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Thyroid transcription factor–1 expression in thyroid-like nasopharyngeal papillary adenocarcinoma: report of 2 cases
Annals of Diagnostic Pathology 9 (2005) 189 – 192
Thyroid transcription factor –1 expression in thyroid-like nasopharyngeal papillary adenocarcinoma: report of 2 cases Fernando Carrizo, MD1, Mario A. Luna, MDT Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Abstract
We present the cases of 2 pediatric patients with low-grade nasopharyngeal papillary adenocarcinoma with features suggestive of thyroid origin. Both cases showed strong nuclear immunoreactivity for thyroid transcription factor–1 protein and positive immunostaining for cytokeratins 7 and 19. After thyroid imaging studies, local excision was performed in both patients. The patients remain free of disease 2 and 15 years after treatment, with no evidence of lesions in the thyroid or elsewhere. D 2005 Elsevier Inc. All rights reserved.
Keywords:
Nasopharynx; Adenocarcinoma; TTF-1; Thyroid
1. Introduction Most tumors arising from the nasopharynx are either keratinizing or nonkeratinizing squamous cell carcinomas [1]. Much less common in this area are glandular neoplasms, including lesions originating from the surface epithelium and from seromucous salivary glands [2,3]. Another possible source of nasopharyngeal tumors is metastatic papillary carcinoma, especially from the thyroid gland. In distinguishing between such possible sources of nasopharyngeal tumors, thyroid transcription factor–1 protein (TTF-1) and thyroglobulin expression can be useful in the differential diagnosis [4]. We present the cases of 2 pediatric patients with lowgrade nasopharyngeal papillary adenocarcinoma (LGNPPA) showing TTF-1 nuclear expression and provide histologic and immunohistochemical findings regarding the neoplasms, along with clinical follow-up data. 2. Case reports 2.1. Case 1 A 9-year-old boy presented with complaints of right nasal fullness with a duration of 3 months and the T Corresponding author. E-mail address: [email protected] (M.A. Luna). 1 Present address: Departamento de Patologı´a, Hospital de Clı´nicas bJose´ de San Martı´n,Q Av Cordoba 2351, Buenos Aires, Argentina. 1092-9134/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.04.019
occasional identification of blood in his saliva. An endoscopic examination disclosed a submucosal mass measuring 2.0 cm in diameter in the right nasopharyngeal wall, along with focal mucosal erosion. No other physical abnormalities were found. Computed tomography and magnetic resonance imaging of the head and neck confirmed a right nasopharyngeal mass. An incisional biopsy was performed. Computed tomography and sonography of the thyroid showed no abnormalities. A transpalatal resection was performed. The patient recovered uneventfully, and there was no evidence of recurrence or other lesions after 2 years of follow-up. 2.2. Case 2 A 13-year-old boy presented with a unilateral nasal obstruction with a duration of 2 months. No additional relevant medical history was found. An endoscopic examination revealed a mass in the roof of the nasopharynx, at the junction of the nasal septum and the vault, measuring 1.5 cm in diameter. The cervical lymph nodes were not palpable, and the rest of the physical examination findings were not remarkable. Imaging studies of the head and neck confirmed the nasopharyngeal mass. With the patient under general anesthesia, an incisional biopsy was performed. Computed tomography and sonography of the thyroid showed no abnormalities. A transpalatal resection was
190
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
Fig. 1. Complex and tightly packed papillae with fibrovascular cores.
performed. There was no evidence of recurrence or other lesions after 15 years of follow-up. 3. Pathological findings 3.1. Gross findings The tumors were described as exophytic with a papillary appearance.
Fig. 3. Cells with overlapping nuclei and clear chromatin lining papillary fronds. Notice the psammoma body.
3.3. Special studies Immunoperoxidase studies in both cases showed strong nuclear immunoreactivity for TTF-1 (Fig. 5). The cells also expressed cytokeratin (CK) 7 and CK 19 (Fig. 6). Immunoperoxidase staining for thyroglobulin was negative, and there was no immunoreactivity for CK 5/6 or CK 20.
3.2. Histopathologic findings
4. Discussion
Histologic examination revealed papillary fronds with fibrovascular cores. The papillae were complex and tightly packed (Fig. 1). They were lined by cuboidal to columnar stratified cells with round to oval vesicular nuclei and eosinophilic cytoplasm (Fig. 2). In other areas, the nuclei overlapped one another and had vesicular to clear chromatin (Fig. 3). The cells exhibited only minor degrees of pleomorphism and hyperchromatism. No mitotic figures were found. Psammoma bodies were seen focally (Fig. 3). Continuity of tumor cells with the normal epithelial lining was identified in both cases (Fig. 4).
Glandular neoplasms of the nasopharynx can be divided into 2 groups: those that originate from the surface mucosal epithelium, such as LGNPPAs, and those that originate from seromucous glands. The histologic phenotypes of the latter type are similar to those of neoplasms in the major salivary glands or oral cavity (eg, adenoid cystic carcinoma or mucoepidermoid carcinoma) [2,3]. Wenig et al [2] described LGNPPAs and made a strong case for this type of tumor being considered a separate entity from other types of adenocarcinoma in the nasopharyngeal region. As in our cases, they too observed continuity of the
Fig. 2. Papillae lined by cuboidal to columnar stratified cells.
Fig. 4. Transition from normal surface mucosa to neoplasm.
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
tumor cells with the normal epithelium and advanced the concept that these adenocarcinomas arose from the mucosal surface rather than from the seromucous glands. A subset of LGNPPAs closely resembles metastatic papillary carcinoma of the thyroid in that both exhibit papillary architecture with fibrovascular cores, overlapping nuclei with clear chromatin, and psammoma bodies [2,5]. This histologic similarity serves as a reminder of the possibility of metastasis to the nasopharynx from other primary sites, and this should therefore be borne in mind in the differential diagnosis of nasopharyngeal tumors. Because papillary carcinoma of the thyroid may express TTF-1 and thyroglobulin, the expression of these markers is useful in the differential diagnosis of papillary carcinomas [4]. Thyroid transcription factor–1 is a homeodomain-containing, tissue-specific transcription factor that belongs to the Nkx2 gene family. It is expressed selectively during embryonic development of the thyroid, lungs, and some parts of the diencephalons [4,6,7]. Occasionally, TTF-1 has been found in other human neoplasms, such as liver, colon, and breast cancers, but it is expressed in the cytoplasm of the cells in these tumors, not in the nuclei, as it is in lung and thyroid neoplasms [6,7]. However, some extrapulmonary small cell carcinomas do show nuclear TTF-1 immunoreactivity [8,9]. Thyroglobulin is expressed only in thyroid lesions, and the degree of positivity varies between subtypes of carcinomas. For example, it is expressed in 100% of Hurtle cell carcinomas, 90% of papillary carcinomas, and 88% of follicular carcinomas, but it is seen in just 7% of medullary carcinomas [4,10,11]. The combination of CKs, although less specific, may also be helpful in distinguishing primary nasopharyngeal tumors from metastasis. Cytokeratins 5/6 and 20 are not found in thyroid neoplasms. Cytokeratin 5/6 is found in normal upper respiratory epithelium [12], and CK 19 is present in 80% to 100% of papillary thyroid carcinomas [12-14]. However, CK 7 may be the most useful marker
Fig. 5. Immunohistochemical reactivity shows diffuse nuclear staining for TTF-1 protein.
191
Fig. 6. Neoplastic cells expressing CK 19.
in distinguishing primary nasopharyngeal tumors from metastasis because it is found in 98% of thyroid neoplasms [12,14]. Carcinomas arising in aberrant ectopic thyroid tissue (ETT) should also be considered in the differential diagnosis of nasopharyngeal tumors, especially when the lesions express TTF-1. This is because the thyroid gland develops as an endodermal bud in the floor of the nasopharynx between the first and second branchial pouches and migrates caudally into the neck, anterior to the tracheobronchial bud, where it becomes a midline structure. The connecting structures, such as the thyroglossal duct between the gland and the floor of the mouth, eventually disappear. However, if the duct persists, it may give rise to a thyroglossal cyst, and this abnormality of the gland may also create a midline structure of ETT. Laterally located ETTs may arise from cells left behind during the migration of the thyroid gland or may result from the improper descent of the lateral anlage of the gland during its development [15]. Another possible mechanism of ETT development is the detachment of evaginated thyroid tissue from lateral lobes of thyroid primordial tissue that remains lateralized in the neck [16]. For the lesions reported here, however, because they were located cephalic to the base of the tongue, not laterally or caudally, this made a neoplasm arising from ETT very unlikely. All of the tumors reported in the literature arising from ETT have been located in the midline or in the lateral neck and never cephalic to the base of the tongue [15,16]. To our knowledge, no TTF-1 immunoreactivity has been previously documented in primary LGNPPAs. This finding complicates the differential diagnosis between this neoplasm and papillary thyroid carcinoma. Thus, the identification of a transition from surface mucosa to neoplastic cells and the predominance of stratified nuclei are of help in recognizing the lesions as a primary nasopharyngeal carcinoma. Thyroid imaging and clinical findings that correlate with the nature of the lesions are also helpful in reaching the proper diagnosis.
192
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
References [1] Fearon B, Forte V, Brama I. Malignant nasopharyngeal tumors in children. Laryngoscope 1990;100:470 - 2. [2] Wenig BM, Hyams VJ, Heffner DK. Nasopharyngeal papillary adenocarcinoma. A clinicopathologic study of a low-grade carcinoma. Am J Surg Pathol 1988;12:946 - 53. [3] Kuo T, Tsang NM. Salivary gland type nasopharyngeal carcinoma: a histologic, immunohistochemical, and Epstein-Barr virus study of 15 cases including a psammomatous mucoepidermoid carcinoma. Am J Surg Pathol 2001;25:80 - 6. [4] Rosai J. Immunohistochemical markers of thyroid tumors: significance and diagnostic applications. Tumori 2003;89:517 - 9. [5] van Hasselt CA, Ng HK. Papillary adenocarcinoma of the nasopharynx. J Laryngol Otol 1991;105:853 - 4. [6] Bejarano PA, Mousavi F. Incidence and significance of cytoplasmic thyroid transcription factor–1 immunoreactivity. Arch Pathol Lab Med 2003;127:193 - 5. [7] Pan CC, Chen PC, Tsay SH, et al. Cytoplasmic immunoreactivity for thyroid transcription factor–1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique. Am J Clin Pathol 2004; 121:343 - 9. [8] Agoff SN, Lamps LW, Philip AT, et al. Thyroid transcription factor–1 is expressed in extrapulmonary small carcinomas but not
[9]
[10]
[11]
[12]
[13]
[14]
[15] [16]
in other extrapulmonary neuroendocrine tumors. Mod Pathol 2000; 13:238 - 42. Ordonez NG. Value of thyroid transcription factor–1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol 2000;24:1217 - 23. de Micco C, Chapel F, Dor AM, et al. Thyroglobulin in medullary thyroid carcinoma: immunohistochemical study with polyclonal and monoclonal antibodies. Hum Pathol 1993;24:256 - 62. Judkins AR, Roberts SA, Livolsi VA. Utility of immunohistochemistry in the evaluation of necrotic thyroid tumors. Hum Pathol 1999; 30:1373 - 6. Chu PG, Weiss LM. Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases. Mod Pathol 2002;15:6 - 10. Cerilli LA, Mills SE, Rumpel CA, et al. Interpretation of RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol 2002;118:186 - 93. Cheung CC, Ezzat S, Freeman JL, et al. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 2001;14: 338 - 442. Todd NW. Common congenital anomalies of the neck. Embryology and surgical anatomy. Surg Clin North Am 1993;73:599 - 610. Sambola-Cabrer I, Fernandez-Real JM, Ricart W, et al. Ectopic thyroid tissue presenting as a submandibular mass. Head Neck 1996;18:87 - 90.
Thyroid transcription factor –1 expression in thyroid-like nasopharyngeal papillary adenocarcinoma: report of 2 cases Fernando Carrizo, MD1, Mario A. Luna, MDT Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Abstract
We present the cases of 2 pediatric patients with low-grade nasopharyngeal papillary adenocarcinoma with features suggestive of thyroid origin. Both cases showed strong nuclear immunoreactivity for thyroid transcription factor–1 protein and positive immunostaining for cytokeratins 7 and 19. After thyroid imaging studies, local excision was performed in both patients. The patients remain free of disease 2 and 15 years after treatment, with no evidence of lesions in the thyroid or elsewhere. D 2005 Elsevier Inc. All rights reserved.
Keywords:
Nasopharynx; Adenocarcinoma; TTF-1; Thyroid
1. Introduction Most tumors arising from the nasopharynx are either keratinizing or nonkeratinizing squamous cell carcinomas [1]. Much less common in this area are glandular neoplasms, including lesions originating from the surface epithelium and from seromucous salivary glands [2,3]. Another possible source of nasopharyngeal tumors is metastatic papillary carcinoma, especially from the thyroid gland. In distinguishing between such possible sources of nasopharyngeal tumors, thyroid transcription factor–1 protein (TTF-1) and thyroglobulin expression can be useful in the differential diagnosis [4]. We present the cases of 2 pediatric patients with lowgrade nasopharyngeal papillary adenocarcinoma (LGNPPA) showing TTF-1 nuclear expression and provide histologic and immunohistochemical findings regarding the neoplasms, along with clinical follow-up data. 2. Case reports 2.1. Case 1 A 9-year-old boy presented with complaints of right nasal fullness with a duration of 3 months and the T Corresponding author. E-mail address: [email protected] (M.A. Luna). 1 Present address: Departamento de Patologı´a, Hospital de Clı´nicas bJose´ de San Martı´n,Q Av Cordoba 2351, Buenos Aires, Argentina. 1092-9134/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.04.019
occasional identification of blood in his saliva. An endoscopic examination disclosed a submucosal mass measuring 2.0 cm in diameter in the right nasopharyngeal wall, along with focal mucosal erosion. No other physical abnormalities were found. Computed tomography and magnetic resonance imaging of the head and neck confirmed a right nasopharyngeal mass. An incisional biopsy was performed. Computed tomography and sonography of the thyroid showed no abnormalities. A transpalatal resection was performed. The patient recovered uneventfully, and there was no evidence of recurrence or other lesions after 2 years of follow-up. 2.2. Case 2 A 13-year-old boy presented with a unilateral nasal obstruction with a duration of 2 months. No additional relevant medical history was found. An endoscopic examination revealed a mass in the roof of the nasopharynx, at the junction of the nasal septum and the vault, measuring 1.5 cm in diameter. The cervical lymph nodes were not palpable, and the rest of the physical examination findings were not remarkable. Imaging studies of the head and neck confirmed the nasopharyngeal mass. With the patient under general anesthesia, an incisional biopsy was performed. Computed tomography and sonography of the thyroid showed no abnormalities. A transpalatal resection was
190
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
Fig. 1. Complex and tightly packed papillae with fibrovascular cores.
performed. There was no evidence of recurrence or other lesions after 15 years of follow-up. 3. Pathological findings 3.1. Gross findings The tumors were described as exophytic with a papillary appearance.
Fig. 3. Cells with overlapping nuclei and clear chromatin lining papillary fronds. Notice the psammoma body.
3.3. Special studies Immunoperoxidase studies in both cases showed strong nuclear immunoreactivity for TTF-1 (Fig. 5). The cells also expressed cytokeratin (CK) 7 and CK 19 (Fig. 6). Immunoperoxidase staining for thyroglobulin was negative, and there was no immunoreactivity for CK 5/6 or CK 20.
3.2. Histopathologic findings
4. Discussion
Histologic examination revealed papillary fronds with fibrovascular cores. The papillae were complex and tightly packed (Fig. 1). They were lined by cuboidal to columnar stratified cells with round to oval vesicular nuclei and eosinophilic cytoplasm (Fig. 2). In other areas, the nuclei overlapped one another and had vesicular to clear chromatin (Fig. 3). The cells exhibited only minor degrees of pleomorphism and hyperchromatism. No mitotic figures were found. Psammoma bodies were seen focally (Fig. 3). Continuity of tumor cells with the normal epithelial lining was identified in both cases (Fig. 4).
Glandular neoplasms of the nasopharynx can be divided into 2 groups: those that originate from the surface mucosal epithelium, such as LGNPPAs, and those that originate from seromucous glands. The histologic phenotypes of the latter type are similar to those of neoplasms in the major salivary glands or oral cavity (eg, adenoid cystic carcinoma or mucoepidermoid carcinoma) [2,3]. Wenig et al [2] described LGNPPAs and made a strong case for this type of tumor being considered a separate entity from other types of adenocarcinoma in the nasopharyngeal region. As in our cases, they too observed continuity of the
Fig. 2. Papillae lined by cuboidal to columnar stratified cells.
Fig. 4. Transition from normal surface mucosa to neoplasm.
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
tumor cells with the normal epithelium and advanced the concept that these adenocarcinomas arose from the mucosal surface rather than from the seromucous glands. A subset of LGNPPAs closely resembles metastatic papillary carcinoma of the thyroid in that both exhibit papillary architecture with fibrovascular cores, overlapping nuclei with clear chromatin, and psammoma bodies [2,5]. This histologic similarity serves as a reminder of the possibility of metastasis to the nasopharynx from other primary sites, and this should therefore be borne in mind in the differential diagnosis of nasopharyngeal tumors. Because papillary carcinoma of the thyroid may express TTF-1 and thyroglobulin, the expression of these markers is useful in the differential diagnosis of papillary carcinomas [4]. Thyroid transcription factor–1 is a homeodomain-containing, tissue-specific transcription factor that belongs to the Nkx2 gene family. It is expressed selectively during embryonic development of the thyroid, lungs, and some parts of the diencephalons [4,6,7]. Occasionally, TTF-1 has been found in other human neoplasms, such as liver, colon, and breast cancers, but it is expressed in the cytoplasm of the cells in these tumors, not in the nuclei, as it is in lung and thyroid neoplasms [6,7]. However, some extrapulmonary small cell carcinomas do show nuclear TTF-1 immunoreactivity [8,9]. Thyroglobulin is expressed only in thyroid lesions, and the degree of positivity varies between subtypes of carcinomas. For example, it is expressed in 100% of Hurtle cell carcinomas, 90% of papillary carcinomas, and 88% of follicular carcinomas, but it is seen in just 7% of medullary carcinomas [4,10,11]. The combination of CKs, although less specific, may also be helpful in distinguishing primary nasopharyngeal tumors from metastasis. Cytokeratins 5/6 and 20 are not found in thyroid neoplasms. Cytokeratin 5/6 is found in normal upper respiratory epithelium [12], and CK 19 is present in 80% to 100% of papillary thyroid carcinomas [12-14]. However, CK 7 may be the most useful marker
Fig. 5. Immunohistochemical reactivity shows diffuse nuclear staining for TTF-1 protein.
191
Fig. 6. Neoplastic cells expressing CK 19.
in distinguishing primary nasopharyngeal tumors from metastasis because it is found in 98% of thyroid neoplasms [12,14]. Carcinomas arising in aberrant ectopic thyroid tissue (ETT) should also be considered in the differential diagnosis of nasopharyngeal tumors, especially when the lesions express TTF-1. This is because the thyroid gland develops as an endodermal bud in the floor of the nasopharynx between the first and second branchial pouches and migrates caudally into the neck, anterior to the tracheobronchial bud, where it becomes a midline structure. The connecting structures, such as the thyroglossal duct between the gland and the floor of the mouth, eventually disappear. However, if the duct persists, it may give rise to a thyroglossal cyst, and this abnormality of the gland may also create a midline structure of ETT. Laterally located ETTs may arise from cells left behind during the migration of the thyroid gland or may result from the improper descent of the lateral anlage of the gland during its development [15]. Another possible mechanism of ETT development is the detachment of evaginated thyroid tissue from lateral lobes of thyroid primordial tissue that remains lateralized in the neck [16]. For the lesions reported here, however, because they were located cephalic to the base of the tongue, not laterally or caudally, this made a neoplasm arising from ETT very unlikely. All of the tumors reported in the literature arising from ETT have been located in the midline or in the lateral neck and never cephalic to the base of the tongue [15,16]. To our knowledge, no TTF-1 immunoreactivity has been previously documented in primary LGNPPAs. This finding complicates the differential diagnosis between this neoplasm and papillary thyroid carcinoma. Thus, the identification of a transition from surface mucosa to neoplastic cells and the predominance of stratified nuclei are of help in recognizing the lesions as a primary nasopharyngeal carcinoma. Thyroid imaging and clinical findings that correlate with the nature of the lesions are also helpful in reaching the proper diagnosis.
192
F. Carrizo, M.A. Luna / Annals of Diagnostic Pathology 9 (2005) 189 –192
References [1] Fearon B, Forte V, Brama I. Malignant nasopharyngeal tumors in children. Laryngoscope 1990;100:470 - 2. [2] Wenig BM, Hyams VJ, Heffner DK. Nasopharyngeal papillary adenocarcinoma. A clinicopathologic study of a low-grade carcinoma. Am J Surg Pathol 1988;12:946 - 53. [3] Kuo T, Tsang NM. Salivary gland type nasopharyngeal carcinoma: a histologic, immunohistochemical, and Epstein-Barr virus study of 15 cases including a psammomatous mucoepidermoid carcinoma. Am J Surg Pathol 2001;25:80 - 6. [4] Rosai J. Immunohistochemical markers of thyroid tumors: significance and diagnostic applications. Tumori 2003;89:517 - 9. [5] van Hasselt CA, Ng HK. Papillary adenocarcinoma of the nasopharynx. J Laryngol Otol 1991;105:853 - 4. [6] Bejarano PA, Mousavi F. Incidence and significance of cytoplasmic thyroid transcription factor–1 immunoreactivity. Arch Pathol Lab Med 2003;127:193 - 5. [7] Pan CC, Chen PC, Tsay SH, et al. Cytoplasmic immunoreactivity for thyroid transcription factor–1 in hepatocellular carcinoma: a comparative immunohistochemical analysis of four commercial antibodies using a tissue array technique. Am J Clin Pathol 2004; 121:343 - 9. [8] Agoff SN, Lamps LW, Philip AT, et al. Thyroid transcription factor–1 is expressed in extrapulmonary small carcinomas but not
[9]
[10]
[11]
[12]
[13]
[14]
[15] [16]
in other extrapulmonary neuroendocrine tumors. Mod Pathol 2000; 13:238 - 42. Ordonez NG. Value of thyroid transcription factor–1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol 2000;24:1217 - 23. de Micco C, Chapel F, Dor AM, et al. Thyroglobulin in medullary thyroid carcinoma: immunohistochemical study with polyclonal and monoclonal antibodies. Hum Pathol 1993;24:256 - 62. Judkins AR, Roberts SA, Livolsi VA. Utility of immunohistochemistry in the evaluation of necrotic thyroid tumors. Hum Pathol 1999; 30:1373 - 6. Chu PG, Weiss LM. Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases. Mod Pathol 2002;15:6 - 10. Cerilli LA, Mills SE, Rumpel CA, et al. Interpretation of RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol 2002;118:186 - 93. Cheung CC, Ezzat S, Freeman JL, et al. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 2001;14: 338 - 442. Todd NW. Common congenital anomalies of the neck. Embryology and surgical anatomy. Surg Clin North Am 1993;73:599 - 610. Sambola-Cabrer I, Fernandez-Real JM, Ricart W, et al. Ectopic thyroid tissue presenting as a submandibular mass. Head Neck 1996;18:87 - 90.