13.

13. Hausknecht RU . Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 333:537-540, 1995

14.

14. Kurman RJ . The morphology, biology and pathology of internediate trophoblast: A look back to the preent. Human Pathol 22:847-855, 1991

15.

15. Kooi S , Van Etten FHPM , Kock HCLV . Histopathology of five tubes after treatment with methotrexate for a tubal pregnancy. Fertil Steril 577:341-345, 1992

16.

16. Menard A , Crequat J , Mandelbrot L , Hauuy J , Madeenat P . Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvagial songraphic control. Fertil Steril 54:47-50, 1990

17.

17. Tulandi T , Bret PM , Mostafa A , Senterman M . Treatent of ectopic pregnancy by transvaginal inratubal methotrexate administration. Obstet Gyecol 77:627-630, 1991

18.

18. Floridon C , Nielsen O , Byrjalsen C , Holund B , Kernrup G , Thomsen SG , Andersen JA . Ectopic pregancy: Histopathology and assessment of cell proiferation with and without methotrexate treatment. Fertil Steril 65:730-738, 1996

19.

19. Frost JK . Pathologic processes affecting cells from inlammation to cancer. In Bibbo M (ed): Compreensive Cytopathology. W.B. Saunders, Philadelhia, pp. 75-76, 1991

20.

20. Montes M , Roberts D , Berkowitz RS , Genest DR . Prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions. Am J Clin Pathol 105:411-416, 1996

21.

21. DeMay RM . The Art and Science of Cytopathology. ASCP Press, Chicago, pp. 119-119, 221-222, 1996

22.

22. Doss BJ , DeMay RM , Larson RA , Williams S , Baunoch DA , Montag AG . Chemotherapy induced epithelial atypia in the female lower genital tract. Mod Pathol 8:89A-89A, 1995

23.

23. Sand PK , Stubblefield PA , Ory SJ . Methotrexate inhiition of normal trophoblasts in vitro. Am J Obstet Gynecol 155:324-329, 1986

24.

24. Sekiya S , Kaiho T , Shirotake S , Iwasawa H , Takeda B , Takamizawa H . Effect of methotrexate ofn the growth and human chorionic gonadotropin secreion of human choriocarcinoma cell lines in vitro. Am J Obstet Gynecol 146:57-64, 1983

25.

25. Friedman S , Skehan P . Morphologic differentiation of human choriocarcinoma cells induced by methotrexate. Cancer Res 39:1960-1967, 1979

26.

26. Silverberg SG , Kurman RJ . Classification and patholgy of gestational trophoblastic disease. In Tumors of the Uterine Corpus and Gestational Trophoblasic Disease. Armed Forces Institute of Pathology, Washington, DC, pp. 233-282, 1991

27.

27. Speeg KV , Azizkhan JC , Stromberg K . The stimulation by methotrexate of human chorionic gonadotropin and placental alkaline phosphatase in cultured choriocarcinoma cells. Cancer Res 36:4570-4576, 1976

28.

28. Koide Y , Takayoshi A , Hreshchyshyn M . Effects of hormones, methotrexate, and dactinomycin on beign trophoblast. Am J Obstet Gyncol 109:453-456, 1971

29.

29. Bagshawe KD . Recent observations related to the chemotherapy and immunology of gestational choriocarcinoma. Adv Cancer Res 18:231-262, 1973

30.

30. Bateman BG , Nunley WC , Kolp LA , Kitchin JD , Felder R . Vaginal sonography findings and hCG dyamics of early intrauterine and tubal pregnancies. Obstet Gynecol 75:421-427, 1990

31.

31. Pauerstein CJ , Croxatto HB , Carlton AE , Ramzy I , Walters MD . Anatomy and pathology of tubal pregancy. Obstet Gynecol 67:301-308, 1986

32.

32. Brown DL , Felker RE , Stovall TG , Emerson DS , Ling FW . Serial endovaginal sonography of ectopic pregancies treated with methotrexate. Obstet Gynecol 77:406-409, 1991

33.

33. Leach RE , Ory SJ . Modern management of ectopic pregnancy. J Reprod Med 34:324-338, 1989

34.

34. Schafer D , Pfuhl J-P , Baumann R , Neubert S , Bender H-G , Naujoks H . Trophoblast tissue culture of huan intrauterine and ectopic pregnancies and treatment with methotrexate. Hum Reprod 7:311-319, 1992