1-877-439-2744 Motherisk Helpline
1-800-436-8477 Morning Sickness
1-877-327-4636 Alcohol and Substance
1-866-937-7678 Exercise in Pregnancy
1-888-246-5840 HIV and HIV Treatment
416-813-6780 Motherisk Helpline
Pregnancy & Breastfeeding Resources
Current Studies at Motherisk
The Safety of Diclectin in Breastfeeding
Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
Diclegis Surveillance Program Study
Diclectin Surveillance Program Study
Study seeks women between 4 and 12 weeks in their pregnancy with morning sickness (NVP)
Pregnancy in Women with Multiple Sclerosis
Alcohol Use during Pregnancy
Lamisil in Pregnancy
Meridia in Pregnancy
Autoimmune Diseases in Pregnancy Project
Cancer in Pregnancy: Malignant Melanoma and Pregnancy
Malignant melanoma is a serious health problem worldwide and is increasing at a rate that exceeds all other solid tumors 1. The increasing incidence is accompanied by an associated decrease in age at presentation. Malignant melanoma during pregnancy has an estimated incidence between 0.14 to 2.8 cases per 1000 births2 and represents 8% of malignancies diagnosed during pregnancy 3. Aprroximately 10,000 melanomas occur in the United States each year in women ages 20 to 40, the peak years of reproduction4. Estrogen receptors have not been identified in melanoma 5,6.
The signs and symptoms of melanoma are similar to the nonpregnant population and the anatomic location of the primary tumor does not differ between pregnant and non-pregnant women. Changes in size, colour and configuration of any pigmented lesion suggest a malignant change and the need for further investigation. Two-thirds of melanomas occur in pre-exisiting nevi. However, some degree of hyper pigmentation during pregnancy is experienced by most women. 8 It has been suggested that this hyper-pigmentation may lead to a delay in diagnosis of the disease 9. A growing number of reports suggest minimal changes in size occur during pregnancy10,11.Bleeding and ulceration are more ominous signs and require immediate attention.
Excisional biopsy is the recommended procedure for any suspicious lesions.
Clinical staging traditionally has included assessment of the local tumor site and adjacent skin, regional lymph node areas and distant organs that are frequently the site of metastatic disease. The decision to perform radiological investigations in the pregnant patient should be based on the presence of symptoms, the stage of the pregnancy, the specific test needed and the estimated dose of ionizing radiation and risks associated with that dose. Intensive radiologic investigation(s) is not required for patients with early disease. Routine elective lymph node dissection is controversial and has not been shown to have a consistent impact on survival 6-10. The use of blue dye or a radio-labelled tracer injected at the primary tumor site to identify the draining or 'sentinal lymph node' has been shown to be accurate with little morbidity and high accuracy 11, 12 . During pregnancy, the radio-labeled technique should be avoided due to the risk of radiation exposure of the fetus.
Therapeutic Abortion and Contraception
There is no conclusive evidence that regression of melanoma occurs after therapeutic abortion19,20,21. Since the influence of pregnancy or hormones on melanoma has not been observed, the general consensus is that oral contraceptives are not contraindicated in patients with a prior history of melanoma 22, regardless of the duration of their use 23.
The effect of pregnancy on melanocytic nevi is unclear. Previous studies have suggested that patients may overestimate changes in melanocytic nevi24,25. A recent prospective study of 22 patients using photographs and objective measurements failed to demonstrate any significant change in size of nevi from the first to the third trimester10. Another area of controversy exists regarding the effect of pregnancy on site of presentation. Some studies have suggested an increased risk in pregnancy of lesions in areas associated with a worse prognosis such as the head and neck and truncal regions 9,26-28 while others have not found this association29,30. Similarly, there is debate as to whether or not pregnancy is associated with increased tumor thickness 7,9,19,20,29,31-33. Stage of the disease at diagnosis and not pregnancy is the only consistent factor influencing the prognosis in terms of survival and disease-free interval.
Surgical removal of the melanoma with adequate margins remains the standard primary therapy for early melanoma. For thin melanomas (<1mm thick) a 1 cm margin is considered adequate; for a Breslow intermediate thickness (1mm > x < 4mm) a 2cm margin is used. The standard surgical margin for thick melanoma remains undefined 34-39. But a margin of at least 2 cm appears to be justified. Elective lymph node dissection is not recommmended 40. Sentinel node biopsy appears to be a promising method to detect occult metastases in the regional lymph nodes 40. For most patients, this procedure can be done with a local anaesthetic with little risk to the fetus. Locally advanced disease requiring more extensive surgery or regional node dissection should be performed with a general anaesthetic when needed.
Node positive disease
The use of adjuvant interferon alpha - 2b in patients with melanoma is controversial and remains experimental40. Recent evidence demonstrating that adjuvant interferon increased overall survival for patients with node positive disease 1 was not confirmed in a follow-up study 18.
The existing literature on use of INF during pregnancy is restricted to case reports involving patients treated for various conditions such as hepatitis, myeloproliferative disorders (essential thrombocytemia and chronic myelogenous leukemia) and multiple myeloma. To date, there is no evidence of teratogenic or adverse effect on the fetus, regardless of timing of treatment during pregnancy. Doses used in the case reports have generally been in the range of 0.5 - 6.5 million units of interferon sc/day, significantly less than the recommended doses for the adjuvant treatment of melanoma41-54. Lack of fetoplacental passage of interferon alpha has been shown in one study of two patients prior to abortion 50. Treatment with interferon does not appear to affect fertility43,47,49.
No information regarding the safety of use of the much higher doses may be used in the treatment of melanoma exists (i.e. 20 million units/m2 intravenous for 4 weeks followed by 10 million units/m2 subcutaneous for 48 weeks). Toxicity of this therapy in the non-pregnant patient is significant. Nearly all patients experience flu like symptoms to a moderate or severe degree. Other significant sideeffects include depression, cognitive changes, bone marrow suppression and liver toxicity. Delay of therapy until the post partum period has been suggested55. The use of altered dosing of interferon in the adjuvant setting is under investigation 56.
Advanced or recurrent disease
Metastatic disease to lymph nodes, as well as isolated metastases to areas such as lung, breast, gastrointestinal tract and brain may be palliated by surgical removal with a potential for long term survival57,58. There is no contraindication to surgery during pregnancy provided that the physiologic changes of pregnancy are understood.
In the non-pregnant patient, chemotherapy and/or radiotherapy remain valid options for treatment of metastatic disease. Agents used in treatment include dacarbazine, the nitrosoureas - carmustine and lomustine, vinca alkaloids, platinum compounds, taxanes and biologic agents such as interferon and interleukin. Use of dacarbazine in pregnancy for malignant melanoma is limited to a case report in which a critically ill woman was treated in the third trimester. Spontaneous labour and a normal delivery occurred at 38 weeks gestation with no abnormalities reported in the offspring. The patient died 8 weeks postpartum after a dramatic response to therapy 59.
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus 60. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be around 10% for single agent chemotherapy61 and 25% for combination chemotherapy 62. It is generally suggested that chemotherapy be avoided during first trimester, when cells are actively dividing. Use of these agents in the second and third trimesters has been associated with an increased risk of stillbirth, intrauterine growth retardation and low birth weight60,63,64. When chemotherapy is administered during pregnancy, timing of delivery of the infant should take into account the expected bone marrow depression and potential problems such as bleeding or infections. Self limiting fetal haematopoetic depression has been described and the neonate should be monitored for complications of this65. Long term neurodevelopmental complications of in utero chemotherapy exposure have not been extensively studied. Limited data exists to suggest that this may be normal in the offspring of patients with haematologic malignancies treated during various stages of the pregnancy66.
The essentially palliative nature of therapy for advanced melanoma and the limited success rate(s) seen with existing therapies suggests that delay in therapy until the later stages of gestation or after delivery and aggressive use of supportive therapy during pregnancy (i.e. analgesics, steroids, oxygen) are reasonable options.
The effect of pregnancy on prognosis of melanoma has been a focus of interest in the medical literature for years. When matched for age, anatomic site and stage, most studies have not demonstrated a difference in survival9,20,27,29-31. However, some studies have demonstrated a shorter disease free interval in pregnant patients compared to controls26,30,31. It has been suggested that small patient numbers and variable follow-up time in these studies may have limited the ability to detect pregnancy related changes in outcome67,68. Also, there is no sufficient data to establish the role of adjuvant chemotherapy or biological therapy during pregnancy 69.
Metastases to the placenta and fetus are rare but have been documented with hematologic as well as solid tumors. Malignant melanoma is the tumor that most frequently metastasizes to the placenta or fetus. Therefore, the placenta should be thoroughly examined for metastasis. If present, the infant should be monitored for development of malignant disease 70. Of the 17 reported cases, only 4 have resulted in fetal death71-73.
Since the majority of recurrences occur in the first 3 years, some authors suggest delaying pregnancy for a few years after initial diagnosis and treatment3,9,74.
There is no evidence that a diagnosis of melanoma adversely affects fertility.
- Kirkwood J. M., Strawderman M. H., Ernstoff M. S. and et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol. 14: 7-17, 1996.
- Derek J. W. and Strassner H. T. Melanoma in pregnancy. Clin Obst Gynecol. 33: 782-791, 1990.
- Colbourn D. S., Nathanson L. and Belilos E. Pregnancy and malignant melanoma. Semin Oncol. 16: 377-387, 1989.
- Teplitzky S, Sabates B, Yu K, Beech DJ. Melanoma during pregnancy: A case-report and review of literature. Journal of the Louisiana States Medical Society.150(11):539-43, 1998.
- Flowers JL, Seigler HF, McCarty KSSR. Absence of estrogen receptor in human melanoma as evaluated by a monoclonal antiestrogen receptor antibody. Arch Dermatol 123:764-765, 1987.
- Miller JG, Gee J, Price A et al. Investigation of estrogen receptors, sex steroids and soluble adhesion molecules in the progression of malignant melanoma. Melanoma Res 7:197-208, 1997.
- Travers RL, Sober AJ, Berwick M. Increased thickness of pregnancy-associated melanoma. BR J Dermatol 132:876-883, 1995.
- Errickson C. V. and Matus N. R. Skin disorders of pregnancy. Am Fam Phys. 49: 605-610, 1994.
- MacKie RM, Bufalino R, Morabito A, Sutherland C and Cascinelli N. Lack of effect of pregnancy on outcome of melanoma. Lancet. 337: 653-655, 1991.
- Pennoyer JW, Grin CM, Driscoll MS et al. Changes in size of melanocytic nevi during pregnancy. J Am Acad Dermatol. 36:378-382,1997.
- Houghton AN, Flannery J, Viola MV. Malignant melanoma of the skin occurring during pregnancy. Cancer.48:407-410,1981.
- Perez CA, Grigsby PW, Nene SM and et al. Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer. 69: 2796, 1992.
- Veronesi U, JA, Bandiera DC and et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer. 49: 2420, 1982.
- Milton GW, Shaw HM, McCarthy WH and et al. Prophylactic lymph node dissection in clinical stage I cutaneous malignant melanoma: results of surgical treatment in 1319 patients. Br J Surg. 69: 108, 1982.
- Reintgen DS, Cox EB, McCarty KMJ and et al. Efficacy of elective lymph node dissection in patients with intermediate thickness primary melanoma. Ann Surg. 198: 379, 1983.
- Sablinska B, Tarlowska L and Stelmachow J Invasive carcinoma of the cervix associated with pregnancy: Correlation between patient age, advancement of cancer and gestation, and result of treatment. Gynecol Oncol. 5: 363, 1977.
- Lutz MH, Underwood JPB, Rozier JC and et al. Genital malignancy in pregnancy. Am J Obstet Gynecol. 129: 536, 1977.
- Kirkwood JM, Ibrahim J, Sondak V and et al. Role of high-dose INF in high risk melanoma: preliminary results of the E1690/S9111/C9190 US Intergroup postoperative adjuvant trial. NCI Cancer Trials Resource. 1998.
- Driscoll MS, Jorgensen GCM and Kels GJM Does pregnancy influence the prognosis of malignant melanoma? J Acad Dermatol. 29: 619-630, 1993.
- Kjems E and Krag C. Melanoma and pregnancy. A review. Acta Oncol. 32: 371-378, 1993.
- Ravid M, Lishner M, Zemlickis D and et al. Malignant melanoma and pregnancy. In: Koren G, Lishner M, Farine D (eds.), Cancer in pregnancy: Maternal andfetal risks. pp. 134-142. Cambridge: Cambridge University Press, 1996.
- Borden E. Melanoma and pregnancy. Seminars in Oncology. Vol27, No6, 2000.
- Smith MA, Fine JA, Barnhill RL, Berwick M. Hormonal and reproductive influences and risk of melanoma in women. Int Jour of Epidemiology 27(5):751-7, 1998.
- Foucar E, Bentley TJ, Laube DW and et al. A histopathologic evaluation of nevocellular nevi in pregnancy. Arch Dermatol. 121: 350-354, 1985.
- Sanchez JL, Figueroa LD and Rodriguez E Behaviour of melanocydtic nevi during pregnancy. Am J Dermatopathol. 6(suppl 1): 89-91, 1984.
- George PA and Fortner JG Melanoma with pregnancy: a report of 115 cases. Cancer. 13: 854-859, 1960.
- Shiu MH, Schottenfeld D, Maclean B and et al. Adverse effect of pregnancy on melanoma. Cancer. 37: 181-187, 1976.
- Wong DJ and Stassner HT Melanoma in pregnancy. Clin Obstet Gynecol. 33: 782-791, 1990.
- McManamny DS, Moss ALH, Pocock PV and et al. Melanoma and pregnancy: a long term follow-up. Br J Obstet Gynaecol. 96: 1419-1423, 1989.
- Slingnuff CLJ, Reintgen D, Vollmer RT and et al. Malignant melanoma arising during pregnancy: a study of 100 patients. Ann Surg. 211: 552-557, 1990.
- Reintgen DS., McCarty KSJ, Vollmer R and et al. Malignant melanoma and pregnancy. Cancer. 55: 1340-1344, 1985.
- Lederman JS and Sober AJ Effect of prior pregnancy on melanoma survival (letter). Arch Dermatol. 121: 716, 1985.
- Travers RL, Sober AJ, Berwick M and et al. Increased thickness of pregnancy-associated melanoma. Br J Derm. 132: 876-883, 1995.
- Veronesi U, Cascinelli N, Adamus J and et al. Primary cutaneous melanoma 2 mm less in thickness: results of a randomized study comparing wide with narrow surgical excision: a preliminary report. N Engl J Med. 318: 1159, 1988.
- Veronesi U and Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg. 126: 438, 1991.
- Cosimi AB, Sober AJ and Mihm MC Conservative surgical management of superficially invasive cutaneous melanoma. Cancer. 53: 1256, 1984.
- Balch CM, Murad TM, Soong S-J and et al. Tumor thickness as a guide to surgical management of clinical stage 1 melanoma patients. Cancer. 43: 883, 1979.
- Karakousis C, Balch C, Urist M and et al. Local recurrence in malignant melanoma: long term results of a surgical trial. (abstract) (abstract.). 48th Annual Cancer Symposium. Society of Surgical Oncology : 1995.
- Balch CH, Urist MM, Karakousis CP and et al. Efficacy of 2-cm surgical margins for intermediate thickness melanomas (1 to 4 mm). Results of a multiinstitutional randomized surgical trial. Ann Surg. 218: 262, 1993.
- Kroon BB, Bergman W, Coebergh JW, Ruiter DJ. Consensus on the management of malignant melanoma of the skin in the Netherlands. Dutch Melanoma Working Party. Melanoma Research. 9(3):207-12, 1999.
- Baer MR Normal full-term pregnancy in a patient with chronic myelogenous leukemia treated with alpha-interferon. Am J Haematol. 37: 66, 1991.
- Baer MR, Ozer H and Foon KA Interferon - alpha therapy during pregnancy in chronic myelogenous leukaemia and hairy cell leukemia. Br J Haematol. 81: 167-169, 1992.
- Petit JJ, Callis M and Fernandez De Sevilla A Normal pregnancy in a patient with essential thrombocythemia treated with interferon-alpha 2B. Am J Hematol. 40: 80, 1992.
- Combs CA Hepatitis C in obstetrics and gynecology. Obstet Gynecol., 79: 621-629, 1992.
- Delmer A, Rio B, Bauduer F and et al. Pregnancy during myelosuppressive treatment for chronic myelogenous leukaemia. Br J Haematol. 82: 783-784, 1992.
- Vianelli N, Gugliotta L, Tura S and et al. Interferon-alpha 2A treatment in a pregnant woman with essential thrombocythemia. Blood. 83: 874-875, 1994.
- Williams JM, Schlesinger PE and Gray AG. Successful treatment of essential thrombocythaemia and recurrent abortion with alpha interferon. Br J Haematol. 88: 647-648, 1994.
- Ferrari VD, Jirillo A, Lonardi F and et al. Pregnancy during alfa-interferon therapy in patients with advanced Hodgkin's Disease. Ann Oncol. 5 (Suppl. 8): 194, 1994.
- Grange JD, Abergel A, Amiot X and et al. Treatment of chronic hepatitis C with interferon alpha before pregnancy. Gastroenterology. 108 (Suppl): A1075, 1995.
- Pons JC, Lebon P, Frydman R and et al. Pharmacokinetics of interferon-alpha in pregnant women and fetoplacental passage. Fetal Diagn Ther. 10: 7-10, 1995.
- Sakata H, Karamitsos J, Kundaria B and et al. Case report of interferon alfa treatment for multiple myeloma during pregnancy. Am J Obstet Gynecol. 172: 217-219, 1995.
- Ruggiero G, Andreana A and Zampino R. Normal pregnancy under inadvertent alpha-interferon therapy for chronic hepatitis C. Hepatol. 24: 646, 1996.
- Delage R, Demers C, Cantin G and et al. Treatment of essential thrombocythemia during pregnancy with interferon-alpha. Obstet Gynecol. 87: 814-817, 1996.
- Lipton JH, Derzko CM and Curtis J Alpha-interferon and pregnancy in a patient with CML. Hematol Oncol. 14: 119-122, 1996.
- International Federation of Gynecology and Obstetrics Staging announcement: FIGO staging of gynecologic cancers: cervical and vulva. Int J Gynecol Cancer. 5: 319, 1995.
- Balch CM, Reintgen DS, Kirkwood JM and et al. Cutaneous Melanoma. In: DeVita VT, Hellman S, Rosenberg SA (eds.), Cancer: principles and practice of oncology. pp. 1947-1994. Philadelphia: Lippincott-Raven, 1997.
- Wornom I. L., Soong S. J., Urist M. M. and et al. Surgery as palliative treatment for distant metastases of melanoma. Ann Surg., 204: 181-185, 1986.
- Overett TK and Shiu MH Surgical treatment of distant metastatic melanoma: indications and results. Cancer. 56: 1222-1230, 1985.
- Harkin KP, Drumm JE, O'Brien P. et al. Metastatic malignant melanoma in pregnancy. Irish Med J. 83:116-117,1990.
- Zemlickis D, Lishner M and Koren G Review of fetal effects of cancer chemotherapeutic agents. In: Koren G, Lishner M, Farine D (eds.), Cancer in pregnancy. 1 ed. pp. 168. Cambridge: Press Syndicate of the University of Cambridge, 1996.
- Nicholson H. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynecol Br Commonwealth., 75: 307, 1968.
- Doll D. C., Ringenberg S. and Yarbro D. W. Management of cancer during pregnancy. Arch Intern Med., 148: 2058, 1988.
- Zemlickis D., Lishner M., Degendorfer P. and et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol., 166: 781-787, 1992.
- Zemlickis D., Lishner M., Degendrofer P. and et al. Fetal outcome following in utero exposure to cancer chemotherapy: the Toronto study. Arch Inter Med., 15: 573, 1992.
- Blatt J., Milvihill J. J., Ziegler J. L. and et al. Pregnancy outcome following cancer chemotherapy. Am J Med., 39: 828, 1980.
- Aviles A., Diaz-Maqueo J. C., Talavera A. and et al. Growth and development of children of mothers treated with chemotherapy during pregnancy: current status of 43 children. Am J Hematol., 36: 243, 1991.
- Adami HO, Thorn M, Bergstrom R and et al. Melanoma in pregnancy. Lancet. 337: 1164-1165, 1991.
- Grin C. M., Driscoll M. S. and Grant-Kels J. M. Pregnancy and the prognosis of malignant melanoma. Semin Oncol., 23: 734-736, 1996.
- Squatrito RC, Harlow SP. Melanoma complicating pregnancy Obstet Gynecol Clin North Am. 25: 407-416, 1998.
- Baergen RN, Johnson D, Moore T, Benirschke K. Maternal melanoma metastatic to the placenta: A case report and review of the literature. Archives of Pathology & Laboratory Medicine.121(5):508-11,1997.
- Dildy III GA, Moise KJJ, Carpenter RJJ and Klima T. Maternal malignancy metastatic to the products of conception: a review. Obstet Gynecol Surv. 44: 535-540, 1989.
- Brossard J, Abish S, Bernstein ML and et al. Maternal malignancy involving the products of conception: a report of malignant melanoma and medulloblastoma. Am J Pediatr Hematol Oncol. 16: 380-383, 1994.
- Zarcone R, Cardone G, Bellini P and et al. Malignant melanoma of the vagina in pregnancy. Panminerva Med. 37: 166-167, 1995.
- Garbe C. Schwangerschaft, hormonpraparate und malignes melanom. Hautarzt. 44: 347-352, 1993.