- Email: [email protected]
Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin?
Available online at www.sciencedirect.com
Annals of Diagnostic Pathology 15 (2011) 135 – 139
Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin? Jaiyeola Thomas, MDa,⁎, Patrick Adegboyega, MDa , Kenny Iloabachie, MDb , John Wesley Mooring, MDa , Timothy Lian, MDb a
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA Department of Oto-rhino-laryngology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
b
Abstract
Keywords:
Sinonasal teratocarcinosarcoma is an uncommon, aggressive, morphologically heterogenous tumor composed of cells derived from the 3 somatic layers. A histogenetic origin from a multipotential adult somatic stem cell with divergent differentiation has been favored over a germ cell origin. This assumption has been based on the lack of germ cell elements and, until recently, the absence of demonstrable amplification of 12p. We report a case that exhibited foci of yolk sac elements with papillary structures and intracytoplasmic periodic acid-Schiff–positive, diastase-resistant, αfetoprotein–positive, hyaline globules. An expanded area of undifferentiated cells, likely precursor cells, in the basal layer of the overlying mucosal epithelium transitions into and merges with the immature epithelial, neuroepithelial, and mesenchymal components. These previously unreported histomorphological features support the hypothesis that this tumor is a teratomatous tumor arising from pluripotent embryonic stem cells in the basal layer of the sinonasal epithelium. That notion is further supported by fluorescence in situ hybridization cytogenetic analysis, which showed a distinct subpopulation of the tumor cells with an extra copy of chromosome 12p13. © 2011 Elsevier Inc. All rights reserved. Sinonasal teratocarcinosarcoma; Yolk sac; Germ cell origin
1. Introduction Sinonasal teratocarcinosarcoma (SNTCS) is an uncommon highly aggressive malignant tumor that is morphologically heterogeneous and composed of cells of different somatic layers, ectodermal, mesenchymal, and endodermal, with varying degrees of malignant differentiation [1-4]. The origin of this tumor remains controversial, although histogenesis from a multipotential adult somatic stem cell with divergent differentiation has been suggested. This assumption has been based on the lack of germ cell elements such as yolk sac elements, germinoma, embryonal carcinoma, or choriocarcinoma, and recently, on the absence of demonstrable amplification of 12p, usually ⁎ Corresponding author. Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130. Tel.: +1 318 675 5899; fax: +1 318 675 5959. E-mail address: [email protected] (J. Thomas). 1092-9134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.01.004
isochromosome 12p (i12p) often associated with tumors of germ cell origin [5]. The ectodermal and endodermal components have variably included squamous, immature neuroepithelium, and glandular elements with or without mucin secretions. The mesenchymal components have included smooth muscle, chondromatous, and rhabdomyoblastic areas with primitive and sarcomatous features. However, in most reported series, no germinoma, embryonal carcinoma, choriocarcinoma, or yolk sac elements have been demonstrated, hence, the assumption that SNTCS is a tumor that arises from multipotential (adult) somatic stem cells. Based on these findings and the lack of i12p, this tumor has been considered unlikely to be of germ cell origin, even though 2 case reports have immunohistochemically documented the presence of few α-fetoprotein (AFP)–positive cells [2,6]. However, a recent report that documented the finding of trisomy 12 in a case of SNTCS with a subclone of cells showing loss of 1p [6] supports the possibility that the tumor is of pluripotential embryonic stem/germ cell origin.
136
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
We present a case report of SNTCS with foci of yolk sac elements, AFP-positive hyaline granules, and area of proliferating undifferentiated basal layer cells of the respiratory epithelium transitioning into primitive clusters of tumor cells and merging with areas of epithelial, neuroepithelial, and mesenchymal elements. Fluorescence in situ hybridization (FISH) cytogenetics for chromosome 12p amplification was also studied. 2. Clinical history The patient is a 51-year-old woman who presented with proptosis and an enlarging nasal mass protruding from her right nasal vestibule, which she noticed 4 to 5 months before presentation. Her history was significant for progressive right-sided blurry vision, nasal airway obstruction, anosmia, and intermittent rhinorrhea. On examination, her right eye was proptotic with restriction of medial gaze, and a tan-colored firm mass was seen extruding from the right nasal cavity. Computed tomography images revealed a large nasal mass involving the entire right nasal cavity, displacing the septum laterally and extending into the cribriform area of the skull base and anterior cranial fossa displacing the right orbital contents and medial rectus muscles. The mass measures approximately 56 × 41 mm, involves the frontal and sphenoid sinuses, and erodes the medial wall of the left maxillary sinus. Examination under anesthesia revealed a hemorrhagic solid brown mass with extensive necrosis filling the entire nasal cavity; only the inferior turbinate was identifiable. An initial incisional biopsy of the mass was done, and the patient subsequently underwent a craniofacial resection and postoperative radiotherapy. 3. Pathologic findings The surgical resection specimen consists of grossly irregular, fragmented hemorrhagic, friable necrotic mass. Microscopic examination showed that most of the viable and diagnostic tissue was present in the initial biopsy specimen and consists of variable epithelial, neuroepithelial, and mesenchymal elements as well as undifferentiated, primitive cellular component. Numerous nests of benign squamous clusters with cytoplasmic vacuolation reminiscent of fetal oral squamous mucosa were identified (Fig. 1A). Collars of primitive myxoid mesenchyme, fibrocollagenous stroma, and sarcomatous stromal cells surround some islands of squamous epithelium. Epithelial glandular differentiation with acinar, tubular, and ductal structures is demonstrated with mucin present in some of the glandular epithelium (Fig. 1B). These are strongly positive with cytokeratin, AE1/AE3, with predominant CK7 staining and focal CK20 positivity. A range of benign to malignant mesenchymal areas is seen with focal fibrous area, hyalinized osteoid-like tissue, chondromyxoid foci,
and undifferentiated sarcomatous areas with skeletal muscle differentiation, positive with desmin (Fig. 1C, D). The primitive undifferentiated areas (Fig. 1E) also stained positive with neuron-specific enolase, synaptophysin, and chromogranin. Primitive neural areas with background neurofibrillary matrix and glial cells were present (Fig. 1F); focus of immature neuroepithelium with poorly formed tubular structures was also noted, and it stained strongly positive with CD56 and synaptophysin. An area of malignant papillary structures reminiscent of yolk sac elements was identified, with central vascular core and outer layer of epithelium. Intracytoplasmic periodic acid-Schiff–positive, diastase-resistant hyaline globules, which were also AFP positive, were present within some of the epithelial cells (Fig. 2A-D). Placental alkaline phosphatase, human chorionic gonadotropin, and CD30 immunohistochemical stains were negative. Focally positive S100 dendritic cells are present, scattered in the squamous islands. CD99 shows strong cytoplasmic dotlike pattern and membrane cytoplasmic staining in spindle cell and epithelial areas, respectively. An expanded area composed of undifferentiated clusters of cells was seen in the basal layer of the overlying respiratory epithelium. These basal cellular clusters were morphologically similar to the undifferentiated components of the tumor and merge with the immature neural fibrillary tissue and primitive undifferentiated cells in the underlying stroma (Fig. 3A and B). 4. Fluorescence in situ hybridization Fluorescence in situ hybridization was done for evaluation of chromosome 12, particularly the presence of an isochromosome (i12p). Fluorescence in situ hybridization analysis using a locus-specific probe for the short arm of chromosome 12 (12p13/ETV6) is predominantly normal for copy number of chromosome 12 and 12p13. However, a subpopulation in the tissue shows an extra copy of 12p13 in approximately 9% of the cells evaluated (87/967). Despite the suboptimal nature of the tissue sections for FISH analysis, 3 copies of 12p are distinct in this subpopulation of cells. Using a pericentromeric probe for chromosome 12, the copy number of chromosome 12 is abnormal in approximately 7% of cells (35/482). 5. Discussion Sinonasal teratocarcinosarcoma is a rare highly aggressive tumor with heterogeneous architectural patterns and is also composed of derivatives of the different 3 germ cell layers, that is, ectoderm, mesoderm, and endoderm. The tumor often manifests both benign and malignant components with the carcinomatous component being predominantly adenocarcinoma and squamous cell carcinoma. In view of the multiplicity of structures and pleomorphism
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
137
Fig. 1. Different components and structures identified in the tumor. (A) Fetal squamous epithelium (original magnification ×200), (B) glandular structure with columnar epithelium and mucin secretion (original magnification ×200), (C) sarcomatous spindle cell area (original magnification ×200), (D) mesenchymal area within hyalin osteoid-like material (original magnification ×200), (E) clusters of undifferentiated blastematous cells (original magnification ×200), (F) neural tissue with fibrillary matrix and ganglion cells (original magnification ×400).
often displayed by this tumor, inadequate sampling can lead to error in diagnosis and inappropriate choice of therapeutic regimen. As occurred in this case, the resected specimen was rather hemorrhagic and necrotic with only limited viable tissue and structures identified. Most of the diagnostic features were identified in the initial biopsy material. Before the publications of Shanmugaratnam et al [1] and Heffner and Hyams [2], who used the terms teratoid carcinosarcoma and teratocarcinoma respectively, previous reports have described similar tumor as nasal blastoma, mixed mesodermal tumor, malignant teratoma, and carcinosarcoma of nasal and paranasal sinuses. These probably represent the same tumor assigned a nomenclature based on the tissue types identified. The tumor could erroneously be diagnosed as adenocarcinoma, squamous cell carcinoma, neuroblastoma, and immature teratoma or
chondromyxoid fibrosarcoma depending on the tissue type identified, especially with limited biopsy tissue samples. Though possible yolk sac elements have been suggested by the identification of few AFP-positive cells [2,6], no report to date has documented the presence of recognizable germ cell elements in SNTCS. In this case, we report the presence of definite yolk cell elements, which, as shown in Fig. 2A-D, was positive with cytokeratin, AFP, and CD99 on immunostaining. The presence of yolk sac elements with some cell population containing extra copies of chromosome 12p on FISH in this case raises the possibility of embryonic stem cell origin. This is supported by the report of Vranic et al [6] that has also documented a subclone of cells in SNTCS with trisomy 12. Recent reports have also documented primary sinonasal choriocarcinoma and yolk sac tumors [7,8], suggesting the likelihood that these tumors represent
138
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
Fig. 2. Foci of tumor showing glandular yolk sac elements. (A) Epithelial structures with Schiller-Duval body (original magnification ×200), (B) complex epithelial glands (original magnification ×200), (C) with intracytoplasmic hyaline globules (original magnification ×400), (D) AFP-positive intracytoplasmic granules (immunostain) (original magnification ×200).
monophasic components of the SNTCS or tumors arising from the same embryonic stem cell. The pseudostratified columnar mucociliary epithelium of the sinonasal mucosa is composed of surface ciliated epithelial cells as well as goblet and basal cells. When the epithelium is damaged, the proliferation and regeneration process involves stem cells and/or progenitor cells in the nasal epithelium that are self-replicating adult stem cells [9,10]. The expression of nestin and stem cell renewal factor, BMI-1, a polycomb gene, has been reported as proof of identification of this group of progenitor cells in various mucosal tissues including sinonasal respiratory epithelium [10].
The adult stem cells are an undifferentiated compartment found among differentiated cells in the basal layer. These cells are capable of self-renewal and can differentiate into the major specialized cells of the tissues at that location. Few studies have evaluated and documented the presence of these stem cells in the nasal epithelium and polyps [9,10]. It has been shown that these multipotential and amplifying cells are capable of differentiation into epithelial cells, olfactory receptor neuron, and nonneuronal cells including sustentacular, glandular, and ductal cells [10]. The finding of an expanded area of primitive cells in the basal layer in this case (Fig. 3A and B) is an additional concrete proof of the presence of this compartment of adult stem cells in the sinonasal
Fig. 3. Sinonasal mucosa with ciliated columnar epithelium and basal layer compartment of proliferating undifferentiated cells, continuous with underlying tumor neuronal matrix and cells (A and B).
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
respiratory epithelium. However, there is the possibility that these group of stem cells may be the result of the proliferation of embryonic germ cell rests that have migrated to the midline during embryonic development; therefore, SNTCS may be another nongonadal germ cell tumor. It has also been documented that adult stem cells can transform into embryonic form (germ cells) by gene reprogramming, which can be induced by viral integration [11-13]. Thus, adult stem cells can be induced to become pluripotent by viruses or through the use of jumping genes—transposon. These induced pluripotent stem cells are similar to embryonic stem cells in morphology, proliferation, and teratomatous transformation [11]. However, these cells are obtained through a process that carries with it significant cancer risk. It is plausible that this mechanism may explain the process by which adult stem cells in the sinonasal epithelium can have divergent differentiation or dedifferentiation into a pluripotent embryonic stem cell capable of differentiating into teratomatous elements including yolk sac elements. The nasal cavity and sinonasal epithelium is an area that is constantly subjected to numerous virally induced inflammatory reactions. This raises the possibility that the SNTCS is a teratoma arising from induced pluripotent somatic stem cells in the basal layer of the sinonasal epithelium. However, no concrete evidence of virus-associated changes has been reported in cases of SNTCS. In conclusion, this case report of SNTCS that has the cytogenetic abnormalities of extra copies of chromosome 12p and previously unreported histomorphological features of germ cell elements (including the presence of intraepithelial undifferentiated cells in the basal epithelium that overlies the tumor and the presence of yolk sac elements) support the hypothesis that SNTCS may be an extragenital germ cell tumor that arises from pluripotent embryonic germ cell rest in the sinonasal region.
139
References [1] Shanmugaratnam K, Kunaratnam N, Chia KB, Chiang GS, Sinniah R. Teratoid carcinosarcoma of paranasal sinuses. Pathology 1983;15: 413-9. [2] Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses. A clinicopathologic study of 20 cases. Cancer 1984;53:2140-54. [3] Wei S, Carroll W, Lazenby A, Bell W, Lopez R, Said-Al-Naief N. Sinonasal teratocarcinosarcoma: report of a case with review of the literature and treatment outcome. Ann Diagn Pathol 2008;12: 415-25. [4] Smith SL, hessel AC, Luna MA, Malpica A, Rosenthal DI, El-Naggar AK. Sinonasal teratocarcinosarcoma of the head and neck. A report of 10 patients treated at a single institution and comparison with reported series. Arch Otolaryngol Head Neck Surg 2008;134:592-5. [5] Salem F, Rosenbum MK, Jhanwar SC, Kancherla P, Ghossein RA, Carlson DL. Teratocarcinosarcoma of the nasal cavity and paranasal sinuses: report of 3 cases with assessment for chromosome 12p status. Hum Pathol 2008;39:605-9. [6] Vranic S, Caughron SK, Djuricic S, Bilalovic N, Zaman S, Suljevic I, et al. Hamartomas, teratomas and teratocarcinosarcomas of the head and neck: report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis and review of the literature. BMC Ear Nose Throat Disord 2008;8:8-18. [7] Bell DM, Porras G, Tortoledo ME, Luna MA. Primary sinonasal choriocarcinoma. Ann Diagn Pathol 2009;13:96-100. [8] Filho BC, McHugh JB, Carrau RL, Kassam AB. Yolk sac tumor in the nasal cavity. Am J Otolaryngol 2008;29:250-4. Epub 2008. [9] Kim TH, Lee HM, Lee SH, Choe H, Kim HK, Lee JH, et al. Expression and distribution pattern of the stem cell marker, nestin, and the stem cell renewal factor, BMI-1, in normal human nasal mucosa and nasal polyps. Acta Otolaryngol 2008:1-6. [10] Iwai N, Zhou Z, Roop DR, Behringer RR. Horizontal basal cells are multipotential progenitors in normal and injured adult olfactory epithelium. Stem Cells 2008;26:1298-306. [11] Okita T, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007;448:313-7. [12] Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development 2009;136:509-23. [13] Carey BW, Markoulaki S, Hanna J, Saha K, Gao Q, Mitalipova M. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci 2009;106:157-62.
Annals of Diagnostic Pathology 15 (2011) 135 – 139
Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin? Jaiyeola Thomas, MDa,⁎, Patrick Adegboyega, MDa , Kenny Iloabachie, MDb , John Wesley Mooring, MDa , Timothy Lian, MDb a
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA Department of Oto-rhino-laryngology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
b
Abstract
Keywords:
Sinonasal teratocarcinosarcoma is an uncommon, aggressive, morphologically heterogenous tumor composed of cells derived from the 3 somatic layers. A histogenetic origin from a multipotential adult somatic stem cell with divergent differentiation has been favored over a germ cell origin. This assumption has been based on the lack of germ cell elements and, until recently, the absence of demonstrable amplification of 12p. We report a case that exhibited foci of yolk sac elements with papillary structures and intracytoplasmic periodic acid-Schiff–positive, diastase-resistant, αfetoprotein–positive, hyaline globules. An expanded area of undifferentiated cells, likely precursor cells, in the basal layer of the overlying mucosal epithelium transitions into and merges with the immature epithelial, neuroepithelial, and mesenchymal components. These previously unreported histomorphological features support the hypothesis that this tumor is a teratomatous tumor arising from pluripotent embryonic stem cells in the basal layer of the sinonasal epithelium. That notion is further supported by fluorescence in situ hybridization cytogenetic analysis, which showed a distinct subpopulation of the tumor cells with an extra copy of chromosome 12p13. © 2011 Elsevier Inc. All rights reserved. Sinonasal teratocarcinosarcoma; Yolk sac; Germ cell origin
1. Introduction Sinonasal teratocarcinosarcoma (SNTCS) is an uncommon highly aggressive malignant tumor that is morphologically heterogeneous and composed of cells of different somatic layers, ectodermal, mesenchymal, and endodermal, with varying degrees of malignant differentiation [1-4]. The origin of this tumor remains controversial, although histogenesis from a multipotential adult somatic stem cell with divergent differentiation has been suggested. This assumption has been based on the lack of germ cell elements such as yolk sac elements, germinoma, embryonal carcinoma, or choriocarcinoma, and recently, on the absence of demonstrable amplification of 12p, usually ⁎ Corresponding author. Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71130. Tel.: +1 318 675 5899; fax: +1 318 675 5959. E-mail address: [email protected] (J. Thomas). 1092-9134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2010.01.004
isochromosome 12p (i12p) often associated with tumors of germ cell origin [5]. The ectodermal and endodermal components have variably included squamous, immature neuroepithelium, and glandular elements with or without mucin secretions. The mesenchymal components have included smooth muscle, chondromatous, and rhabdomyoblastic areas with primitive and sarcomatous features. However, in most reported series, no germinoma, embryonal carcinoma, choriocarcinoma, or yolk sac elements have been demonstrated, hence, the assumption that SNTCS is a tumor that arises from multipotential (adult) somatic stem cells. Based on these findings and the lack of i12p, this tumor has been considered unlikely to be of germ cell origin, even though 2 case reports have immunohistochemically documented the presence of few α-fetoprotein (AFP)–positive cells [2,6]. However, a recent report that documented the finding of trisomy 12 in a case of SNTCS with a subclone of cells showing loss of 1p [6] supports the possibility that the tumor is of pluripotential embryonic stem/germ cell origin.
136
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
We present a case report of SNTCS with foci of yolk sac elements, AFP-positive hyaline granules, and area of proliferating undifferentiated basal layer cells of the respiratory epithelium transitioning into primitive clusters of tumor cells and merging with areas of epithelial, neuroepithelial, and mesenchymal elements. Fluorescence in situ hybridization (FISH) cytogenetics for chromosome 12p amplification was also studied. 2. Clinical history The patient is a 51-year-old woman who presented with proptosis and an enlarging nasal mass protruding from her right nasal vestibule, which she noticed 4 to 5 months before presentation. Her history was significant for progressive right-sided blurry vision, nasal airway obstruction, anosmia, and intermittent rhinorrhea. On examination, her right eye was proptotic with restriction of medial gaze, and a tan-colored firm mass was seen extruding from the right nasal cavity. Computed tomography images revealed a large nasal mass involving the entire right nasal cavity, displacing the septum laterally and extending into the cribriform area of the skull base and anterior cranial fossa displacing the right orbital contents and medial rectus muscles. The mass measures approximately 56 × 41 mm, involves the frontal and sphenoid sinuses, and erodes the medial wall of the left maxillary sinus. Examination under anesthesia revealed a hemorrhagic solid brown mass with extensive necrosis filling the entire nasal cavity; only the inferior turbinate was identifiable. An initial incisional biopsy of the mass was done, and the patient subsequently underwent a craniofacial resection and postoperative radiotherapy. 3. Pathologic findings The surgical resection specimen consists of grossly irregular, fragmented hemorrhagic, friable necrotic mass. Microscopic examination showed that most of the viable and diagnostic tissue was present in the initial biopsy specimen and consists of variable epithelial, neuroepithelial, and mesenchymal elements as well as undifferentiated, primitive cellular component. Numerous nests of benign squamous clusters with cytoplasmic vacuolation reminiscent of fetal oral squamous mucosa were identified (Fig. 1A). Collars of primitive myxoid mesenchyme, fibrocollagenous stroma, and sarcomatous stromal cells surround some islands of squamous epithelium. Epithelial glandular differentiation with acinar, tubular, and ductal structures is demonstrated with mucin present in some of the glandular epithelium (Fig. 1B). These are strongly positive with cytokeratin, AE1/AE3, with predominant CK7 staining and focal CK20 positivity. A range of benign to malignant mesenchymal areas is seen with focal fibrous area, hyalinized osteoid-like tissue, chondromyxoid foci,
and undifferentiated sarcomatous areas with skeletal muscle differentiation, positive with desmin (Fig. 1C, D). The primitive undifferentiated areas (Fig. 1E) also stained positive with neuron-specific enolase, synaptophysin, and chromogranin. Primitive neural areas with background neurofibrillary matrix and glial cells were present (Fig. 1F); focus of immature neuroepithelium with poorly formed tubular structures was also noted, and it stained strongly positive with CD56 and synaptophysin. An area of malignant papillary structures reminiscent of yolk sac elements was identified, with central vascular core and outer layer of epithelium. Intracytoplasmic periodic acid-Schiff–positive, diastase-resistant hyaline globules, which were also AFP positive, were present within some of the epithelial cells (Fig. 2A-D). Placental alkaline phosphatase, human chorionic gonadotropin, and CD30 immunohistochemical stains were negative. Focally positive S100 dendritic cells are present, scattered in the squamous islands. CD99 shows strong cytoplasmic dotlike pattern and membrane cytoplasmic staining in spindle cell and epithelial areas, respectively. An expanded area composed of undifferentiated clusters of cells was seen in the basal layer of the overlying respiratory epithelium. These basal cellular clusters were morphologically similar to the undifferentiated components of the tumor and merge with the immature neural fibrillary tissue and primitive undifferentiated cells in the underlying stroma (Fig. 3A and B). 4. Fluorescence in situ hybridization Fluorescence in situ hybridization was done for evaluation of chromosome 12, particularly the presence of an isochromosome (i12p). Fluorescence in situ hybridization analysis using a locus-specific probe for the short arm of chromosome 12 (12p13/ETV6) is predominantly normal for copy number of chromosome 12 and 12p13. However, a subpopulation in the tissue shows an extra copy of 12p13 in approximately 9% of the cells evaluated (87/967). Despite the suboptimal nature of the tissue sections for FISH analysis, 3 copies of 12p are distinct in this subpopulation of cells. Using a pericentromeric probe for chromosome 12, the copy number of chromosome 12 is abnormal in approximately 7% of cells (35/482). 5. Discussion Sinonasal teratocarcinosarcoma is a rare highly aggressive tumor with heterogeneous architectural patterns and is also composed of derivatives of the different 3 germ cell layers, that is, ectoderm, mesoderm, and endoderm. The tumor often manifests both benign and malignant components with the carcinomatous component being predominantly adenocarcinoma and squamous cell carcinoma. In view of the multiplicity of structures and pleomorphism
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
137
Fig. 1. Different components and structures identified in the tumor. (A) Fetal squamous epithelium (original magnification ×200), (B) glandular structure with columnar epithelium and mucin secretion (original magnification ×200), (C) sarcomatous spindle cell area (original magnification ×200), (D) mesenchymal area within hyalin osteoid-like material (original magnification ×200), (E) clusters of undifferentiated blastematous cells (original magnification ×200), (F) neural tissue with fibrillary matrix and ganglion cells (original magnification ×400).
often displayed by this tumor, inadequate sampling can lead to error in diagnosis and inappropriate choice of therapeutic regimen. As occurred in this case, the resected specimen was rather hemorrhagic and necrotic with only limited viable tissue and structures identified. Most of the diagnostic features were identified in the initial biopsy material. Before the publications of Shanmugaratnam et al [1] and Heffner and Hyams [2], who used the terms teratoid carcinosarcoma and teratocarcinoma respectively, previous reports have described similar tumor as nasal blastoma, mixed mesodermal tumor, malignant teratoma, and carcinosarcoma of nasal and paranasal sinuses. These probably represent the same tumor assigned a nomenclature based on the tissue types identified. The tumor could erroneously be diagnosed as adenocarcinoma, squamous cell carcinoma, neuroblastoma, and immature teratoma or
chondromyxoid fibrosarcoma depending on the tissue type identified, especially with limited biopsy tissue samples. Though possible yolk sac elements have been suggested by the identification of few AFP-positive cells [2,6], no report to date has documented the presence of recognizable germ cell elements in SNTCS. In this case, we report the presence of definite yolk cell elements, which, as shown in Fig. 2A-D, was positive with cytokeratin, AFP, and CD99 on immunostaining. The presence of yolk sac elements with some cell population containing extra copies of chromosome 12p on FISH in this case raises the possibility of embryonic stem cell origin. This is supported by the report of Vranic et al [6] that has also documented a subclone of cells in SNTCS with trisomy 12. Recent reports have also documented primary sinonasal choriocarcinoma and yolk sac tumors [7,8], suggesting the likelihood that these tumors represent
138
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
Fig. 2. Foci of tumor showing glandular yolk sac elements. (A) Epithelial structures with Schiller-Duval body (original magnification ×200), (B) complex epithelial glands (original magnification ×200), (C) with intracytoplasmic hyaline globules (original magnification ×400), (D) AFP-positive intracytoplasmic granules (immunostain) (original magnification ×200).
monophasic components of the SNTCS or tumors arising from the same embryonic stem cell. The pseudostratified columnar mucociliary epithelium of the sinonasal mucosa is composed of surface ciliated epithelial cells as well as goblet and basal cells. When the epithelium is damaged, the proliferation and regeneration process involves stem cells and/or progenitor cells in the nasal epithelium that are self-replicating adult stem cells [9,10]. The expression of nestin and stem cell renewal factor, BMI-1, a polycomb gene, has been reported as proof of identification of this group of progenitor cells in various mucosal tissues including sinonasal respiratory epithelium [10].
The adult stem cells are an undifferentiated compartment found among differentiated cells in the basal layer. These cells are capable of self-renewal and can differentiate into the major specialized cells of the tissues at that location. Few studies have evaluated and documented the presence of these stem cells in the nasal epithelium and polyps [9,10]. It has been shown that these multipotential and amplifying cells are capable of differentiation into epithelial cells, olfactory receptor neuron, and nonneuronal cells including sustentacular, glandular, and ductal cells [10]. The finding of an expanded area of primitive cells in the basal layer in this case (Fig. 3A and B) is an additional concrete proof of the presence of this compartment of adult stem cells in the sinonasal
Fig. 3. Sinonasal mucosa with ciliated columnar epithelium and basal layer compartment of proliferating undifferentiated cells, continuous with underlying tumor neuronal matrix and cells (A and B).
J. Thomas et al. / Annals of Diagnostic Pathology 15 (2011) 135–139
respiratory epithelium. However, there is the possibility that these group of stem cells may be the result of the proliferation of embryonic germ cell rests that have migrated to the midline during embryonic development; therefore, SNTCS may be another nongonadal germ cell tumor. It has also been documented that adult stem cells can transform into embryonic form (germ cells) by gene reprogramming, which can be induced by viral integration [11-13]. Thus, adult stem cells can be induced to become pluripotent by viruses or through the use of jumping genes—transposon. These induced pluripotent stem cells are similar to embryonic stem cells in morphology, proliferation, and teratomatous transformation [11]. However, these cells are obtained through a process that carries with it significant cancer risk. It is plausible that this mechanism may explain the process by which adult stem cells in the sinonasal epithelium can have divergent differentiation or dedifferentiation into a pluripotent embryonic stem cell capable of differentiating into teratomatous elements including yolk sac elements. The nasal cavity and sinonasal epithelium is an area that is constantly subjected to numerous virally induced inflammatory reactions. This raises the possibility that the SNTCS is a teratoma arising from induced pluripotent somatic stem cells in the basal layer of the sinonasal epithelium. However, no concrete evidence of virus-associated changes has been reported in cases of SNTCS. In conclusion, this case report of SNTCS that has the cytogenetic abnormalities of extra copies of chromosome 12p and previously unreported histomorphological features of germ cell elements (including the presence of intraepithelial undifferentiated cells in the basal epithelium that overlies the tumor and the presence of yolk sac elements) support the hypothesis that SNTCS may be an extragenital germ cell tumor that arises from pluripotent embryonic germ cell rest in the sinonasal region.
139
References [1] Shanmugaratnam K, Kunaratnam N, Chia KB, Chiang GS, Sinniah R. Teratoid carcinosarcoma of paranasal sinuses. Pathology 1983;15: 413-9. [2] Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses. A clinicopathologic study of 20 cases. Cancer 1984;53:2140-54. [3] Wei S, Carroll W, Lazenby A, Bell W, Lopez R, Said-Al-Naief N. Sinonasal teratocarcinosarcoma: report of a case with review of the literature and treatment outcome. Ann Diagn Pathol 2008;12: 415-25. [4] Smith SL, hessel AC, Luna MA, Malpica A, Rosenthal DI, El-Naggar AK. Sinonasal teratocarcinosarcoma of the head and neck. A report of 10 patients treated at a single institution and comparison with reported series. Arch Otolaryngol Head Neck Surg 2008;134:592-5. [5] Salem F, Rosenbum MK, Jhanwar SC, Kancherla P, Ghossein RA, Carlson DL. Teratocarcinosarcoma of the nasal cavity and paranasal sinuses: report of 3 cases with assessment for chromosome 12p status. Hum Pathol 2008;39:605-9. [6] Vranic S, Caughron SK, Djuricic S, Bilalovic N, Zaman S, Suljevic I, et al. Hamartomas, teratomas and teratocarcinosarcomas of the head and neck: report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis and review of the literature. BMC Ear Nose Throat Disord 2008;8:8-18. [7] Bell DM, Porras G, Tortoledo ME, Luna MA. Primary sinonasal choriocarcinoma. Ann Diagn Pathol 2009;13:96-100. [8] Filho BC, McHugh JB, Carrau RL, Kassam AB. Yolk sac tumor in the nasal cavity. Am J Otolaryngol 2008;29:250-4. Epub 2008. [9] Kim TH, Lee HM, Lee SH, Choe H, Kim HK, Lee JH, et al. Expression and distribution pattern of the stem cell marker, nestin, and the stem cell renewal factor, BMI-1, in normal human nasal mucosa and nasal polyps. Acta Otolaryngol 2008:1-6. [10] Iwai N, Zhou Z, Roop DR, Behringer RR. Horizontal basal cells are multipotential progenitors in normal and injured adult olfactory epithelium. Stem Cells 2008;26:1298-306. [11] Okita T, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007;448:313-7. [12] Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development 2009;136:509-23. [13] Carey BW, Markoulaki S, Hanna J, Saha K, Gao Q, Mitalipova M. Reprogramming of murine and human somatic cells using a single polycistronic vector. Proc Natl Acad Sci 2009;106:157-62.