Primitive Neuroectodermal Tumor Presenting with Elevating Carcinoembryonic Antigen
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1 台灣癌症醫誌 (J. Cancer Res. Pract.) 1(2), , 2014 DOI: /JCRP Case Report small round-cell malignancies, ubiquitous in location and of presumed neuroectodermal origin, probably developing from migrating embryonic cells of the neural crest [2] and was called primitive neuroectodermal tumor (PNET) [3]. This type of tumor is usually diagnosed in children and young adults [4]. Rejournal homepage: Primitive Neuroectodermal Tumor Presenting with Elevating Carcinoembryonic Antigen Hsiao-Hsiang Cheng, Chuang-Chi Liaw* Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Medical Foundation, Lin-Kuo Branch, Taiwan Abstract. Primitive neuroectodermal tumor (PNET) is a rare disease and mostly diagnosed in children and young adults. This tumor is presumed to be of neuroectodermal origin, probably developing from migrating embryonic cells of the neural crest. Carcinoembryonic antigen is a glycoprotein and frequently elevated in patients with a variety of epithelial malignancies. We report hereby a 59-year old male patient with pelvic PNET, and the initial presentation was merelyelevating serum CEA of unknown origin. This case might help to support the theory that PNET may have a potential for epithelial or neuroendocrine differentiation. 病例報告 Keywords : PNET, CEA 原始神經外胚層腫瘤患者伴隨血清腫瘤胎源抗原升高 鄭小湘廖宗琦 * 林口長庚紀念醫院血液腫瘤科 中文摘要原始神經外胚層腫瘤 (PNET) 是一種罕見的疾病, 它主要發生於兒童和年輕成人 這個腫瘤的起源是假設來自於神經外胚層, 並猜測可能來自胚胎的神經脊細胞 腫瘤胎源抗原 (CEA) 是一種糖蛋白 ; 在某些上皮腫瘤的病患, 它的數值常常會升高 我們報告一名 59 歲男性患者, 診斷有骨盆腔的 PNET, 而他開始最初的臨床表現是未明原因的血清 CEA 升高 這個病例或許可支持 PNET 的細胞有上皮或神經內分泌分化的能力 關鍵字 : 原始神經外胚層腫瘤 腫瘤胎源抗原 INTRODUCTION In 1918, Stout described a tumor of the ulnar nerve with the gross features of a sarcoma, but composed of small round cells focally arranged as rosettes; and it was designated as neuroepithelioma first [1]. The concept of this entity evolved to include a group of Open access under CC BY-NC-ND license.
2 H. H. Cheng et al./jcrp 1(2014) cently, PNET and Ewing's sarcoma have been classified into the same tumor family on the basis of molecular genetic analysis because of their similar histologic and immunohistochemical characteristics, also sharing nonrandom chromosomal translocations [5,6]. Carcinoembryonic antigen (CEA) is an approximately 180 kda glycoprotein, originally identified by in 1965 by Gold and Freedman [7,8]. Serum levels of CEA are frequently elevated in patients with a variety of epithelial malignancies [9-11]. There has been only one report of peripheral PNET/ Ewing's sarcoma/with elevated serum levels of Figure 1. Computed tomography scan of pelvis show- CEA in the literature, and the case was a 7-year-old ing a 3 x 3 cm mass in right rectoischial patient [12]. To the best of our knowledge, this is the fossa first case of primary Ewing's sarcoma/peripheral PNET with elevated serum levels of CEA in an adult patient. CASE REPORT A 59-year-old man was referred to the out-patient department of medical oncology because of incidental finding of elevated CEA in a health examination. His initial CEA level was ng/ml (normal value: < 5 ng/ml for non-smokers and < 7 ng/ml for smokers). No headache, chest pain, abdominal pain, bone pain, cough, dyspnea, anorexia, general malaise, bowel habit change, body weight loss, or other symptoms Figure 2. Formalin-fixed excised round tumor showing lobulated, gray-white, and elastic contents were mentioned. The pateint had hypertension and diabetes mellitus with regular medical control. He denied smoking and alcohol use. He was 166 cm in height and 88 kg in weight and was fair looking. There was no abnormal finding in the physical examination. On account of abnormal elevating of CEA without obvious symptoms or signs, we rechecked his Figure 3. Haematoxylin and eosin section showing *Corresponding author: Chuang-Chi Liaw M.D. malignant tumor composed of moderately *通訊作者 廖宗琦醫師 uniform round and oval cells, and arranged Tel: ext.8825 in sheets and trabecules with cystic space Fax: and rossetts. The overall pattern favored a e102309@adm.cgmh.org.tw PNET. (Original magnification of 40x10)
3 154 H. H. Cheng et al./jcrp 1(2014) A B C D E F G Figure 4. Immunohistochemical staining showing diffuse positivity of tumor cells for CD99 (A) and CEA (B); focal positivity for vimentin (C) and NSE (D); and negativity for AE1/AE3 (E), EMA (F), and BCL-2 (G). (Original magnification of 40x10) serum CEA, which was elevated to 56.9 ng/ml in one month. The hemogram and biochemistry were also in the normal range. The chest X-ray, panendoscopy, colonscopy, and liver echo all showed negative findings. Then, chest, abdomen and pelvic computed tomography scans (CT scan) were arranged. There was no specific finding in the chest or abdomen, but a mass about 3x2 cm in dimension with a suspicious necrotic part was noted in the right rectoischial fossa (Figure 1). After discussion with the patient, an en bloc excision of the tumor was performed. A lobulated tumor, located at the apex of the ischiorectal space near the right pelvic sidewall was found. The size was 5x6x4 cm, and the tumor had a heterogenous content (cystic and solid component) with no invasion to the surrounding structures (Figure 2). Hemotoxyline and eosin staining (Figure 3) showed a malignant tumor composed of moderately uniform round and oval cells, arranged in sheets and
4 H. H. Cheng et al./jcrp 1(2014) and necrosis was seen. Immunohiscochemical study showed that the tumor was diffusely positive with CD99 (MIC2) (Figure 4A), focally with vimentin and NSE (Neuron Specific Enolase) (Figure 4C,D). It was negative for AE1/AE3, EMA (Epithelial Membranous Antigen), or BCL-2 (B-cell lymphoma 2) (Figure 4E-G). The overall pattern favored a PNET. As elevat ing serum CEA was noted, the tumor was also stained for CEA, which showed unusually diffuse positivity (Figure 4B). After the operation, the patient received adjuvant concurrent chemoradiotherapy. His serum CEA, originally ng/ml before operation, decreased to Figure 5. Computed tomography scan showing lung metastasis 73.4 ng/ml 2 weeks after the operation, and then dropped to 10.7 ng/ml 3 months after the operation when he finished his adjuvant therapy. But his serum CEA never returned to normal, and became gradually trabecules with cystic space and rossetts. Tumor elevated during follow up. The repeat CT scan showed nuclei were large with mitotic figures 7-10/10HPF, negative finding for tumor recurrence. Fourteen months B A C Figure 6. Computed tomography scan showing progressive more extensive lung metastasis (A), local recurrence (B), and left rib metastasis (C)
5 156 H. H. Cheng et al./jcrp 1(2014) after the operation, the patient s serum CEA elevated to ng/ml, and a chest CT scan showed multiple pulmonary metastasis (Figure 5). He hesitated for palliative chemotherapy. Five months later, the serum CEA level reached 1250 ng/ml and the CT scan demonstrated more extensive pulmonary metastasis, local recurrence, and left rib metastasis (Figure 6). Therefore, the patient started to receive palliative chemotherapy with epirubicin and ifosphamide. Unfortunately, he died of sepsis. The overall survival was approximately 24 months. DISCUSSION PNET is a rare and aggressive disease. There were only 17 diagnosed cases of PNET in Taiwan in 2008 [13]. It is defined as embryonal tumors composed of undifferentiated or poorly differentiated neuroepithelial cells which have the capacity for or display of divergent differentiation along neuronal astrocytic, ependymal, muscular or melanotic lines [14]. Morphologically, the appearance of PNET tumors is similar to that of other small round blue cell tumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma, mesenchymal chondrosarcoma, medulloblastoma, dedifferentiated synovial sarcoma, desmoplastic small round cell tumors, and rhabdomyosarcoma. As a group, these tumors often pose difficult diagnostic problems when examined by light microscopy alone. Nowadays, demonstration of MIC2 glycoprotein expression by immunocytochemical staining (CD99) aids in diagnosis of PNET [15,16]. In our case, the H.E staining showed typical findings of PNET, and the immunohistochemistry study also confirmed the diagnosis (positive for CD99). As the initial presentation of the case was elevating serum CEA, we also stained he tumor with CEA to see if the tumor was CEA-producting. The result was positive and the patient s serum CEA fluctuated as his disease course changed. The fluctuation of the serum CEA levels confirmed the patient s PNET was CEA-producting. Carcinoembryonic antigen (CEA) is a 180 kda GPI-linked cell-surface glycoprotein normally expressed in the fetal gut and on the luminal surface of the adult colon [8,17]. During colorectal carcinoma oncogenesis, CEA loses its polarity and becomes overexpressed throughout the tumor tissue. High levels of CEA expression have also been observed in epithelial tumors in the lung [18,19], breast [20], thyroid [21-23], and ovaries [24]. PNET is in the same family as Ewing s sarcoma. Ewing s sarcoma family of tumors (ESFT) have been found to have potential for epithelial differentiation. The immunohistochemial (IHC) study of Machado et al confirmed the epithelial marker expression of EMA and CEA in ESFT. Thus, epithelial marker expression does not necessarily rule out the diagnosis of ESFT. In the study of Machadol et al, 57 (20.8%) out of 415 specimens of ESFT had stained positive for CEA. However, no correlation was shown between epithelial marker expression and histological subtypes of ESFT [25]. Further or more advanced molecular genetic techniques are necessary to confirm the diagnosis of sarcoma. Our patient did not have the study of reverse transcription polymerase chain reaction (RT-PCR) to demonstrate the EWS-FLI1 fusion gene because the technique was unavailable in our hospital at that time. Our case also suggested that PNET might have potential for epithelial or neuroendocrine differentiation. However, more data are necessary to support this statement. REFERENCES 1. Stout AP. A tumor of the ulnar nerve. Proc NY Pathol Soc 18: 2-12, Dehner LP. Neuroepithelioma (primitive neuroectodermal tumor) and Ewing's sarcoma. At least a partial consensus. Arch Pathol Lab Med 118: 606-7, Hart MN, Earle KM. Primitive neuroectodermal tumors of the brain in children. Cancer 32: 890-7, Dehner LP. Peripheral and central primitive neu-
6 H. H. Cheng et al./jcrp 1(2014) roectodermal tumors. A nosologic concept seeking a consensus. Arch Pathol Lab Med 110: , Jurgens HF. Ewing's sarcoma and peripheral primitive neuroectodermal tumor. Curr Opin Oncol 6: 391-6, May WA, Denny CT. Biology of EWS/FLI and related fusion genes in Ewing's sarcoma and primitive neuroectodermal tumor. Curr Top Microbiol Immunol 220: , Gold P, Freedman SO. Demonstration of tumor-specific antigens in human colonic carcinoma by immunological tolerance and absorption techniques. J Exp Med 121: , Coligan JE, Lautenschleger JT, Egan ML, et al. Isolation and characterization of carcinoembryonic antigen. Immunochemistry 9: , Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9: 67-81, Hobbs JR. Laboratory monitoring and screening for cancer. Lancet 2: , Edgington TS, Astarita RW, Plow EF. Association of an isomeric species of carcinoembryonic antigen with neoplasia of the gastrointestinal tract. N Engl J Med 293: 103-7, Tamiya T, Ono Y, Daido S, et al. Primary Ewing's sarcoma/peripheral primitive neuroectodermal tumor at the vertex of the skull with elevated serum carcinoembryonic antigen: case report. J Neuro Oncol 52: , Bureau of Health Promotion DoH, ROC. Taiwan Cancer Registry (2008). In Edition de Alava E, Gerald WL. Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 18: , Ambros IM, Ambros PF, Strehl S, et al. MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 67: , Fellinger EJ, Garin-Chesa P, Triche TJ, et al. Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32mic2. Am J Pathol 139: , Krupey J, Wilson T, Freedman SO, et al. The preparation of purified carcinoembryonic antigen of the human digestive system from large quantities of tumor tissue. Immunochemistry 9: , Vincent RG, Chu TM. Carcinoembryonic antigen in patients with carcinoma of the lung. J Thorac Cardiovasc Surg 66: 320-8, Primack A. The production of markers by bronchogenic carcinoma: a review. Semin Oncol 1: , Steward AM, Nixon D, Zamcheck N, et al. Carcinoembryonic antigen in breast cancer patients: serum levels and disease progress. Cancer 33: , Isaacson P, Judd MA. Carcinoembryonic antigen in medullary carcinoma of thyroid. Lancet 2: , Ishikawa N, Hamada S. Association of medullary carcinoma of the thyroid with carcinoembryonic antigen. Br J Cancer 34: 111-5, Rochman H, degroot LJ, Rieger CH, et al. Carcinoembryonic antigen and humoral antibody response in patients with thyroid carcinoma. Cancer Res 35: , Khoo SK, Mackay EV. Carcinoembryonic antigen in cancer of the female reproductive system: sequential levels and effects of treatment. Aust N Z J Obstet Gynaecol 13: 1-17, Machado I, Navarro S. Epithelial marker expression does not rule out a diagnosis of Ewing's sarcoma family of tumours. Virchows Arch 459: , 2011.
Primitive Neuroectodermal Tumor Presenting with Elevating Carcinoembryonic Antigen
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