Cancer/Radiothérapie 19 (2015) 106–110
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Case report
Elevated carcinoembryonic antigen tumour marker caused by head and neck cancer: A case report and literature study Élévation de l’antigène carcinoembryonique dans un cancer des voies aérodigestives supérieures : à propos d’un cas clinique et revue de la littérature S.I. Vingerhoedt a,∗ , E. Hauben b , R. Hermans c , V.L. Vander Poorten d , S. Nuyts a a
Department of Radiation Oncology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium Department of Pathology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium c Department of Radiology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium d Department of Otorhinolaryngology, Head and Neck Surgery and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium b
a r t i c l e
i n f o
Article history: Received 24 June 2014 Received in revised form 16 September 2014 Accepted 25 September 2014 Keywords: Head and neck cancer Minor salivary gland tumours Mucoepidermoid carcinoma CEA
S u m m a r y Carcinoembryonic antigen is a tumour marker commonly increased in gastrointestinal and pulmonary cancers. We report a case of a 46-year-old man with a mucoepidermoid carcinoma of the base of tongue with an elevated and traceable serum carcinoembryonic antigen level. This antigen proved to be a valuable marker in the treatment follow-up. When a raised carcinoembryonic antigen level is found, salivary gland malignancies should be taken into the differential diagnosis and clinical examination of the head and neck region should not be overlooked. © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Cancer ORL Tumeur des glandes salivaires Cancer mucoépidermoïde Antigène carcinoembryonique
L’antigène carcinoembryonique est un marqueur tumoral qui est généralement augmenté dans les cancers gastro-intestinaux et pulmonaires. Nous rapportons un cas d’un homme de 46 ans atteint d’un cancer mucoépidermoïde de la base de la langue avec une concentration d’antigène carcinoembryonique élevée et trac¸able. L’antigène carcinoembryonique est un marqueur à surveiller dans le suivi post-thérapeutique. Lorsque la concentration sérique d’antigène carcinoembryonique augmente, une tumeur des glandes salivaires doit être évoquée dans le diagnostic différentiel, avec un examen clinique de la sphère des voies aérodigestives supérieures. © 2014 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction The carcinoembryonic antigen is a well-known and used tumour marker especially in colorectal cancer [1]. We present a case of elevated serum carcinoembryonic antigen level in a patient with a mucoepidermoid carcinoma. The assumed
association between the presence of mucoepidermoid carcinoma and a raised serum carcinoembryonic antigen level was studied. We further give a short summary of the epidemiology, histological grading and therapy of mucoepidermoid carcinomas.
2. Case report ∗ Corresponding author at: Department of Radiation Oncology, Herestraat 49, 3000 Leuven, Belgium. E-mail address: sofi[email protected] (S.I. Vingerhoedt).
A 46-year-old non-smoker without important medical history presented in the winter of 2011 with complaints of pyroris. His general practitioner performed a blood test, which showed an
http://dx.doi.org/10.1016/j.canrad.2014.09.008 1278-3218/© 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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Fig. 1. A, B. Axial and sagittal baseline CT showing a tumoural mass at the right base of tongue with extension into the right vallecula. C, D. Axial and sagittal CT at 4 months after the end of therapy showing no evidence for tumoural disease. Complete therapy response. A, B. Scanographies axiale et sagittale de référence montrant une masse tumorale à la base droite de la langue avec extension dans la vallécule droite. C, D. Scanographies axiale et sagittale à 4 mois après la fin du traitement ne montrant plus aucun signe de maladie tumorale. Réponse complète à la thérapie.
increased serum carcinoembryonic antigen level up to 28.6 ng/mL. The patient was referred to the gastroenterology outpatient clinic at the University Hospitals Leuven. CT of the chest and abdomen showed no evidence of malignancy. Esophagogastroduodenoscopy and biopsy indicated a Barrett esophagitis without dysplasia. Colonoscopy was negative. Therapy with proton-pump inhibitors was started. At that time no abnormality was noted in the upper aerodigestive tract. During the summer of 2012, the patient experienced an uncomfortable feeling in his throat with complaints of odynophagia and changes in speech. Clinical examination was negative apart from indirect laryngoscopy revealing an abnormal mass at the base of tongue. A CT study of the neck confirmed a large tumoural process (26 × 37 × 36 mm) in the right base of the tongue with extension into the right vallecula (Fig. 1A and B). No suspect lymph nodes were seen. A transoral biopsy revealed a low-grade mucoepidermoid carcinoma. Further investigation for hematological metastases by CT of the chest and ultrasound of the abdomen proved negative, so the tumour was staged cT3N0M0. The serum concentration of carcinoembryonic antigen was elevated at that time to 41.5 ng/mL.
In general, the preferred treatment for a low-grade mucoepidermoid carcinoma of minor salivary gland origin is surgical removal, if indicated combined with postoperative radiotherapy [2]. At this site of origin however, a radical, non-mutilating, function preserving resection is very hard to perform. Given the large volume of the tumour at the base of the tongue (Fig. 1A and B) and the imminent danger of upper airway obstruction, a combination treatment approach consisting of maximal surgical debulking and postoperative radiation was chosen. For the debulking procedure, a robot-assisted transoral resection (da Vinci surgical systems Intuitive Surgical Inc, Sunnyvale, California) was attempted. Due to the nature of the obstruction, intubation was impossible and a tracheostomy had to be performed. Even then satisfactory exposure using the Larynx advanced retractor system (LARS, Fentex, Tuttlingen, Germany) was very difficult given the combination of a large tongue, a limited mouth opening and a normal dentition in this patient. In this way, using the robotic system, only a partial resection was feasible, and subsequently the remnant tumour was resected further using a distensible laryngoscope (Karl Storz, Tuttlingen, Germany) in combination with an Acublade® system (Lumenis, Santa Clara, CA, USA) mounted on an operating
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Fig. 2. Immunohistochemical staining of a low-grade mucoepidermoid carcinoma, using a monoclonal antibody against carcinoembryonic antigen (DAKO ready to use), showing positive cytoplasmatic staining of the tumoural cells. Representative image shown (×200). Coloration immuno-histochimique d’un cancer mucoépidermoïde de la base de la langue utilisant un anticorps monoclonal contre l’antigène carcinoembryonique (DAKO ready to use) révélant une coloration cytoplasmique positive des cellules tumorales. Une image représentative est montrée (×200).
microscope. Anatomopathological examination showed a lowgrade mucoepidermoid carcinoma resected in two pieces, one with a maximal diameter of 1.6 cm and one with a maximal diameter of 3.0 cm, but with positive lateral and deep section margins. There was no lymphovascular or perineural invasion. Immunostaining with a monoclonal antibody against carcinoembryonic antigen was positive in the mucous cells (Fig. 2). The postoperative carcinoembryonic antigen level fell to 7.3 ng/mL. As planned, postoperative radiation therapy was performed. A total dose of 66 Gy in 33 fractions of 2 Gy was given on the initial tumour region using intensity-modulated radiotherapy (IMRT). Clinical evaluation 2 months after the end of the therapy, showed complete clinical remission of the tumour with a normalized carcinoembryonic antigen level of 1.2 ng/mL. Radiographic control was performed 4 months post-therapy and revealed a complete therapy response (Fig. 1C–D). At last follow-up, 14 months after therapy, patient remained free of disease with a normal carcinoembryonic antigen level (Fig. 3). 3. Discussion Salivary gland malignancies have an overall incidence in the Western world of about 2.5 to 3.0 per 100,000 per year [3]. According to the EUROCARE - 4 studies published in 2007, 5741 new cases of salivary gland cancer were diagnosed in Europe between 1995 and 1999 with a mean five-years overall survival of 64.6% [4]. The most common type of salivary gland cancer is the mucoepidermoid carcinoma [3,5]. Lung and breast are known as other organs where mucoepidermoid carcinomas occur [6,7]. Roughly 10% to 15% of the salivary gland malignancies arise in the minor salivary glands. Minor salivary glands are composed of acini with a short ductal system and no capsule [8]. Between 450 and 1000 minor salivary glands are widely spread in the upper aerodigestive tract, middle ear, nose, paranasal sinuses, pharynx and larynx. The majority (90%) is located in the oral cavity and oropharynx [2]. Mucoepidermoid carcinoma is histologically classified into three grades: high-, intermediate- and low-grade tumours [9,10]. The tumours are composed of varying proportions of mucous, epidermoid, intermediate, columnar and clear cells. There is a
predilection for women and a broad age range with the highest prevalence in the fifth decade of life [11–14]. Intraoral minor salivary gland mucoepidermoid carcinomas are primarily treated by surgery [2,15–17]. Postoperative radiotherapy with a minimal total dose of 60 Gy can be associated to increase local control [16–21]. Patients with unresectable tumours can be offered a treatment with primary radiotherapy [16] with a total dose of > 66 Gy using 2 Gy per fraction [22,23] or using accelerated hyperfractionation (1.6 Gy per fraction) [24]. In this case, the carcinoembryonic antigen level proved to be a sensitive tumour marker. Carcinoembryonic antigen is a glycoprotein, which is involved in cell adhesion. It is an oncofetal antigen that is normally produced in gastrointestinal tissue only during fetal development. In adulthood, carcinoembryonic antigen can be abnormally elevated in the serum of cancer patients, especially in adenocarcinomas as those arising in the colon, lung, breast, etc. [25]. The use of carcinoembryonic antigen as a tumour marker is most commonly known in colorectal cancer. Because it lacks sensitivity, serum carcinoembryonic antigen is not a useful population-screening tool for colorectal cancer. However, in patients with established disease, the level of the serum carcinoembryonic antigen correlates with disease load, therapy response and prognosis [1]. In salivary gland cancers, the value of carcinoembryonic antigen as a tumour marker has rarely been reported. In an immunohistochemical study of 1986, Takahashi et al. suggested that the presence of carcinoembryonic antigen could be used as a marker to differentiate between benign and malign areas of carcinoma in pleomorphic adenoma of the salivary gland. In malignant salivary gland carcinomas, carcinoembryonic antigen was abnormally and excessively localized in the cytoplasm of the epithelial cells and in the luminal contents of neoplastic glands [26]. In another immunohistochemical study of 2013, Schneider et al. assessed the expression of 21 tumour antigens in 158 parotid gland tumour samples to differentiate between benign and malign salivary tumours. Positive immunostaining of carcinoembryonic antigen was seen in 67.6% of the malignant tumours and in 29% of the benign tumours [27]. Two following studies investigated the expression of carcinoembryonic antigen in mucoepidermoid carcinoma s. A first study of Lu et al. showed that carcinoembryonic antigen was negative in all normal salivary gland tissue and positive in 78.9% of the malignant tissue. The positive rates and staining intensity of carcinoembryonic antigen in carcinoma tissue gradually decreased with the decline of tumour differentiation [28]. The second study of da Cruz Perez et al. showed that 87.5% (14/16) of mucoepidermoid carcinomas had positive immunostaining for carcinoembryonic antigen [29]. These studies indicate that carcinoembryonic antigen can be an important marker of malignancy in salivary gland tumours, especially in mucoepidermoid carcinomas. In 1996, Angelov et al. showed that the average concentration of carcinoembryonic antigen in patients with mucoepidermoid carcinoma in serum (14.94 ng/mL) and in saliva (216.67 ng/mL) was significantly higher than in the healthy group and in the pleomorphic adenoma group (P < 0.001). A correlation was found between high serum concentrations and salivary secretions of carcinoembryonic antigen, and a high immunohistochemical intensity of carcinoembryonic antigen expression in the tumour tissue. An increased synthesis and secretion of carcinoembryonic antigen was determined by the prevalence of tubular structures, a high proliferative activity in pleomorphic adenoma and its malignant transformation [30,31]. He et al. had a similar experience in 2009, comparing the level of salivary and serum carcinoembryonic antigen in 80 patients with oral minor salivary gland malignant tumours, to the level in 40 patients with benign tumours and in 80 healthy controls. Mean salivary carcinoembryonic antigen level was significantly higher in the malignant tumours (47.57 ng/mL) than in the benign tumours (20.99 ng/mL) and the healthy group
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Fig. 3. Evolution of the level of carcinoembryonic antigen as a tumour marker in function of time and treatments. 12/12/2012: surgery; 16/01–01/03/2013: postoperative radiotherapy. Évolution de la concentration d’antigène carcinoembryonique en fonction du temps et de traitements.
(11.36 ng/mL) (P < 0.001). Serum carcinoembryonic antigen level was increased in only 8.75% (7/80) of the malignant tumour cases with an average level of 9.16 ng/mL. This study reveals a better correlation between the carcinoembryonic antigen level in saliva than in serum in patients with oral minor salivary gland tumours, indicating direct secretion of various proteins into the saliva. To detect tumour markers in saliva may be of important clinical significance [32]. Only two previous studies have reported the role of a raised serum carcinoembryonic antigen level in survival and recurrence of salivary gland tumours. Kuhel et al. reported a case of a patient with an adenoid cystic carcinoma of the trachea and elevated serum carcinoembryonic antigen level, which declined after surgical resection. The serum carcinoembryonic antigen level raised again when the patient developed abdominal metastases and then decreased after tumour debulking. Immunohistochemical study of the tumour was positive for carcinoembryonic antigen [33]. Another case report of Noriyuki et al. presented a case of a 38-yearold woman with a low-grade mucoepidermoid carcinoma of the right upper lung with an elevated serum carcinoembryonic antigen level (12.4 ng/mL). Positive immunostaining of carcinoembryonic antigen was seen in 45% of the tumour cells. Postoperatively, the carcinoembryonic antigen level normalized. At last follow-up, 17 months after therapy, patient had no evidence of recurrence with a normal serum carcinoembryonic antigen level [34].
4. Conclusions In this case report an elevated carcinoembryonic antigen level led to several technological exams, looking for a primary gastrointestinal tumour. During follow-up, a salivary gland tumour was diagnosed. After treatment of this tumour and during further follow-up, carcinoembryonic antigen level proved to be a useful tumour marker. Positive immunostaining of the salivary gland tumour followed by the normalization of the serum carcinoembryonic antigen level after treatment, pinpointed it as a reliable tumour marker reflecting tumourload. In line with these findings, several other studies and case reports in the literature also suggest this possible role for the measurement of serum and salivary carcinoembryonic antigen levels following the immunohistochemical confirmation of its expression in malignant salivary gland tumour tissue. Whereas a raised carcinoembryonic antigen level classically leads to the investigation of colorectal and lung cancer, salivary
gland malignancies should be taken into the differential diagnosis and clinical examination of the head and neck region should not be overlooked. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Goldstein MJ, Mitchell EP. Carcinoembryogenic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 2005;23:338–51. [2] Vander Poorten VL, Hunt J, Bradley PJ, Haigentz Jr M, Rinaldo A, Mendenhall WM, et al. Recent trends in the management of minor salivary gland carcinoma. Head Neck 2014;36:444–55. [3] Speight PM, Barrett AW. Salivary gland tumours. Oral Dis 2002;8:229–40. [4] Berrino F, De Angelis R, Sant M, Rosso S, Bielska-Lasota M, Coebergh JW, et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study. Lancet Oncol 2007;8:773–83. [5] McHugh JB, Visscher DW, Barnes EL. Update on selected salivary gland neoplasms. Arch Pathol Lab Med 2009;133:1763–74. [6] Leonardi HK, Jung-Legg Y, Legg MA, Neptune WB. Tracheobronchial mucoepidermoid carcinoma. Clinicopathological features and results of treatment. J Thorac Cardiovasc Surg 1978;76:431–8. [7] Horii R, Akiyama F, Ikenaga M, Iwase T, Sakamoto G. Mucoepidermoid carcinoma of the breast. Pathol Int 2006;56:549–53. [8] Vander Poorten VL, Balm AJ, Hilgers FJ, Tan IB, Keus RB, Hart AA. Stage as major long-term outcome predictor in minor salivary gland carcinoma. Cancer 2000;89:1195–204. [9] Luna MA. Salivary mucoepidermoid carcinoma: revisited. Adv Anat Pathol 2006;13:293–307. [10] Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, Fahmy A, et al. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 2001;25:835–45. [11] Nance MA, Seethala RR, Wang Y, Chiosea SI, Myers EN, Johnson JT, et al. Treatment and survival outcomes based on histologic grading in patients with head and neck mucoepidermoid carcinoma. Cancer 2008;113:2082–9. [12] McHugh CH, Roberts DB, El-Naggar AK, Hanna EY, Garden AS, Kies MS, et al. Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer 2012;118:3928–36. [13] Byrd SA, Spector ME, Carey TE, Bradford CR, McHugh JB. Predictors of recurrence and survival for head and neck mucoepidermoid carcinoma. Otolaryngol Head Neck Surg 2013;149:402–8. [14] Bai S, Clubwala R, Adler E, Sarta C, Schiff B, Smith RV, et al. Salivary mucoepidermoid carcinoma: a multi-institutional review of 76 patients. Head Neck Pathol 2013;7:105–12. [15] Bell RB, Dierks EJ, Homer L, Potter BE. Management and outcome of patients with malignant salivary gland tumours. J Oral Maxillofac Surg 2005;63:917–28. [16] Halimi P, Gardner M, Petit F. Tumours of the salivary glands. Cancer Radiother 2005;9:251–60. [17] Bouyon A, Hans S, Durdux C, Housset M. Postoperative treatment of malignant tumours of the parotid gland: radiotherapy, concomitant chemotherapy and radiation therapy. Cancer Radiother 2007;11:465–75.
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[18] Terhaard CH, Lubsen H, Van der Tweel I, Hilgers FJ, Eijkenboom WM, Marres HA, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck 2004;26:681–92. [19] Le QT, Birdwell S, Terris DJ, Gabalski EC, Varghese A, Fee Jr WE, et al. Postoperative irradiation of minor salivary gland malignancies of the head and neck. Radiother Oncol 1999;52:165–71. [20] Garden AS, Weber RS, Ang KK, Morrison WH, Matre J, Peters LJ. Postoperative radiation therapy for malignant tumours of the minor salivary glands. Outcome and patterns of failure. Cancer 1994;73:2563–9. [21] Hosokawa Y, Shirato H, Kagei K, Hashimoto S, Nishioka T, Tei K, et al. Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 1999;35:105–11. [22] Chen AM, Bucci MK, Quivey JM, Garcia J, Eisele DW, Fu KK. Long-term outcome of patients treated by radiation therapy alone for salivary gland carcinomas. Int J Radiat Oncol Biol Phys 2006;66:1044–50. [23] Terhaard CH, Lubsen H, Rasch CR, Levendag PC, Kaanders HH, Tjho-Heslinga RE, et al. The role of radiotherapy in the treatment of malignant salivary gland tumours. Int J Radiat Oncol Biol Phys 2005;61:103–11. [24] Wang CC, Goodman M. Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 1991;21:569–76. [25] Fletcher RH. Carcinoembryonic antigen. Ann Intern Med 1986;104:66–73. [26] Takahashi H, Tsuda N, Tezuka F, Okabe H. Immunohistochemical localization of carcinoembryonic antigen in carcinoma in pleomorphic adenoma of salivary gland: use in the diagnosis of benign and malignant lesions. Tohoku J Exp Med 1986;149:329–40.
[27] Schneider S, Kloimstein P, Pammer J, Brannath W, Brasl MC, Erovic BM. New diagnostic markers in salivary gland tumours. Eur Arch Otorhinolaryngol 2014;271:1999–2007. [28] Lu MH, Yu W, Du WH, Chen FT, Wang CH, Zhou ZG, et al. Immunohistochemical localization of CEA, EMA and keratin in salivary mucoepidermal carcinoma. Shanghai Kou Qiang Yi Xue 1993;2:149–51. [29] da Cruz Perez DE, Pires FR, Alves FA, Almeida OP, Kowalski LP. Salivary gland tumours in children and adolescents: a clinicopathologic and immunohistochemical study of fifty-three cases. Int J Pediatr Otorhinolaryngol 2004;68:895–902. [30] Angelov A, Klissarova A, Dikranian K. Radioimmunological and immunohistochemical study of carcinoembryonic antigen in pleomorphic adenoma and mucoepidermoid carcinoma of the salivary glands. Gen Diagn Pathol 1996;141:229–34. [31] Lopes MA, da Cruz Perez DE, de Abreu Alves F, de Almeida OP, Kowalski LP. Clinicopathologic and immunohistochemical study of intraoral mucoepidermoid carcinoma. Otolaryngol Head Neck Surg 2006;134:622–6. [32] He H, Chen G, Zhou L, Liu Y. A joint detection of CEA and CA-50 levels in saliva and serum of patients with tumours in oral region and salivary gland. J Cancer Res Clin Oncol 2009;135:1315–21. [33] Kuhel WI, Chow H, Godwin TA, Minick CR, Libby DM. Elevated carcinoembryonic antigen levels correlating with disease recurrence in a patient with adenoid cystic carcinoma. Head Neck 1995;17:431–6. [34] Noriyuki T, Okumichi T, Kimura A, Koga R, Takeshima Y. Mucoepidermoid carcinoma with high level serous carcinoembryogenic antigen; report of a case. Kyobu Geka 2005;58:592–5.
Disponible en ligne sur
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Case report
Elevated carcinoembryonic antigen tumour marker caused by head and neck cancer: A case report and literature study Élévation de l’antigène carcinoembryonique dans un cancer des voies aérodigestives supérieures : à propos d’un cas clinique et revue de la littérature S.I. Vingerhoedt a,∗ , E. Hauben b , R. Hermans c , V.L. Vander Poorten d , S. Nuyts a a
Department of Radiation Oncology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium Department of Pathology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium c Department of Radiology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium d Department of Otorhinolaryngology, Head and Neck Surgery and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium b
a r t i c l e
i n f o
Article history: Received 24 June 2014 Received in revised form 16 September 2014 Accepted 25 September 2014 Keywords: Head and neck cancer Minor salivary gland tumours Mucoepidermoid carcinoma CEA
S u m m a r y Carcinoembryonic antigen is a tumour marker commonly increased in gastrointestinal and pulmonary cancers. We report a case of a 46-year-old man with a mucoepidermoid carcinoma of the base of tongue with an elevated and traceable serum carcinoembryonic antigen level. This antigen proved to be a valuable marker in the treatment follow-up. When a raised carcinoembryonic antigen level is found, salivary gland malignancies should be taken into the differential diagnosis and clinical examination of the head and neck region should not be overlooked. © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Cancer ORL Tumeur des glandes salivaires Cancer mucoépidermoïde Antigène carcinoembryonique
L’antigène carcinoembryonique est un marqueur tumoral qui est généralement augmenté dans les cancers gastro-intestinaux et pulmonaires. Nous rapportons un cas d’un homme de 46 ans atteint d’un cancer mucoépidermoïde de la base de la langue avec une concentration d’antigène carcinoembryonique élevée et trac¸able. L’antigène carcinoembryonique est un marqueur à surveiller dans le suivi post-thérapeutique. Lorsque la concentration sérique d’antigène carcinoembryonique augmente, une tumeur des glandes salivaires doit être évoquée dans le diagnostic différentiel, avec un examen clinique de la sphère des voies aérodigestives supérieures. © 2014 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction The carcinoembryonic antigen is a well-known and used tumour marker especially in colorectal cancer [1]. We present a case of elevated serum carcinoembryonic antigen level in a patient with a mucoepidermoid carcinoma. The assumed
association between the presence of mucoepidermoid carcinoma and a raised serum carcinoembryonic antigen level was studied. We further give a short summary of the epidemiology, histological grading and therapy of mucoepidermoid carcinomas.
2. Case report ∗ Corresponding author at: Department of Radiation Oncology, Herestraat 49, 3000 Leuven, Belgium. E-mail address: sofi[email protected] (S.I. Vingerhoedt).
A 46-year-old non-smoker without important medical history presented in the winter of 2011 with complaints of pyroris. His general practitioner performed a blood test, which showed an
http://dx.doi.org/10.1016/j.canrad.2014.09.008 1278-3218/© 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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Fig. 1. A, B. Axial and sagittal baseline CT showing a tumoural mass at the right base of tongue with extension into the right vallecula. C, D. Axial and sagittal CT at 4 months after the end of therapy showing no evidence for tumoural disease. Complete therapy response. A, B. Scanographies axiale et sagittale de référence montrant une masse tumorale à la base droite de la langue avec extension dans la vallécule droite. C, D. Scanographies axiale et sagittale à 4 mois après la fin du traitement ne montrant plus aucun signe de maladie tumorale. Réponse complète à la thérapie.
increased serum carcinoembryonic antigen level up to 28.6 ng/mL. The patient was referred to the gastroenterology outpatient clinic at the University Hospitals Leuven. CT of the chest and abdomen showed no evidence of malignancy. Esophagogastroduodenoscopy and biopsy indicated a Barrett esophagitis without dysplasia. Colonoscopy was negative. Therapy with proton-pump inhibitors was started. At that time no abnormality was noted in the upper aerodigestive tract. During the summer of 2012, the patient experienced an uncomfortable feeling in his throat with complaints of odynophagia and changes in speech. Clinical examination was negative apart from indirect laryngoscopy revealing an abnormal mass at the base of tongue. A CT study of the neck confirmed a large tumoural process (26 × 37 × 36 mm) in the right base of the tongue with extension into the right vallecula (Fig. 1A and B). No suspect lymph nodes were seen. A transoral biopsy revealed a low-grade mucoepidermoid carcinoma. Further investigation for hematological metastases by CT of the chest and ultrasound of the abdomen proved negative, so the tumour was staged cT3N0M0. The serum concentration of carcinoembryonic antigen was elevated at that time to 41.5 ng/mL.
In general, the preferred treatment for a low-grade mucoepidermoid carcinoma of minor salivary gland origin is surgical removal, if indicated combined with postoperative radiotherapy [2]. At this site of origin however, a radical, non-mutilating, function preserving resection is very hard to perform. Given the large volume of the tumour at the base of the tongue (Fig. 1A and B) and the imminent danger of upper airway obstruction, a combination treatment approach consisting of maximal surgical debulking and postoperative radiation was chosen. For the debulking procedure, a robot-assisted transoral resection (da Vinci surgical systems Intuitive Surgical Inc, Sunnyvale, California) was attempted. Due to the nature of the obstruction, intubation was impossible and a tracheostomy had to be performed. Even then satisfactory exposure using the Larynx advanced retractor system (LARS, Fentex, Tuttlingen, Germany) was very difficult given the combination of a large tongue, a limited mouth opening and a normal dentition in this patient. In this way, using the robotic system, only a partial resection was feasible, and subsequently the remnant tumour was resected further using a distensible laryngoscope (Karl Storz, Tuttlingen, Germany) in combination with an Acublade® system (Lumenis, Santa Clara, CA, USA) mounted on an operating
108
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Fig. 2. Immunohistochemical staining of a low-grade mucoepidermoid carcinoma, using a monoclonal antibody against carcinoembryonic antigen (DAKO ready to use), showing positive cytoplasmatic staining of the tumoural cells. Representative image shown (×200). Coloration immuno-histochimique d’un cancer mucoépidermoïde de la base de la langue utilisant un anticorps monoclonal contre l’antigène carcinoembryonique (DAKO ready to use) révélant une coloration cytoplasmique positive des cellules tumorales. Une image représentative est montrée (×200).
microscope. Anatomopathological examination showed a lowgrade mucoepidermoid carcinoma resected in two pieces, one with a maximal diameter of 1.6 cm and one with a maximal diameter of 3.0 cm, but with positive lateral and deep section margins. There was no lymphovascular or perineural invasion. Immunostaining with a monoclonal antibody against carcinoembryonic antigen was positive in the mucous cells (Fig. 2). The postoperative carcinoembryonic antigen level fell to 7.3 ng/mL. As planned, postoperative radiation therapy was performed. A total dose of 66 Gy in 33 fractions of 2 Gy was given on the initial tumour region using intensity-modulated radiotherapy (IMRT). Clinical evaluation 2 months after the end of the therapy, showed complete clinical remission of the tumour with a normalized carcinoembryonic antigen level of 1.2 ng/mL. Radiographic control was performed 4 months post-therapy and revealed a complete therapy response (Fig. 1C–D). At last follow-up, 14 months after therapy, patient remained free of disease with a normal carcinoembryonic antigen level (Fig. 3). 3. Discussion Salivary gland malignancies have an overall incidence in the Western world of about 2.5 to 3.0 per 100,000 per year [3]. According to the EUROCARE - 4 studies published in 2007, 5741 new cases of salivary gland cancer were diagnosed in Europe between 1995 and 1999 with a mean five-years overall survival of 64.6% [4]. The most common type of salivary gland cancer is the mucoepidermoid carcinoma [3,5]. Lung and breast are known as other organs where mucoepidermoid carcinomas occur [6,7]. Roughly 10% to 15% of the salivary gland malignancies arise in the minor salivary glands. Minor salivary glands are composed of acini with a short ductal system and no capsule [8]. Between 450 and 1000 minor salivary glands are widely spread in the upper aerodigestive tract, middle ear, nose, paranasal sinuses, pharynx and larynx. The majority (90%) is located in the oral cavity and oropharynx [2]. Mucoepidermoid carcinoma is histologically classified into three grades: high-, intermediate- and low-grade tumours [9,10]. The tumours are composed of varying proportions of mucous, epidermoid, intermediate, columnar and clear cells. There is a
predilection for women and a broad age range with the highest prevalence in the fifth decade of life [11–14]. Intraoral minor salivary gland mucoepidermoid carcinomas are primarily treated by surgery [2,15–17]. Postoperative radiotherapy with a minimal total dose of 60 Gy can be associated to increase local control [16–21]. Patients with unresectable tumours can be offered a treatment with primary radiotherapy [16] with a total dose of > 66 Gy using 2 Gy per fraction [22,23] or using accelerated hyperfractionation (1.6 Gy per fraction) [24]. In this case, the carcinoembryonic antigen level proved to be a sensitive tumour marker. Carcinoembryonic antigen is a glycoprotein, which is involved in cell adhesion. It is an oncofetal antigen that is normally produced in gastrointestinal tissue only during fetal development. In adulthood, carcinoembryonic antigen can be abnormally elevated in the serum of cancer patients, especially in adenocarcinomas as those arising in the colon, lung, breast, etc. [25]. The use of carcinoembryonic antigen as a tumour marker is most commonly known in colorectal cancer. Because it lacks sensitivity, serum carcinoembryonic antigen is not a useful population-screening tool for colorectal cancer. However, in patients with established disease, the level of the serum carcinoembryonic antigen correlates with disease load, therapy response and prognosis [1]. In salivary gland cancers, the value of carcinoembryonic antigen as a tumour marker has rarely been reported. In an immunohistochemical study of 1986, Takahashi et al. suggested that the presence of carcinoembryonic antigen could be used as a marker to differentiate between benign and malign areas of carcinoma in pleomorphic adenoma of the salivary gland. In malignant salivary gland carcinomas, carcinoembryonic antigen was abnormally and excessively localized in the cytoplasm of the epithelial cells and in the luminal contents of neoplastic glands [26]. In another immunohistochemical study of 2013, Schneider et al. assessed the expression of 21 tumour antigens in 158 parotid gland tumour samples to differentiate between benign and malign salivary tumours. Positive immunostaining of carcinoembryonic antigen was seen in 67.6% of the malignant tumours and in 29% of the benign tumours [27]. Two following studies investigated the expression of carcinoembryonic antigen in mucoepidermoid carcinoma s. A first study of Lu et al. showed that carcinoembryonic antigen was negative in all normal salivary gland tissue and positive in 78.9% of the malignant tissue. The positive rates and staining intensity of carcinoembryonic antigen in carcinoma tissue gradually decreased with the decline of tumour differentiation [28]. The second study of da Cruz Perez et al. showed that 87.5% (14/16) of mucoepidermoid carcinomas had positive immunostaining for carcinoembryonic antigen [29]. These studies indicate that carcinoembryonic antigen can be an important marker of malignancy in salivary gland tumours, especially in mucoepidermoid carcinomas. In 1996, Angelov et al. showed that the average concentration of carcinoembryonic antigen in patients with mucoepidermoid carcinoma in serum (14.94 ng/mL) and in saliva (216.67 ng/mL) was significantly higher than in the healthy group and in the pleomorphic adenoma group (P < 0.001). A correlation was found between high serum concentrations and salivary secretions of carcinoembryonic antigen, and a high immunohistochemical intensity of carcinoembryonic antigen expression in the tumour tissue. An increased synthesis and secretion of carcinoembryonic antigen was determined by the prevalence of tubular structures, a high proliferative activity in pleomorphic adenoma and its malignant transformation [30,31]. He et al. had a similar experience in 2009, comparing the level of salivary and serum carcinoembryonic antigen in 80 patients with oral minor salivary gland malignant tumours, to the level in 40 patients with benign tumours and in 80 healthy controls. Mean salivary carcinoembryonic antigen level was significantly higher in the malignant tumours (47.57 ng/mL) than in the benign tumours (20.99 ng/mL) and the healthy group
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Fig. 3. Evolution of the level of carcinoembryonic antigen as a tumour marker in function of time and treatments. 12/12/2012: surgery; 16/01–01/03/2013: postoperative radiotherapy. Évolution de la concentration d’antigène carcinoembryonique en fonction du temps et de traitements.
(11.36 ng/mL) (P < 0.001). Serum carcinoembryonic antigen level was increased in only 8.75% (7/80) of the malignant tumour cases with an average level of 9.16 ng/mL. This study reveals a better correlation between the carcinoembryonic antigen level in saliva than in serum in patients with oral minor salivary gland tumours, indicating direct secretion of various proteins into the saliva. To detect tumour markers in saliva may be of important clinical significance [32]. Only two previous studies have reported the role of a raised serum carcinoembryonic antigen level in survival and recurrence of salivary gland tumours. Kuhel et al. reported a case of a patient with an adenoid cystic carcinoma of the trachea and elevated serum carcinoembryonic antigen level, which declined after surgical resection. The serum carcinoembryonic antigen level raised again when the patient developed abdominal metastases and then decreased after tumour debulking. Immunohistochemical study of the tumour was positive for carcinoembryonic antigen [33]. Another case report of Noriyuki et al. presented a case of a 38-yearold woman with a low-grade mucoepidermoid carcinoma of the right upper lung with an elevated serum carcinoembryonic antigen level (12.4 ng/mL). Positive immunostaining of carcinoembryonic antigen was seen in 45% of the tumour cells. Postoperatively, the carcinoembryonic antigen level normalized. At last follow-up, 17 months after therapy, patient had no evidence of recurrence with a normal serum carcinoembryonic antigen level [34].
4. Conclusions In this case report an elevated carcinoembryonic antigen level led to several technological exams, looking for a primary gastrointestinal tumour. During follow-up, a salivary gland tumour was diagnosed. After treatment of this tumour and during further follow-up, carcinoembryonic antigen level proved to be a useful tumour marker. Positive immunostaining of the salivary gland tumour followed by the normalization of the serum carcinoembryonic antigen level after treatment, pinpointed it as a reliable tumour marker reflecting tumourload. In line with these findings, several other studies and case reports in the literature also suggest this possible role for the measurement of serum and salivary carcinoembryonic antigen levels following the immunohistochemical confirmation of its expression in malignant salivary gland tumour tissue. Whereas a raised carcinoembryonic antigen level classically leads to the investigation of colorectal and lung cancer, salivary
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