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Polyserositis as an Unusual Sign of Methotrexate Toxicity
GYNECOLOGIC ONCOLOGY ARTICLE NO.
61, 446–447 (1996)
0172
CASE REPORT Polyserositis as an Unusual Sign of Methotrexate Toxicity ZVI KLEIN, M.D.,* MARCO ALTARAS, M.D.,† YORAM BEYTH, M.D.,*
AND
AMIRAM FISHMAN, M.D.†
*Department of Obstetrics and Gynecology and †Gynecological Oncology Unit, Sapir Medical Center, Kfar Saba, 44281 Israel; affiliated with Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel Received October 4, 1995
We present a 46-year-old patient who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy for persistent trophoblastic disease. Single-agent chemotherapy with alternate methotrexate 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was instituted on the first postoperative day. Various adverse symptomatology developed, culminating in a unique side effect, polyserositis. To the best of our knowledge, the wide spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX. q 1996 Academic Press, Inc.
Methotrexate (MTX), a folic acid anatagonist, has a unique role in chemotherapy for treating neoplastic and connective tissue disease [1]. Its efficacy has been proven in the treatment of gestational trophoblastic disease [2]. Methotrexate has a series of adverse effects, including elevated liver enzymes, stomatitis, gastroenteritis, dermatitis, myelosuppression, pleuritis, pneumonitis, anaphylaxis, and depression [3–9]. These toxic effects are generally minor, transient, and dose-dependent problems. We present a patient who demonstrated a wide spectrum of the above side effects as well as an unusual presentation of polyserositis very early during the first course of MTX administration. CASE REPORT
A 46-year-old woman, G4P3, presented with moderate uterine bleeding. Ten days prior to her admission, she had undergone dilatation and curettage at another institution for abnormal uterine bleeding. The histopathology of the biopsy specimen was incorrectly reported as ‘‘blighted ovum.’’ Her past medical history was unremarkable and the system review was negative. Her current physical examination was normal, except for a slightly enlarged uterus and moderate vaginal bleeding. CBC, SMA-20, and urinalysis were within normal limits, while serum b-hCG levels were 29,000 mIU/ ml. Chest roentgenogram was normal.
446
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
/ 6d0c$$4307
05-10-96 14:41:10
Due to the vaginal bleeding, a recurettage was performed yielding a small amount of necrotic material. Histopathology revealed invasive hydatidiform mole. Rising levels of serum b-hCG were reported over 1 week following the second curretage (30,000 to 51,000 mIU/ml) and the patient was diagnosed with persistent trophoblastic disease. Metastatic workup was then started, including computed tomography (CT) scan of the brain, chest, abdomen, and pelvis with no abnormal findings. The patient subsequently underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy which progressed uneventfully. Single-agent chemotherapy with alternate MTX 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was administered from the first postoperative day. On the second postoperative day, the patient began to complain of copious amounts of watery vaginal discharge. On pelvic examination, a clear serous discharge was noted from the vaginal cuff. Urinary tract evaluation including cystography, IVP and intravenous indigo–carmine dye injections were normal with no evidence for urine leakage or fistula. Laboratory analysis of the fluid showed transudate characteristics. The clear serous discharge continued for 5 days with a gradual decrease of its volume. On several ultrasound examinations, there was no evidence of intraabdominal or pelvic fluid collection. A chest roentgenogram, performed on the eighth day of chemotherapy due to febrile morbidity and dyspnea suspected as related to pneumonitis, showed mild bilateral pleural effusion. Echocardiography was performed due to a presumed diagnosis of polyserositis demonstrated pericardial effusion, although there was no cardiac symptomatology. During the first days of chemotherapy administration, the patient developed severe oral mucositis and grade 2 diarrhea. Acute dermatitis around the abdominal incision was noted on the third day which rapidly progressed to exfoliate dermatitis with large ulcerating lesions. Due to these unexpected side effects, renal function was tested and found to be within normal limits (GFR Å 98 ml/ min). Liver function, during the second postsurgical week,
goa
AP: Gyn Onc
447
CASE REPORT
indicated mild damage: serum glutamic oxaloacetic transaminose (SGOT) levels raised to 90 u/liter and serum glutamic pyruvic transaminase (SGPT) to over 100 u/liter. bhCG levels dropped to 20 mIU/ml on the 14th postoperative day. The patient subsequently became febrile with a neutrophil count of 700 on the 10th postoperative day. She was treated with broad spectrum antibiotics and growth-colony-stimulating factor (G-CSF). She was discharged afebrile in good condition on the 16th postoperative day. One week later, bhCG levels were negative. DISCUSSION
MTX, a potent folate analog, is a well-known chemotherapeutic drug for trophablastic diseases. It binds to and inhibits dihydrofolate reductase, an enzyme that is essential for the production of reduced cofactors necessary for the synthesis of DNA and RNA [3]. Toxicity is thought to be most related to duration of drug exposure, dose, and the competetive inhibition of folates [10]. Most adverse reactions to MTX are minor and do not necessitate discontinuation of therapy. These minor side effects include gastrointestinal discomfort, nausea, mucositis, headache, rash, central nervous system disorders, fatigue, and alopecia. Major toxicities occur much less often and are principally related to pulmonary disease, liver dysfunction, and bone marrow suppression [10, 11]. Our patient showed a unique side effect, polyserositis, which is not generally associated with MTX treatment. To the best of our knowledge, this case is the first to be described in the English literature that shows fulminant serositis which began with a copious amount of clear vaginal discharge, initially thought to be urine, and developing into pleural and pericardial effusion. This serositis was a dominant side effect in our patient, starting on the second day of the therapeutic course with MTX. Discontinuation of MTX therapy was considered due to dyspnea and fever. In addition to the known side effects of MTX, and the acute polyserositis, our patient displayed some rare adverse
/ 6d0c$$4307
05-10-96 14:41:10
goa
reactions, such as pneumonitis which occurs among 3–10% of the patients [9] and is probably a noncytotoxic reaction [12]. To the best of our knowledge, this spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX. REFERENCES 1. Floridon, C., and Thomsen, S. G. Methotrexate treatment of ectopic pregnancy: A review, Acta Obstet. Gynecol. Scand. 73, 746–752 (1994). 2. Bengtsson, G., Bryman, I., and Thorburn, J. Low dose oral methotrexate as second-line therapy for persistent trophoblast after conservative treatment of ectopic pregnancy, Obstet. Gynecol. 79(4), 589–591 (1991). 3. Goodman and Gilman’s: The pharmaceutical basis of therapeutics (A. G. Gilman, C. S. Goodman, T. W. Rall, and F. Murad, Eds.), Macmillan, New York, 7th ed., pp. 1263–1267 (1985). 4. Tanaka, T., Hagashi, H., and Kutsuzawa, T. Treatment of interstitial ectopic pregnancy with methotrexate: Report of a successful case, Fertil. Steril. 37, 851–852 (1982). 5. Stovall, T. G., Ling, F. W., Gray, L. A., and Carson, S. A. Methotrexate treatment of unruptured ectopic pregnancy: A report of 100 cases, Obstet. Gynecol. 71, 749–753 (1991). 6. Kooi, S., and Kock, H. Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: A report of 25 patients, Fertil. Steril. 54, 580–584 (1990). 7. Sauer, M. V., Gorrill, M. J., and Rodi, I. A. Nonsurgical management of unruptured ectopic pregnancy: An extended clinical trial, Fertil. Steril. 48, 752–755 (1987). 8. Ichinoe, K., Wake, N., Shinkai, N., and Shilna, Y. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies, Am. J. Obstet. Gynecol. 156, 484–487 (1987). 9. Carroll, G. J., Thomas, R., and Phatouros, C. C. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate, J. Rheum. 21, 51–54 (1994). 10. Goodman, T. A., and Polisson, R. P. Methotrexate: Adverse reactions and major toxicities, Diagn. Issues 20(2), 513–528 (1994). 11. Espinoza, L. R., Zakraoui, L., Espinoza, C. G., and Gutierrez, F. Psoriatic arthritis: Clinical response and side effects to methotrexate therapy, J. Rheum. 19(6), 872–877 (1992). 12. Schoenfeld, A., Mashiach, R., Vardy, M., and Ovadia, J. Methotrexate pneumonitis in nonsurgical treatment of ectopic pregnancy, Obstet. Gynecol. 80, 520–521 (1992).
AP: Gyn Onc
61, 446–447 (1996)
0172
CASE REPORT Polyserositis as an Unusual Sign of Methotrexate Toxicity ZVI KLEIN, M.D.,* MARCO ALTARAS, M.D.,† YORAM BEYTH, M.D.,*
AND
AMIRAM FISHMAN, M.D.†
*Department of Obstetrics and Gynecology and †Gynecological Oncology Unit, Sapir Medical Center, Kfar Saba, 44281 Israel; affiliated with Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel Received October 4, 1995
We present a 46-year-old patient who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy for persistent trophoblastic disease. Single-agent chemotherapy with alternate methotrexate 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was instituted on the first postoperative day. Various adverse symptomatology developed, culminating in a unique side effect, polyserositis. To the best of our knowledge, the wide spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX. q 1996 Academic Press, Inc.
Methotrexate (MTX), a folic acid anatagonist, has a unique role in chemotherapy for treating neoplastic and connective tissue disease [1]. Its efficacy has been proven in the treatment of gestational trophoblastic disease [2]. Methotrexate has a series of adverse effects, including elevated liver enzymes, stomatitis, gastroenteritis, dermatitis, myelosuppression, pleuritis, pneumonitis, anaphylaxis, and depression [3–9]. These toxic effects are generally minor, transient, and dose-dependent problems. We present a patient who demonstrated a wide spectrum of the above side effects as well as an unusual presentation of polyserositis very early during the first course of MTX administration. CASE REPORT
A 46-year-old woman, G4P3, presented with moderate uterine bleeding. Ten days prior to her admission, she had undergone dilatation and curettage at another institution for abnormal uterine bleeding. The histopathology of the biopsy specimen was incorrectly reported as ‘‘blighted ovum.’’ Her past medical history was unremarkable and the system review was negative. Her current physical examination was normal, except for a slightly enlarged uterus and moderate vaginal bleeding. CBC, SMA-20, and urinalysis were within normal limits, while serum b-hCG levels were 29,000 mIU/ ml. Chest roentgenogram was normal.
446
0090-8258/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
/ 6d0c$$4307
05-10-96 14:41:10
Due to the vaginal bleeding, a recurettage was performed yielding a small amount of necrotic material. Histopathology revealed invasive hydatidiform mole. Rising levels of serum b-hCG were reported over 1 week following the second curretage (30,000 to 51,000 mIU/ml) and the patient was diagnosed with persistent trophoblastic disease. Metastatic workup was then started, including computed tomography (CT) scan of the brain, chest, abdomen, and pelvis with no abnormal findings. The patient subsequently underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy which progressed uneventfully. Single-agent chemotherapy with alternate MTX 1 mg/kg/day and leucovorin 0.1 mg/kg for 8 days was administered from the first postoperative day. On the second postoperative day, the patient began to complain of copious amounts of watery vaginal discharge. On pelvic examination, a clear serous discharge was noted from the vaginal cuff. Urinary tract evaluation including cystography, IVP and intravenous indigo–carmine dye injections were normal with no evidence for urine leakage or fistula. Laboratory analysis of the fluid showed transudate characteristics. The clear serous discharge continued for 5 days with a gradual decrease of its volume. On several ultrasound examinations, there was no evidence of intraabdominal or pelvic fluid collection. A chest roentgenogram, performed on the eighth day of chemotherapy due to febrile morbidity and dyspnea suspected as related to pneumonitis, showed mild bilateral pleural effusion. Echocardiography was performed due to a presumed diagnosis of polyserositis demonstrated pericardial effusion, although there was no cardiac symptomatology. During the first days of chemotherapy administration, the patient developed severe oral mucositis and grade 2 diarrhea. Acute dermatitis around the abdominal incision was noted on the third day which rapidly progressed to exfoliate dermatitis with large ulcerating lesions. Due to these unexpected side effects, renal function was tested and found to be within normal limits (GFR Å 98 ml/ min). Liver function, during the second postsurgical week,
goa
AP: Gyn Onc
447
CASE REPORT
indicated mild damage: serum glutamic oxaloacetic transaminose (SGOT) levels raised to 90 u/liter and serum glutamic pyruvic transaminase (SGPT) to over 100 u/liter. bhCG levels dropped to 20 mIU/ml on the 14th postoperative day. The patient subsequently became febrile with a neutrophil count of 700 on the 10th postoperative day. She was treated with broad spectrum antibiotics and growth-colony-stimulating factor (G-CSF). She was discharged afebrile in good condition on the 16th postoperative day. One week later, bhCG levels were negative. DISCUSSION
MTX, a potent folate analog, is a well-known chemotherapeutic drug for trophablastic diseases. It binds to and inhibits dihydrofolate reductase, an enzyme that is essential for the production of reduced cofactors necessary for the synthesis of DNA and RNA [3]. Toxicity is thought to be most related to duration of drug exposure, dose, and the competetive inhibition of folates [10]. Most adverse reactions to MTX are minor and do not necessitate discontinuation of therapy. These minor side effects include gastrointestinal discomfort, nausea, mucositis, headache, rash, central nervous system disorders, fatigue, and alopecia. Major toxicities occur much less often and are principally related to pulmonary disease, liver dysfunction, and bone marrow suppression [10, 11]. Our patient showed a unique side effect, polyserositis, which is not generally associated with MTX treatment. To the best of our knowledge, this case is the first to be described in the English literature that shows fulminant serositis which began with a copious amount of clear vaginal discharge, initially thought to be urine, and developing into pleural and pericardial effusion. This serositis was a dominant side effect in our patient, starting on the second day of the therapeutic course with MTX. Discontinuation of MTX therapy was considered due to dyspnea and fever. In addition to the known side effects of MTX, and the acute polyserositis, our patient displayed some rare adverse
/ 6d0c$$4307
05-10-96 14:41:10
goa
reactions, such as pneumonitis which occurs among 3–10% of the patients [9] and is probably a noncytotoxic reaction [12]. To the best of our knowledge, this spectrum of side effects, the short time lapse after onset of chemotherapy, and their severity are uncommon in a patient receiving her first chemotherapeutic treatment with MTX. REFERENCES 1. Floridon, C., and Thomsen, S. G. Methotrexate treatment of ectopic pregnancy: A review, Acta Obstet. Gynecol. Scand. 73, 746–752 (1994). 2. Bengtsson, G., Bryman, I., and Thorburn, J. Low dose oral methotrexate as second-line therapy for persistent trophoblast after conservative treatment of ectopic pregnancy, Obstet. Gynecol. 79(4), 589–591 (1991). 3. Goodman and Gilman’s: The pharmaceutical basis of therapeutics (A. G. Gilman, C. S. Goodman, T. W. Rall, and F. Murad, Eds.), Macmillan, New York, 7th ed., pp. 1263–1267 (1985). 4. Tanaka, T., Hagashi, H., and Kutsuzawa, T. Treatment of interstitial ectopic pregnancy with methotrexate: Report of a successful case, Fertil. Steril. 37, 851–852 (1982). 5. Stovall, T. G., Ling, F. W., Gray, L. A., and Carson, S. A. Methotrexate treatment of unruptured ectopic pregnancy: A report of 100 cases, Obstet. Gynecol. 71, 749–753 (1991). 6. Kooi, S., and Kock, H. Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: A report of 25 patients, Fertil. Steril. 54, 580–584 (1990). 7. Sauer, M. V., Gorrill, M. J., and Rodi, I. A. Nonsurgical management of unruptured ectopic pregnancy: An extended clinical trial, Fertil. Steril. 48, 752–755 (1987). 8. Ichinoe, K., Wake, N., Shinkai, N., and Shilna, Y. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies, Am. J. Obstet. Gynecol. 156, 484–487 (1987). 9. Carroll, G. J., Thomas, R., and Phatouros, C. C. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate, J. Rheum. 21, 51–54 (1994). 10. Goodman, T. A., and Polisson, R. P. Methotrexate: Adverse reactions and major toxicities, Diagn. Issues 20(2), 513–528 (1994). 11. Espinoza, L. R., Zakraoui, L., Espinoza, C. G., and Gutierrez, F. Psoriatic arthritis: Clinical response and side effects to methotrexate therapy, J. Rheum. 19(6), 872–877 (1992). 12. Schoenfeld, A., Mashiach, R., Vardy, M., and Ovadia, J. Methotrexate pneumonitis in nonsurgical treatment of ectopic pregnancy, Obstet. Gynecol. 80, 520–521 (1992).
AP: Gyn Onc