journal homepage:

Transcription

1 台灣癌症醫誌 (J. Cancer Res. Pract.) 28(2),86-93, 2012 Case Report journal homepage: nal Malignant Melanoma Cheng-Ta Lai, Chien-Kuo Liu*, Tzu-Chi Hsu, His-Hsien Hsu, Ming-Jen Chen, Wei-Hung Leung, Ching-Kuo Yang, Yu-Ting Hung Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan bstract. nal malignant melanoma is notorious for its poor outcomes, accounting for approximately 1% of all anorectal malignancies. In the entire alimentary tract, the disease most frequently originates in the anal canal. Further, as a percentage of all melanomas, 0.4% to 1.6% arise in the anorectal region. Consequently, it is no surprise that, other than the skin and the retina, the anal canal is the most common site of melanoma. Here we presented a case with intact clinical manifestations and comprehensive treatment. ecause anal malignant melanoma cases are quite rare, few case series have been reported in the literature, which further compounds the difficulties inherent in treatment of this disease. dditionally, the decision to surgically intervene in cases of malignant melanoma remains controversial, in part because complete remission is hard to achieve with any surgical method. Thus, radiotherapy, chemotherapy, immunotherapy and target therapy should first be considered in the treatment of anorectal melanoma to help improve overall survival rate. 病例報告 Keywords : malignant melanoma, anorectal melanoma 肛門惡性黑色素瘤 賴正大劉建國 * 許自齊許希賢陳明仁梁偉雄楊靖國洪毓廷 馬偕紀念醫院大腸直腸外科 中文摘要肛門惡性黑色素瘤以少見 癒後不佳著稱, 約佔肛門直腸惡性腫瘤的百分之一 黑色素癌在整個消化道中, 好發的位置以肛門最為常見 在全身的黑色素瘤中, 肛門直腸黑色素瘤所佔之比例約為百分之 0.4 至百分之 1.6 之間, 位居第三, 排名於皮膚及視網膜之後 過去有關的文獻記載稀少, 本病例呈現完整的病史及各種典型的臨床表徵 在治療方面, 因過去均以少數個案病例序列報告為主, 對於決定適當的治療方式實屬困難 外科手術介入的角色迄今沒有定論, 所有的手術方式都被認為無法完全根治 因此放射治療 化學治療 免疫治療 抑或是標靶治療都應考慮加入治療計畫之中, 以改善病患的存活率 關鍵字 : 惡性黑色素瘤 肛門直腸黑色素瘤

2 C. T. Lai et al./jcrp 28(2012) INTRODUCTION norectal melanoma is a rare and aggressive type of cancer with a generally unfavorable prognosis. When considering treatment options for the disease, however, surgical intervention is controversial [1]. Some authors have stated that wide local excision (WLE) is the first choice for primary anorectal melanoma if negative margins can be achieved [2,3]. We reported a rare case of anal melanoma stage IIa as T3aN0M0, where surgical intervention was attempted. Ultimately, distal metastasis developed a short time after surgery, even though negative surgical margin was achieved by comprehensive abdominoperineal resection (PR). CSE REPORT 54-year-old woman with a history of uterine myoma had undergone myomectomy at the age of 46. She was seen at our colorectal clinic complaining of anal pain lasting one week. We observed thrombotic hemorrhoid at the posterior aspect of the anus and performed partial hemorrhoidectomy, where pathology results revealed malignant melanoma of the anus (Figures 1, 2). Due to reservations stated by the patient, we performed radical resection 4 months later, when we identified tumor progression and invasion of the anterior aspect of the anus. Results from abdominal computed tomography (CT) and positron emission tomography (PET) indicated no distant metastasis prior to surgery. We performed abdominoperineal resection (PR), inguinal lymph node dissection, and bilateral salpingo-oophorectomy as a radical treatment, as well as paraaortic and pelvis lymph node sampling. Intraoperative frozen section analysis con- *Corresponding author: Chien-Kuo Liu M.D. * 通訊作者 : 劉建國醫師 Tel: ext.2161 Fax: crs.liuck@msa.hinet.net Figure 1. Hemorrhoidectomy; Hematoxylin and eosin stain () 20X () 200X. Malignant melanoma infiltrating in the desmoplastic stroma; melanin deposition can be observed () Spindle cell pattern with numerous mitoses () firmed the presence of anal melanoma without local or regional lymph node involvement (Figure 3). We achieved R0 resection, which was confirmed pathologically, and staged the melanoma as T3aN0M0. ccording to the National Comprehensive Cancer Network guidelines [4], there was no absolute indication for adjuvant chemotherapy, immunotherapy, and radiotherapy. The patient underwent an uneventful postoperative course. Following discharge, we followedup her condition on an outpatient basis.

3 88 C. T. Lai et al./jcrp 28(2012) Figure 2. Hemorrhoidectomy; Positive immunohistological stain with () CD-117 and () HM-45 Six months post-surgery, the patient noticed a reddish dome-shaped nodule on her scalp. dermatologist excised the scalp nodule, and subsequent pathology revealed metastatic melanoma (Figure 4). The patient was then referred to a medical oncologist, who identified diffuse metastasis. The patient s PET scan showed increased 2-deoxy-2-fluoro-D-glucose (FDG) uptake in the right laryngeal muscle, left anterior abdomen, left erector spinal muscle (L4 level), right inguinal region, and multifoci of the bones (lower sternum, right posterior second rib, bilateral anterior seventh ribs, C7, T2, T9, L2 to 4 vertebrae, bilateral sacroiliac joints, left pubis, and left femoral head). She received a chemotherapy CVD regimen (cisplatin 20 mg/m 2 per day 4, vinblastine 2 mg/m 2 per day 4, and dacarbazine 800 mg/m 2 1) and an immunotherapy regimen of interleukin-2 ( IU/m 2 per day) on alternating days for a total of 5 courses until confirmation of stable disease status. Fourteen months after the PR, the patient displayed left abducent nerve palsy with left ptosis and urinary incontinence accompanied by eye-nose-eye test dysmetria upon follow-up examination. rain and lumbar spine magnetic resonance imaging (MRI) revealed: (1) an enhancing lesion of approximately 2.3 cm 1.7 cm in the right portion of the S2, (2) multiple enhancing nodules scattered in the intradural space of the visible spine, with suspected metastasis, and (3) multiple metastases involving the bilateral cerebral and cerebellar hemispheres and brainstem (Figure 5). The patient rapidly experienced increasing intracranial pressure and expired because of central failure after chemotherapy and 2D palliative brain radiotherapy. DISCUSSION norectal melanoma is considered an uncommon malignancy. number of small series reports have described its low incidence and prevalence. norectal melanoma accounts for approximately 1% of all anorectal malignancies. The most common site for its de- velopment within the alimentary tract is the anal canal [5]. In 1857, Moore first described anal melanomas [6] as rare tumors arising from the melanoblastic cells in the anorectal mucosa. nal melanomas are the fifth most common melanoma [7] and more common in women than in men [6]. The mean age of disease onset is 60 years [8]. The anal canal is the third most common site of melanoma after the skin and retina, with 0.4% to 1.6% of all melanomas occurring in the anorectal region [9]. norectal melanoma typically has poor outcome and the overall survival duration is 10 to 19 months

4 C. T. Lai et al./jcrp 28(2012) Figure 3. PR; anus, Frozen section; Hematoxylin and eosin stain () 20X () 200X. Spindle cell pattern () and () with melanin deposition () post-diagnosis [1]. Rectal melanoma also customarily leads to unfavorable outcomes, with a 5-year survival rate between 10% and 20%. The extent of the disease correlates with overall survival [4]. review of 85 patients with anorectal melanoma treated at Memorial Sloan Kettering over a 64-year period identified an overall 5-year survival rate of 17% [1], and described poor response to radiotherapy and chemotherapy. Selection of the most appropriate surgical procedure is, thus, crucial in providing optimal treatment for these patients [1,10]. nal melanoma is a lethal disease, often initially misdiagnosed as a benign condition such as hemorrhoid or anal fistula [11]. Delayed diagnosis because of nonspecific symptoms might increase the likelihood of a poor outcome. The most common initial complaints are bleeding, rectal pain, tenesmus, and changes in bowel habits. lthough our case displayed the previously described symptoms, these symptoms are unspecific, which can make differential diagnosis from other benign or malignant anorectal lesions problematic [12]. Patients, thus, usually receive a diagnosis of anal melanoma through incidental findings and at a more advanced stage. large multi-institutional research report described that localized tumors account for less than 40% of anal melanomas [13]. Radiographic analysis is ineffective for the diagnosis of early stage anal melanoma because the tumors are most commonly observed only when bulky with infiltration and lymphadenopathy [14]. iopsy typically confirms the initial diagnosis, with histopathological analysis revealing spindle-shaped and pleomorphic cells. Immunohistological markers are the calcium-binding protein S-100, the melanoma antigen HM-45, the melanoma-expressed protein Melan, and microphthalmia-associated transcription factor (MTF) [15]. The use and extent of surgical interventions are not associated with improved overall survival in anorectal melanoma patients. dditionally, age at the time of diagnosis and the use of radiation therapy are also not significantly associated with increased survival

5 90 C. T. Lai et al./jcrp 28(2012) C D E Figure 4. Scalp, excision; Hematoxylin and eosin stain () 20X () 40X (C) 400X. The epidermis is ulcerated; there is an ill-defined cellular tumor in the dermis () Muscle invasion was noted () Spindle cell pattern with melanin deposition (C) Positive immunohistological stain with (D) S-100 (E) HM-45 rates [13]. Selection of the most appropriate surgical procedure for patients with anorectal melanoma is often controversial [9,12,16]. Radical resection should be the first option considered for patients with localized anorectal malignant melanoma, especially for those without evidence of nodal metastasis [10].

6 C. T. Lai et al./jcrp 28(2012) C D E Figure 5. Spine () () and rain (C) (D) (E) (F); n enhancing lesion about 2.3 x 1.7cm in size is found at the right portion of the S2 on T1 weighted image () Multiple enhancing nodules are scattered in the intradural space on MR myelogram () Multiple metastasis involving bilateral cerebral and cerebellar hemispheres, brainstem and the cervical spinal cord on T2FLIR image (C) (D) (E) (F) F

7 92 C. T. Lai et al./jcrp 28(2012) Studies have shown similar survival rates following wide local excision (WLE) or PR, irrespective of whether patients have localized or regional stages of the disease [9,17,18]. In a systematic review by Droesch et al. [2], which included 14 studies over 30 years, there was no demonstrable stage-specific survival advantage for the use of PR for anorectal melanoma. Local recurrence was higher in the WLE group compared with the PR group, although there were no differences in overall survival rates [2,3]. Radical lymph node dissection should be performed with great care due to its related comorbidity. The sentinel node biopsy technique could potentially have been of benefit to our patient because it can accurately identify lymph nodes that should be removed [11]. ecause patients undergoing WLE have a comparable survival rate to patients undergoing PR, investigators have proposed that WLE could be characterized as the appropriate initial treatment for anorectal melanoma [2]. They recommended PR only in cases in which WLE alone is unable to resect the melanoma, or as salvage treatment in rare cases of local recurrence [19]. In our case, we performed PR as the optimal procedure to achieve adequate oncological clearance. Laparoscopy is also useful in management of this disease and can reduce morbidity [20]. laparoscopic approach should thus be considered for future management of patients with anorectal melanoma. Other adjuvant therapeutic options include immunotherapy, brachytherapy (with caesium-137), and chemotherapy; however, further clinical trials are needed to fully elucidate their effectiveness [21]. djuvant radiation therapy is tolerable and useful for locoregional control [16]. One report has also described that melanomas with activating KIT mutations, and possibly with KIT gene amplifications, respond to therapy with tyrosine kinase inhibitors [22]. In our case, chemotherapy and immunotherapy were performed late after the development of systemic metastases. Early systemic chemotherapy, immunotherapy, and target therapy accompanied by locoregional adjuvant radiotherapy might be helpful to patients prior to widespread metastasis. Several studies on melanoma have identified primary tumor lymphangiogenesis and its predictive relevance to lymph node metastasis [23]. n antiangiogenic vaccination approach could potentially be used for a number of different tumor types. ngiogenesis is a critical mechanism in tumor progression and could, therefore, provide a target for anticancer treatment [24]. The research team of Maniotis et al. introduced the concept of vasculogenic mimicry (VM) in melanoma in 1999 [25]. They evaluated colon cancer and melanoma, the functional activity of VM, and implications for tumor shedding, identifying that tumors shed approximately cells/g of tumor per day [25]. recent study further identified that melanoma lymph node metastases with extensive neovascularization, VM, and leaky vessels directly contribute to hematogenous spread, and that melanoma cells contribute to the formation of tumor capillaries [26]. In our case, an incidental finding of anal melanoma with negative PET/CT scan results developed into quantifiable metastases throughout the body within 6 months. Tumor volume doubling times can be determined from Gompertzian growth curves [27]. Variations in our patient s Gompertzian growth curves might indicate reasons for the delayed discovery of her extensive metastases. REFERENCES 1. rady MS, Kavolius JP, Quan SH. norectal melanoma. 64 year experience at Memorial Sloan Kettering Cancer Center. Dis Colon Rectum 38: , Droesch JT, Flum DR, Mann GN. Wide local excision or abdominoperineal resection as the initial treatment for anorectal melanoma? m J Surg 189: , Pessaux P, Pocard M, Elias D, et al. Surgical management of primary anorectal melanoma. r J Surg 91: , 2004.

8 C. T. Lai et al./jcrp 28(2012) NCCN Guidelines Version Melanoma 5. Sayari S, Moussi, el Haj Salah R, et al. Primary anorectal melanoma: a case report. Tunis Med 88: , Moore WD. Recurrent melanosis of the rectum after removal from the verge of the anus in a man aged 65. Lancet 1: 290-4, Klas JV, Rothenberger D, Wong WD, et al. Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes. Cancer 85: , Zhong J, Zhou JN, Xu FP, et al. Diagnosis and treatment of anorectal malignant melanoma a report of 22 cases with literature review. Chinese Journal of Cancer 25: , elli F, Gallino GF, Lo Vullo S, et al. Melanoma of the anorectal region: the experience of the National Cancer Institute of Milano. The experience of the National Cancer Institute of Milano. EJSO 35: , Chiu YS, Unni KK, eart RW Jr. Malignant melanoma of the anorectum. Dis Colon Rectum 23: , Meguerditchian N, Meterissian SH, Dunn K. norectal melanoma: diagnosis and treatment. Dis Colon Rectum 54: , Roviello F, Cioppa T, Marrelli D, et al. Primary ano rectal melanoma: considerations on a clinical case and review of the literature. Chir Ital 55: , Podnos YD, Tsai NC, Smith D, et al. Factors affecting survival in patients with anal melanoma. m Surg 72: , Kim KW, Ha HK, Kim Y, et al. Primary malignant melanoma of the rectum: CT findings in eight patients. Radiology 232: 181-6, Heyn J, Placzek M, Ozimek, et al. Malignant melanoma of the anal region. Clin Exp Dermatol 32: , Homsi J, Garrett C. Melanoma of the anal canal: a case series. Dis Colon Rectum 50: 1004, Kiran RP, Rottoli M, Pokala N, et al. Long term outcomes after local excision and radical surgery for anal melanoma: data from a population database. Dis Colon Rectum 53: , Nilsson PJ, Ragnarsson-Olding K. Importance of clear resection margins in anorectal malignant melanoma. r J Surg 97: , Thibault C, Sagar P, Nivatvongs S, et al. norectal melanoma an incurable disease? Dis Colon Rectum 40: , Ramalingam G, Gan EY, Kutt-Sing W. Laparoscopic abdominoperineal resection for anorectal melanoma: a case report and review of the literature. Surg Laparosc Endosc Percutan Tech 19: e , Pirenne Y, ouckaert W, Vangertruyden G. Rectal melanoma - a rare tumor. cta Chir elg 108: , Satzger I, Küttler U, Völker, et al. nal mucosal melanoma with KIT-activating mutation and response to imatinib therapy--case report and review of the literature. Dermatology 220: 77-81, Stacker S, Farnsworth RH, Karnezis T, et al. Molecular pathways for lymphangiogenesis and their role in human disease. Novartis Found Symp 281: 38-43; discussion 44-53, , Seliger, Maeurer MJ, Ferrone S. TP off-tumors on. Immunol Today 18: , Maniotis J, Folberg R, Hess, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. m J Pathol 155: , Mihic-Probst D, Ikenberg K, Tinguely M, et al. Tumor cell plasticity and angiogenesis in human melanomas. PLoS One 7(3), Rofstad EK, rustad T. Radiation and heat sensitivity of cells from human melanoma xenografts. Lack of correlations with tumour growth parameters. Eur J Cancer Clin Oncol 19(3): , 1983.