Novel Insights from Clinical Practice Received: February 7, 2017 Accepted after revision: February 20, 2017 Published online: May 11, 2017 Acta Cytologica 2017;61:237–241 DOI: 10.1159/000464271 Adenoid Cystic Carcinoma of the Larynx Presenting as a Thyroid Mass and Brief Literature Review Sadegh Shirian a, c Maryam Maghbool b Azita Aledavood c Shahrzad Negahban c Bijan Khademi d, e Yahya Daneshbod c a Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, b Department of Pathology, Fasa University of Medical Sciences, Fasa, and c Dr. Daneshbod Pathology Laboratory, Shiraz Molecular Pathology Research Center, and d Department of Otolaryngology and e Otolaryngology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Established Facts • Adenoid cystic carcinoma is the most common malignant tumor in the major and minor salivary glands. It can originate from minor salivary glands of the larynx and present as thyroid nodule by direct tumor invasion or as metastasis. • Adenoid cystic carcinoma of the larynx and trachea is very rare. Novel Insights • Cytopathological, immunohistochemical, radiographic, and ultrasonographic features of the larynx presenting as a thyroid mass is very rarely reported. Abstract Background: Adenoid cystic carcinoma (ACC) of the larynx and trachea is very rare. Case: A 45-year-old man with ACC of the larynx presenting as a thyroid mass is reported in this study. Physical examination revealed a large solid thyroid nodule in the left lobe without any lymphadenopathy. A technetium thyroid scan showed multinodular goiter with © 2017 S. Karger AG, Basel E-Mail firstname.lastname@example.org www.karger.com/acy cold nodules in the left lobe, isthmus, and functioning nodules in the right lobe. A large thyroid mass originating from the left side of the larynx, mostly the left vocal cord and the infraglottic part, was seen using enhanced magnetic resonance imaging after rupture of the thyroid cartilage on the left side. Ultrasound-guided fine needle aspiration smears and cell blocks of the thyroid nodule showed highly cellular smears composed of large tissue fragments, three-dimensional clusters, and sheets of neoplastic cells with slightly en- Correspondence to: Dr. Maryam Maghbool Department of Pathology, Fasa University of Medical Sciences Fasa 71345-1734 (Iran) E-Mail maghbol.maryam @ yahoo.com Dr. Yahya Daneshbod Dr. Daneshbod Pathology Laboratory Shiraz Molecular Pathology Research Center Shiraz (Iran) E-Mail daneshbk @ yahoo.com Downloaded by: Vanderbilt University Library 220.127.116.11 - 10/26/2017 4:30:21 PM Keywords Adenoid cystic carcinoma · Thyroid · Larynx · Fine needle aspiration · Cytopathology © 2017 S. Karger AG, Basel Introduction Thyroid nodules are common, and the accuracy of prevalence estimates is largely dependent on the method applied for their identification . The estimated prevalence of thyroid nodules ranges from 4 to 7% using palpation alone ; however, it increases to 20–76% in the adult population using ultrasound (US) examination . About 95% of nodules are benign, and only 5% of them are diagnosed as malignant . The most common thyroid tumors are papillary and follicular carcinomas. Metastatic tumors in the thyroid gland are uncommon but well established. About 1.4–3% of all thyroid malignancies become metastatic. The most common thyroid metastases are from renal cell carcinoma,  breast carcinoma, endocervical adenocarcinoma, and lung carcinoma. Adenoid cystic carcinoma (ACC) is the most common malignant tumor in the major and minor salivary glands. It can originate from minor salivary glands of the larynx and present as thyroid nodule by direct extension or in metastatic form . In our patient, a thyroid mass was suspected based on the initial clinical and US manifestations; therefore, US-guided fine needle aspiration (FNA), total laryngectomy, and thyroidectomy were performed. Pathological, immunohistochemical, radiographic, and US features of ACC in this context are presented. The literature on ACC is also reviewed. Case Report A 45-year-old man presented with mild hoarseness and a 3-month history of a left-sided neck mass. No history of dyspnea, fever, dysphagia, and neck pain or weight loss were identified. Physical examination revealed a large solid thyroid nodule in the left lobe without any lymphadenopathy. US illustrated enlargement of the left thyroid lobe with multiple nodularity. A technetium thyroid scan showed multinodular goiter with cold nodules in the left lobe, isthmus, and functioning nodules in the right lobe (Fig. 1a). A large thyroid mass originating from the left side of the larynx, mostly the left vocal cord and the infraglottic part, was seen after rupture of the thyroid cartilage on the left side using en- 238 Acta Cytologica 2017;61:237–241 DOI: 10.1159/000464271 hanced magnetic resonance imaging (Fig. 1b). The airways were narrow with a marked midline shift. The carotid sheath showed lateral deviation because of a pressure effect. Chest X-ray and direct laryngoscopy results were normal. The mass was in direct contact with the esophagus. US-FNA smears and cell blocks of the thyroid nodule showed highly cellular smears composed of large tissue fragments, three-dimensional clusters, and sheets of neoplastic cells with slightly enlarged round and hyperchromatic nuclei, scanty blue cytoplasm surrounded with variably sized pinkto-purple (Wright stain) mucoid-like matrix and many isolated naked neoplastic cells as well as red blood cells (Fig. 1c). A cell block specimen showed the cribriform pattern of ACC (Fig. 1d). Immunohistochemically, cell blocks were positive for C-kit and CK 7 on the cribriform growth pattern of the tumoral cells (Fig. 2a, b). However, protein expression of thyroglobulin and thyroid transcription factor (TTF-1) was not detectable (Fig. 2a). The patient underwent total laryngectomy and thyroidectomy, and laryngeal submucosal adenoid cystic carcinoma with thyroid invasion was confirmed (Fig. 2c). Histological evaluation showed ACC invading the thyroid gland (Fig. 2d). Discussion The primary aim of this study was to describe a patient with ACC of the larynx presenting as a thyroid mass. Although ACC is not an uncommon tumor in the salivary glands, its occurrence in the larynx and trachea is very rare . Evaluation of cytology specimens in thyroid nodules is based on three major criteria; cellularity/colloid ratio, smear pattern, and cytomorphological features . If the cytological findings do not determine the definite origin of the thyroid mass, the possibility of direct tumor invasion or metastasis must be considered. FNAs of ACC are usually cellular smears with a monomorphic population of basaloid cells in tight clusters with scant cytoplasm, high nuclear/cytoplasmic ratio, coarse chromatin, small nucleoli, and indistinct cell borders. Acellular hyaline stroma in globular or cylindromatous formation is present in cribriform and tubular subtypes and mimicking ropy colloid or amyloid materials; therefore, it can lead to the misdiagnosis of papillary or medullary carcinoma of the thyroid . Other differential diagnoses that should be considered are pleomorphic adenoma, basal cell adenoma, epithelial-myoepithelial and polymorphous low-grade carcinomas, and skin appendage tumors. In cytologic smears of thyroid nodules, ACC must be differentiated from thyroid neoplasms such as follicular, medullary, papillary, and anaplastic carcinomas [6, 7]. In difficult situations, immunocytochemistry can be applied on cytology specimens to distinguish primary thyroid neoplasms from secondary tumors. ThyroglobuShirian/Maghbool/Aledavood/Negahban/ Khademi/Daneshbod Downloaded by: Vanderbilt University Library 18.104.22.168 - 10/26/2017 4:30:21 PM larged round and hyperchromatic nuclei. Immunohistochemical study showed that the cell block expressed C-kit and CK 7 on the cribriform growth pattern of the tumoral cells. However, protein expression of thyroglobulin and thyroid transcription factor-1 was not detectable. Conclusion: To approach a thyroid nodule, direct invasion or metastatic tumors of other organs must be borne in mind. the cribriform growth pattern of the tumoral cells. a Negative immunoreactivity of tumoral cells for TTF-1 and positive in background thyroid cells (double arrowhead). Inset: positivity for C-kit and CK 7. c Gross pathological specimen of total laryngectomy and thyroidectomy. Arrowheads show site of laryngeal perforation. d Adenoid cystic carcinoma invading the thyroid gland. HE. ×200. d a b c d Color version available online c lin, calcitonin, and TTF-1 are markers which stain positive in primary thyroid neoplasms. Myoepithelial markers, such as muscle-specific actin and S-100, are positive in ACC . To date, 9 cases of laryngeal ACC with thyroid invasion have been reported (Table 1) [4, 5, 8–12]. Thyroid nodules are common findings, and about 97% of them are primary (benign or malignant). Only 1.4–3% of all thyroid malignancies are metastatic tumors. The most common metastatic tumors are renal cell carcinomas, breast carcinomas, endocervical adenocarcinomas, and lung carcinomas . Adjacent neoplasms directly invade the Adenoid Cystic Carcinoma of the Larynx Acta Cytologica 2017;61:237–241 DOI: 10.1159/000464271 239 Downloaded by: Vanderbilt University Library 22.214.171.124 - 10/26/2017 4:30:21 PM Fig. 2. Cell blocks show scattered positivity for CK 7 (a, arrow head) and C-kit (b) on b Color version available online Fig. 1. a Thyroid scan shows a cold nodule in the left thyroid lobe. b Enhanced MRI of the neck shows a large thyroid mass in the left side. c Fine needle aspiration cytology of the thyroid nodule shows a monomorphic population of basaloid cells in tight clusters with scant cytoplasm, high nuclear/cytoplasmic ratios, coarse chromatin, small nucleoli, and indistinct cell borders in cellular smears. Wright stain. ×200. d Cell block specimen showing a cribriform pattern of adenoid cystic carcinoma. HE. ×200. a Table 1. Review of the literature on laryngeal adenoid cystic carcinoma with thyroid invasion First author Year Sex Age, years Site Treatment Kashiwagi  2016 F 33 Immediately below the vocal cords Total laryngectomy with elective bilateral neck dissection Yang  2005 M NA Trachea Thyroidectomy, laryngotracheal resection, radiotherapy Natarajan  2004 M 76 Submucosal glands of the pyriform sinus and adjacent larynx No treatment due to arrest Idowu  2004 F 60 Larynx, left vocal cord, and trachea Total laryngectomy and thyroidectomy with radiotherapy Hogg  1999 F 72 Deep into the left cricopharyngeus muscle Total laryngectomy Na  1995 M 33 Trachea Total laryngectomy and total thyroidectomy F 35 Trachea Total thyroidectomy (1st) and tracheal resection (2nd) 45 Trachea Total laryngectomy and right thyroidectomy 38 Trachea Tracheal resection and partial thyroidectomy 66 Beneath the mucosa of the upper trachea Upper 5 tracheal ring excision and thyroidectomy 1984 F thyroid gland. The most common forms of direct thyroid invasion are epithelial malignant tracheolaryngeal neoplasms of squamous origin . Nonsquamous carcinomas are very rare (<1%), and ACC is the most prevalent form . ACCs are rare and account for <1% of malignant laryngeal tumors. They mostly arise from subepithelial minor salivary glands of the subglottic area and present as submucosal masses [4, 5]. They are slow-growing malignant tumors which spread by direct extension, perineural invasion, and hematogenous metastasis. Lymphatic invasion is rare in ACC cases. Direct spread of a thyroid malignancy to the trachea is a rare phenomenon; moreover, the reverse situation is extremely rare . In conclusion, to approach a thyroid nodule, direct tumor invasion or metastasis to other organs must also be considered. To obtain an accurate medical history, clinical and radiographic examinations are essential for the evaluation of thyroid nodules, but not useful for choosing the suitable treatment approaches, which largely depend on immunohistochemical, pathological, and US-FNA cytopathological findings. 240 Acta Cytologica 2017;61:237–241 DOI: 10.1159/000464271 Acknowledgments The authors would like to thank the Shiraz Molecular Pathology Research Center and Shahrekord University and Ms. H. Shojaeefard for her technical help. Statement of Ethics The institutional review board of the Dr. Daneshbod Laboratory approved the study. The author group obtained written informed consent from the patient. Disclosure Statement The authors have no conflicts of interest to declare. Shirian/Maghbool/Aledavood/Negahban/ Khademi/Daneshbod Downloaded by: Vanderbilt University Library 126.96.36.199 - 10/26/2017 4:30:21 PM Zirkin  References Adenoid Cystic Carcinoma of the Larynx 7 Nagao T, Sato E, Inoue R, Oshiro H, H Takahashi R, Nagai T, et al: Immunohistochemical analysis of salivary gland tumors: application for surgical pathology practice. Acta Histochem Cytochem 2012;45:269–282. 8 Kashiwagi T, Kanaya H, Konno W, Goto K: Hirabayashi H, Haruna S: Adenoid cystic carcinoma of the larynx presenting with unusual subglottic mass: case report. Auris Nasus Larynx 2016;43:562–565. 9 Yang PY, Liu MS, Chen CH, Lin CM, Tsao TC: Adenoid cystic carcinoma of the trachea: a report of seven cases and literature review. Chang Gung Med J 2005;28:357–363. 10 Natarajan S, Greaves TS, Raza AS, Cobb CJ: Fine-needle aspiration of an adenoid cystic carcinoma of the larynx mimicking a thyroid mass. Diagn Cytopathol 2004;30:115–118. 11 Hogg R, Kuo M, Olliff J, Das Gupta AR: Invasion of the recurrent laryngeal nerve by adenoid cystic carcinoma. An unusual cause of true vocal fold paralysis. J Laryngol Otol 1999; 113:260–262. 12 Na DG, Han MH, Kim KH, Chang KH, Yeon KM: Primary adenoid cystic carcinoma of the cervical trachea mimicking thyroid tumor: CT evaluation. J Comput Assist Tomogr 1995;19:559–563. 13 Curran AE, Allen CM, Beck FM, Damm DD, Murrah VA: Distinctive pattern of glial fibrillary acidic protein immunoreactivity useful in distinguishing fragmented pleomorphic adenoma, canalicular adenoma and polymorphous low grade adenocarcinoma of minor salivary glands. Head Neck Pathol 2007;1:27– 32. 14 Li W, Ellerbroek NA, Libshitz HI: Primary malignant tumors of the trachea: a radiologic and clinical study. Cancer 1990;66:894–899. 15 Azar T, Abdul-Karim FW, Tucker HM: Adenoid cystic carcinoma of the trachea. Laryngoscope 1998;108:1297–1300. Acta Cytologica 2017;61:237–241 DOI: 10.1159/000464271 241 Downloaded by: Vanderbilt University Library 188.8.131.52 - 10/26/2017 4:30:21 PM 1 Rosen Y, Rosenblatt P, Saltzman E: Intraoperative pathologic diagnosis of thyroid neoplasms. Report on experience with 504 specimens. Cancer 1990;66:2001–2006. 2 Popoveniuc G, Jonklaas J: Thyroid nodules. Med Clin North Am 2012;96:329–349. 3 Mazzaferri EL: Management of a solitary thyroid nodule. N Engl J Med 1993;328:553–559. 4 Zirkin HJ, Tovi F: Tracheal carcinoma presenting as a thyroid tumor. J Surg Oncol 1984; 26:268–271. 5 Idowu MO, Reiter ER, Powers CN: Adenoid cystic carcinoma, a pitfall in aspiration cytology of the thyroid. Am J Clin Pathol 2004;121: 551–556. 6 Guth S, Theune U, Aberle J, Galach A, Bamberger CM: Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39:699–706.