March 2009.indd SQU MED J, APRIL 2009, VOL. 9, ISS. 1, PP. 79-83, EPUB 16TH MAR 2009 SUBMITTED - 9TH JUNE 08 REVISION REQ. 26TH AUG 08, REVISION RECD. 6TH SEPT 08 ACCEPTED - 14TH SEPT 08 Metastatic Malignant Melanoma during Pregnancy Case report and a Review of the literature *Mariam Mathew,1 Shahila Sheik,1 Kuntal Rao,1 Ikram A Burney,2 Sukhpal Sawhney,3 Aisha Al-Hamdani4 تقرير حالة - احلمل خالل منتشر خبيث �ورم ميالنيني ادبيات مراجعة مع احلمداني عائشة سوهني، سخبال برني، اكرام راو، كانتال شيك، شاهيال ماثيو، مرمي أشارت السابقة التقارير إلى املشيمة واجلنني. ينتقل أن احلمل ميكن أثناء يحصل وعندما ، كبير بشكل اخلبيث امليالنيني الورم انتشار يزداد امللخص: احلوامل عند يختلف ال اخلبيث امليالنني ورم أن وجدت احلديثة املضبطة ــات الدراس أن غير ، سيئا مآله ويكون ــريعا س يكون احلوامل عند ــاره انتش أن إلى املرض. مآل كفيالن بتحسني الفوري والعالج املبكر التشخيص املرض. مرحلة احلسبان في اخذ ما إذا غيرهم عن عمان. حالة، تقرير احلمل، انتشار، بيث، خَ ميالنينيٌّ الكلمات: وَرَمٌ مفتاح Departments of 1Obstetrics & Gynaecology, 2Medicine, 3Radiology & Molecular Imaging and 4Pathology, Sultan Qaboos University Hospital, Mus- cat, Sultanate of Oman *To whom correspondence should be addressed. Email: mathewz@omantel.net.om ABSTRACT Malignant melanoma is one of the most rapidly increasing cancers and, when it occurs during pregnancy, it can fre- quently metastasise to the placenta and the foetus. Earlier reports suggested a rapid progress of the disease during pregnancy with a poor prognosis; however, recent controlled studies found that stage for stage, the prognosis of melanoma during pregnancy is similar to that in a non-pregnant state. Early diagnosis and prompt treatment can avoid a tragic outcome. Key words: Malignant melanoma; Pregnancy; Metastasis; Case report; Oman. C A S E R E P O R T MELANOMAS ARE RELATIVELY COMMON in white-skinned women of childbear-ing age and many may have the diagno- sis made during pregnancy;1 in dark-skinned races the incidence is reported to be much less. The gen- eral incidence of melanoma has been increasing over the last few decades at a rate greater than any other malignancy;2 melanoma is now a major cause of can- cer death in women of childbearing age. The incidence in pregnancy has been estimated to range from 0.14 to 2.8 per 1,000 live births and melanoma accounts for about 8% of all malignant tumors arising during preg- nancy. 3 As there are now an increasing numbers of pregnancies in older women, it is expected that more melanomas will be seen. For several years, it was assumed that hormo- nal changes during pregnancy might cause a rapid progress of melanoma with poor maternal and fetal outcomes. However most of the recent studies found no difference in overall survival between pregnant and non-pregnant women with melanoma.4, 5 Additionally, melanoma is known to metastasise to the placenta and the foetus. Metastasis to the products of conception portends a poor prognosis for the mother.6 We report a case of metastatic malignant melano- ma diagnosed in the second trimester of pregnancy in a light skinned Asian-Arab lady. The consequences of a delay in diagnosis are discussed. C A S E R E P O R T A 28 year old light-skinned lady, gravida 2 and para 1, was referred at 27 weeks gestation to the Department of Obstetrics and Gynaecology, Sultan Qaboos Uni- versity Hospital for management of a locally advanced malignant melanoma. The history dated back to 12 weeks of gestation when the patient presented with left groin pain. She was found to have left inguinal lymphadenopathy and was treated with antibiotics M A R I A M M AT H E W, S H A H I L A S H E I K , K U N TA L R A O , I K R A M A B U R N E Y, S U K H PA L S AW H N E Y A N D A I S H A A L - H A M D A N I 80 and subsequently referred to surgeons with no relief. A needle core biopsy from the node at 16 weeks of ges- tation revealed a metastatic malignant tumor. Subse- quently, the slide review and immuno-histochemistry studies done at a tertiary centre showed positive stain- ing for S-100, melanin-A, vimentin and focal positivity for human melanoma black (HMB)-45 confirming the diagnosis of a metastatic malignant melanoma. The patient did not arrive at our institution until 11 weeks after the initial biopsy, where the examination revealed a left inguinal dark mass measuring 10 x 7cm size and extending from the left anterior superior iliac spine to the pubic symphysis. The mass was mostly solid and lobulated with some cystic component and was very tender [Figure 1]. A complete physical ex- amination revealed a raised nevus 8 x 7mm size with Figure 1: Pregnant uterus with mass in the left groin Figure 2: T2W coronal oblique magnetic reso- nance imaging scan of pelvis shows lobulated mass in left inguinal region with infiltration of skin and sub-cutaneous tissues. Dilated lymphatics seen extending up to vulva (arrows) Figure 3: Chest X-Ray PA view: Shows multiple, scattered, nodular, metastatic lesions in both lungs M E TA S TAT I C M A L I G N A N T M E L A N O M A D U R I N G P R E G N A N C Y 81 satellite lesions in the upper lateral part of left thigh. Both breasts had mobile non-tender firm masses: 3 x 3cm in the right breast and 2 x 1cm in the left breast. An ultrasound scan of the foetus revealed a well grown foetus of 27 weeks gestation with normal placenta and amniotic fluid volume. After a multidisciplinary eval- uation by the oncologist, the pain management team and the neonatologist, it was decided to deliver the foetus. A magnetic resonance imaging (MRI) of the left groin [Figure 2] was done to ascertain the extent of the tumour in the anterior abdominal wall and the labour was induced at 28 weeks of gestation, resulting in a male baby weighing 1,310gm with an Apgar score of 8 at 1 minute and 9 at 5 minutes. Gross as well as histological examination of placenta did not show any metastasis. A complete physical examination, includ- ing an examination of the optic fundi, did not reveal any sign of disease in the newborn. The patient re- ceived cabergoline for suppression of lactation. A metastatic workup soon after delivery revealed extensive involvement of the lungs [Figure 3], liver, spleen [Figure 4], and both breasts [Figure 5]. A nee- dle core biopsy from the breast lesion confirmed the presence of metastatic melanoma [Figure 6]. A mag- Figure 4: Contrast Enhanced CT Scan shows hypodense, metastatic lesions in right lobe of liver and spleen (arrows) Figure 5: Ultrasound scan of both breasts showing thick walled necrotic masses Figure 6: (A) needle core breast biopsy showing malignant cells with mitotic figures (single arrow) and nuclear inclusions (double arrow), hematoxylin and eosin stain X 60. (B) Immunohistochemistry studies showing strong S-100 positivity M A R I A M M AT H E W, S H A H I L A S H E I K , K U N TA L R A O , I K R A M A B U R N E Y, S U K H PA L S AW H N E Y A N D A I S H A A L - H A M D A N I 82 netic resonance imaging (MRI) scan of the brain did not show any metastasis. The patient was started on combination chemotherapy with cisplatin, vinblastine and dacarbazine with subjective improvement follow- ing the first cycle. The treatment was complicated and delayed by the refusal of the patient to continue with intravenous chemotherapy. A chest X-ray following 2 cycles of chemotherapy showed a stable disease state. However, once the intravenous chemotherapy was discontinued, the disease progressed and the patient died 4 months after the delivery. The baby was well for two weeks, then developed a bowel perforation due to necrotising enterocolitis and was transferred to another tertiary care centre with paediatric surgery facilities. Laparotomy revealed multiple bowel perforations; unfortunately, the baby died of septicaemia at 3 months of age. D I S C U S S I O N Malignant melanoma is the most aggressive form of skin cancer with an increasing incidence over the past decade. Although it used to be more common in men, it now affects equal numbers in both sexes. The mean age for diagnosis is 52 years, some 10 years earlier than the more common tumors such as breast, lung and prostate. About 30-35% of women with melanoma are at the childbearing age at the time of diagnosis. The most likely aetiology is reported as intermittent, blis- tering sun exposure among susceptible individuals.7 Common sites of metastasis of malignant melano- ma include the lymph nodes, lungs, liver, spleen and the brain. Breast metastasis has been reported in cases of cutaneous melanoma, mainly from the upper limb and trunk. Our patient had bilateral breast metastasis from a primary tumour in the left lower limb which is extremely rare.8 For several years, it was widely held that the prog- nosis of melanoma was worse during pregnancy and that subsequent pregnancies increased the risk of recurrence.9,10 Also, the use of estrogen containing hormonal preparations was thought to be associated with a worse prognosis. The myths have arisen as a re- sult of the misconception that because skin darkens in pregnancy, melanomas are hormonally sensitive;2 how- ever, recent studies have not found estrogen receptors in melanoma cells.1, 11 These myths about melanoma were strengthened by a report in 1951 from Pack and Scharnagel9 who reviewed 1,050 patients with malig- nant melanoma. Out of the ten pregnant women in this study, five died within 3 years of diagnosis due to progressive disease. The authors concluded that the women diagnosed with localised melanoma during pregnancy had a worse prognosis, but in this study, only ten pregnant women were included without any comparison group or staging of the disease. Multiple controlled series and investigations have found, how- ever, that stage for stage melanoma is not adversely affected by pregnancy. The prognosis, recurrence and incidence of melanoma seem to be unaffected by pregnancy.4, 5, 12 Melanoma is one of several tumors which metas- tasise to the placenta, including lymphomas, leukae- mias, breast and lung cancer.13 Although melanoma is the most common maternal malignant tumour to metastasise to the placenta, the occurrence is very rare. A review of literature showed 87 cases of placen- tal/foetal involvement with maternal malignancies. Of these 72 (83%) reported placental involvement only, 10 (11%) reported foetal metastasis without placen- tal examination, and 5 (6%) reported both placental and foetal metastasis.6 During the period from 1918 to 2002, melanoma was the cancer most commonly found to involve the placenta and foetus, accounting for 27 of 87 (31%) cases. Microscopic evaluation of the placenta was performed in 24 of 27 patients, and pla- cental involvement was documented in all 24 patients. Six of the 27 reports indicated foetal metastasis, but 3 reports did not document corresponding placental involvement. 6 Male infants seemed to be at a higher risk than fe- males for developing metastasis of any maternal can- cer. Males comprised 80% of all infants with metastasis of melanoma and 75% with metastasis of all cancers.6 Previously published reviews have calculated an ap- proximate 25% mortality risk to babies born to moth- ers with placental involvement. Infants developing clinical evidence of maternally derived metastasis have an exceptionally poor prognosis, with death typically occurring within 3 months of diagnosis. The neonates delivered with concomitant placental involvement, but without clinical evidence of the disease, should be considered a high risk population. They should be pe- riodically evaluated for development of melanoma for at least 24 months postpartum. Adjuvant treatment of infants born to women with placental metastasis of melanoma has not been reported.14 The management of melanoma during pregnancy requires several difficult decisions as the disease in- M E TA S TAT I C M A L I G N A N T M E L A N O M A D U R I N G P R E G N A N C Y 83 volves both the mother and the foetus. Decision mak- ing should be based on: 1) The impact of pregnancy on the outcome of the metastatic melanoma; 2) the ges- tational age and the risk of metastasis to the placenta and foetus; 3) the safety of radio diagnostic tests and chemotherapy during pregnancy, and 4) the treatment options for metastatic melanoma during pregnancy. Although surgery is the definitive therapy for early stage disease, rapidly progressive metastatic disease during pregnancy is difficult to treat. Chemothera- peutic regimens for metastatic disease administered during pregnancy have not demonstrated significant efficacy.15 The decision to deliver our patient at 28 weeks of gestation was to give the mother the best chance of survival. The neonatal survival in our institution at 28 weeks is more than 90%. The dilemma was the mode of delivery; induction of vaginal delivery versus cesar- ean section. At 28 weeks, the failure of labour induc- tion is very high, but cesarean section was also risky as the tumor was infiltrating into the incision site. Hence we decided to try induction of labour first; fortunately the patient responded. The delay in the diagnosis of our case may be be- cause of the low index of suspicion; considering that this was a young, Asian-Arab woman, where the risk of melanoma was perceived to be less. The rapid pro- gression of the disease as mentioned may have been due to the natural history of the disease, although it is impossible to know whether hormonal changes during pregnancy had an impact. Whereas most of the data regarding malignant melanoma comes from white-skinned races, its natural history and progres- sion during pregnancy in coloured races, although light-skinned as in our case, may be different. C O N C L U S I O N Malignant melanoma is not uncommon during preg- nancy, although this is the first case reported from our institution in the past eighteen years. As early diag- nosis may lead to cure, it is essential that all clinicians who care for pregnant women understand this disease. Obstetricians and midwives should do a full skin ex- amination of all parts of the body during evaluation of the pregnant women and any suspicious nevi should be biopsied. Treatment of early stage melanoma is the same irrespective of whether or not the patient is pregnant. 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