BRIEF REPORT
Anaplastic Thyroid Carcinoma With Rhabdoid Features Gong Feng, M.D., William B. Laskin, M.D., Pauline M. Chou, M.D., and Xiaoqi Lin, M.D., Ph.D.*
Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive neoplasm, characterized by complete or partial composition by undifferentiated cells. We report a case of ATC with rhabdoid features in a 68-year-old male, who presented with a rapidly enlarging neck mass. Fine-needle aspiration (FNA) of the thyroid mass showed discohesive, pleomorphic round to polygonal rhabdoid cells with one to multiple eccentric, large, rounded nuclei with a prominent nucleolus, moderate to abundant, globoid cytoplasm which oftentimes harbor a pale para-nuclear inclusion. The cytoplasm of some cells contained variously sized, eosinophilic granules. Rare cells contained neutrophils in their cytoplasm. Mitoses including atypical mitotic figures and necrosis were readily seen. Histologic examination of needle core biopsy (NCB) revealed individual dispersed and sheets of pleomorphic neoplastic cells with similar cytomorphologic features as described above. The tumor extensively infiltrated a myxocollagenous stroma containing lymphocytes and neutrophils, and demonstrated foci of necrosis. Tumor cells were immunoreactive for keratins AE1/AE3, CAM5.2, and CK19; PAX-8, and p63, but negative for S-100, HMB-45, calcitonin, TTF-1, thyroglobulin, CD56, HBME-1, glypican-3, PAX-5, myogenin, CD31, and INI1. The differential diagnosis of this malignant rhabdoid tumor is discussed. Diagn. Cytopathol. 2015;00:000–000. VC 2015 Wiley Periodicals, Inc.
Key Words: anaplastic thyroid carcinoma; fine-needle aspiration; cytology; rhabdoid cells; immunohistochemicstry
Anaplastic (undifferentiated) thyroid carcinoma (ATC) is a rare, highly aggressive subtype of thyroid carcinoma composed completely or partially of undifferentiated cells exhibiting electron microscopic or immunohistochemical
Department of Pathology, Northwestern University, Chicago, Illinois *Correspondence to: Xiaoqi Lin, M.D., Ph.D., Department of Pathology, Feinberg School of Medicine, Northwestern University, 251 E. Huron St., Galter Pavilion 7-132F, Chicago, IL 60611, USA. E-mail: [email protected]. Received 18 September 2014; Revised 25 November 2014; Accepted 17 December 2014 DOI: 10.1002/dc.23254 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). C 2015 WILEY PERIODICALS, INC. V
evidence of epithelial differentiation.1 It usually occurs in elderly female patients.1 Clinically, most of patients with ATC present with a rapidly enlarging neck mass with local compressive symptoms.1–3 Both cervical adenopathy and distal metastasis have been documented in more than 40% of patients at the time of diagnosis. Diagnosis of ATC is often made based on the clinical presentation, biochemical profile, radiograph, light microscopic, and immunohistochemical features. The pathologic diagnosis and primary tumor-lymph node-metastasis (TNM) staging of the tumor help physicians to tailor treatment plans for the patients, which often include a combination of radiotherapy, chemotherapy, and surgery. Clinically, the initial diagnosis of ATC is usually made by fine-needle aspiration (FNA), which renders an accurate diagnosis in 90% patients.4 Core biopsy is performed to obtain diagnostic tissue, when FNA fails to provide an adequate specimen, and open biopsy is reserved as the last diagnostic modality. FNA aspirates of ATC are often highly cellular and yield neoplastic cells that are commonly spindled cell, pleomorphic giant cell, or squaPaucicellular and lymphocyte-rich moid.1–4 lymphoepithelioma-like aspirates have also been reported.1,2 In all instances, the cells comprising the tumor show marked nuclear pleomorphism with coarsely clumped chromatin and bizarre nucleoli,1,4 and numerous mitotic figures with presence of atypical forms. In this report, we detail the features of an ATC with rhabdoid features diagnosed on FNA cytology and needle core biopsy (NCB).
Case Presentation Clinical Findings Our patient was a 68-year-old male who presented with a 1-month history of a rapidly progressive anteroinferior neck mass associated with ear pain, sore throat, voice change, dysphagia with solid food and large pills, and Diagnostic Cytopathology, Vol. 00, No 00
1
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FENG ET AL.
difficulty breathing when supine. Physical examination revealed a large, firm, fixed thyroid mass, which was mildly tender to palpation. CT scan revealed a 10.5 cm left thyroid mass with focal necrosis, which displaced the trachea toward the right, encased the left common carotid artery, abutted the left subclavian artery and the superior margin of the proximal aortic arch, and extended into the thoracic inlet and anterior mediastinum. There were innumerable small pulmonary metastases (largest, 1.1 cm). Patient’s carcinoantigens, thyroid-stimulating hormone (TSH)-3rd generation, and calcitonin level were within normal range. Patient underwent FNA and NCB. He passed away 1 month after diagnosis.
eccentric, rounded nuclei containing a prominent nucleolus, and moderate to abundant, globoid cytoplasm which oftentimes harbored a pale para-nuclear inclusion (rhabdoid) (Figs. C-1A–C). The cytoplasm of some cells stained dense blue in the center and pale peripherally or pale in the center and dense blue peripherally, and contained variously sized, eosinophilic granules. Rare cells contained neutrophils in their cytoplasm. Mitoses including atypical mitotic figures were readily seen. Abundant neutrophils, myxoid stroma, and necrotic debris were noted in the background. FNA cytology diagnosis was “high grade malignant neoplasm with rhabdoid/plasmacytoid features.”
FNA and Needle Core Biopsy
NCB Histology
An ultrasound-guided FNA biopsy with 25-gauge needles and NCB with 20-gauge needles of the thyroid mass were performed. FNA smears were stained with Diff-Quik stain on-site for specimen adequacy and preliminary diagnosis. Cores were fixed in 10% formalin, processed under standard procedure, and stained with hematoxylin and eosin (H&E) stain.
Histologic examination of NCB revealed individually dispersed and sheets of pleomorphic neoplastic cells with similar cytomorphologic features as described above, notably eccentric round nuclei with coarse chromatin and a central, distinct nucleolus; and abundant cytoplasm with spherical pale paranuclear inclusions (Fig. C-1D). Some neoplastic cells had more delicate cytoplasm or intracytoplasmic neutrophils. The tumor extensively infiltrated an inflammatory myxocollagenous stroma containing lymphocytes and neutrophils. Foci of necrosis were readily identified.
Immunohistochemical Staining Formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, and blocked with methanolic 3% hydrogen peroxide. The immunohistochemical (IHC) stains for keratin AE1/AE3 (M3515, DakoCytomation, Carpinteria, CA), keratin CAM5.2 (349205, BD Biosciences, San Jose, CA), CK19 (M0888, DakoCytomation, Carpinteria, CA), PAX-8 (CP379, Biocare, Concord, CA), p63 (463M-16, Cell Marque, Rocklin, CA), S-100 (7902914, Ventana, Tucson, ZA), HMB-45 (M0634, DakoCytomation, Carpinteria, CA), calcitonin (A0576, DakoCytomation, Carpinteria, CA), thyroglobulin (A0251, DakoCytomation, Carpinteria, CA), TTF-1 (343M-98, Cell Marque, Rocklin, CA), PAX-5 (312R-16, Cell Marque, Rocklin, CA), myogenin (296M-16, Cell Marque, Rocklin, CA), CD56 (NCL-CD56-504, Novocastra, UK), HBME-1 (M3505, DakoCytomation, Carpinteria, CA), glypican-3 (BO134R, BioMosaics, Burlington, VT), CD31 (M0823, DakoCytomation, Carpinteria, CA), and INI-1 (612110, San Jose, CA) were performed in an automated immunostainer with appropriate controls. After incubation with the primary antibodies, the detection was performed with Iview DAB detection kit (Catalog number 760-091, Ventana, Tucson, AZ). Tumor with more than 10% tumor cells showing moderate to strong staining was considered as positive.
Results FNA Cytology FNA smears showed discohesive, pleomorphic, round to polygonal epithelioid cells with one or more, large, 2
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Immunohistochemistry and Chemical (IHC) Staining Tumor cells were immunoreactive for keratins AE1/AE3, CAM5.2, and CK19 (Fig. C-1E); PAX-8 (Fig. C-1F), p63 (Fig. C-1G), and INI-1, but negative for S-100, HMB-45, calcitonin, thyroglobulin, CD56, HBME-1, glypican-3, TTF-1, PAX-5, myogenin (Fig. C-1H), and CD31.
Discussion In this report, we described an ATC with rhabdoid features. In the adult population, the rhabdoid phenotype is considered a morphologic progression of tumors of diverse tissue histotype to a higher grade, more aggressive neoplasms. ATC with rhabdoid features is extremely rare.5 Therefore, the differential diagnosis of such a tumor is broad and includes “dedifferentiated” carcinomas, melanomas, medullary carcinoma of the thyroid, medullary carcinoma of the kidney, and variety of sarcomas. ATC with rhabdoid cells has the potential to mimic sarcomas with rhabdoid features, such as rhabdomyosarcoma, proximal-type epithelioid sarcoma, high-grade synovial sarcomas, and malignant epithelioid peripheral nerve sheath tumor. Although true primary sarcoma of thyroid is extremely unusual,1 blood-borne metastases can occur. Commonly used IHC markers for demonstrating vascular differentiation (CD31 and CD34), muscular differentiation (desmin, myogenin, myo-D1, smooth muscle actin, caldesmon), and peripheral nerve sheath tumor
Diagnostic Cytopathology DOI 10.1002/dc
ATC WITH RHABDOID FEATURES
Fig. C-1. Fine-needle aspiration cytology, needle core biopsy histology, and immunostains of anaplastic thyroid carcinoma. A–C: Fine-needle aspiration cytology, Diff-Quik stain, 2003, 4003, and 4003. D: Needle-core biopsy histology, H&E stain, 4003. E: Immunostain for CK19, 4003. F: Immunostain for PAX-8, 4003. G: Immunostain for p63, 4003. H: Immunostain for myogenin, 4003.
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(S100 and CD57) are powerful tools in distinguishing ATC from sarcomas.1 In our case, IHC studies showed positive staining with epithelial markers, keratins AE1/ AE3, CAM 5.2, and CK19. These keratins can be expressed in synovial sarcoma, epithelioid sarcoma, and epithelioid angiosarcoma, but presence of PAX-8 and p63 militate against these latter diagnoses and favor ATC. Rhabdoid melanoma is a rare variant of malignant melanoma.6–8 In addition, melanoma can show multinucleated giant cells, and pleomorphic epithelioid and spindle cells, further mimicking ATC. Clinically, thyroid is not a common site for melanoma metastasis. The most common initial presentation for metastatic melanoma in thyroid is a solitary nodule or multinodular goiter.9 Cytologically and histologically, the presence of melanin pigment in the tumor cytoplasm is helpful to distinguish melanoma from ATC. Core biopsy and cellblock for histologic examination and IHC studies for melanocyterelated markers (S-100, HMB-45, MART-1/melan A, SOX10, and MITF) and thyroid-related markers (TTF-1, thyroglobin, and PAX-8) are helpful for differential diagnosis,7 especially when tumor is composed almost entirely of rhabdoid cells. In our case, the tumor cells are immunonegative for S-100 and HMB-45, but immunoreactive for PAX-8 and p63. This immunoprofile excludes melanoma. Plasmacytoid features in medullary carcinoma overlap with a rhabdoid tumor. Patient with medullary carcinoma may show hypercalcemia and elevated serum level of calcitonin, or exhibit manifestations of MEN II. In contrast to the nuclei of medullary carcinoma which commonly have stippled chromatin and inconspicuous nucleoli,1,10,11 the nuclei of ATC possess coarse chromatin and have prominent nucleoli. In addition, IHC studies for calcitonin and other less specific neuroendocrine markers,1,10,11 PAX-8, and p63 will be helpful in separating the two entities. Apart from low-molecular-weight keratin and vimentin, which represent the two most commonly expressed proteins in rhabdoid cells of anaplastic thyroid carcinoma,12 immunomarkers TTF-1, PAX-8, and INI1 are especially relevant to the topic under discussion. As more specific markers of thyroid origin, TTF-1 and PAX-8 immunoexpression have been reported in large surgical pathology series in 6–57%, and 0–79% of cases of anaplastic thyroid carcinoma, respectively.13–20 However, these more comprehensive studies did not specifically address thyroid tumors with a rhabdoid phenotype. Agarwal et al. found TTF-1 expression in the rhabdoid component of a poorly differentiated thyroid carcinoma.21 The only report in the English language literature examining PAX-8 immunoexpression in rhabdoid thyroid carcinoma cells failed to identify expression of the transcriptional factor in five cytology specimens tested.22 To our knowledge, we are the first group to report diffuse expression of PAX-8 in a 4
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case of anaplastic thyroid carcinoma with a rhabdoid phenotype. Immunoexpression of SMARCB1 (INI1), the ATPasedependent chromatic remodeling and transcriptional regulating protein complex, is characteristically lost in primary childhood malignant rhabdoid tumors due to bialleic deletions or mutations in INI1 on chromosome 22.23 In adults, the status of INI1 expression helps distinguish composite rhabdoid tumors where a rhabdoid cell component, pathogenetically related to primary childhood malignant rhabdoid tumor, coexists with a more differentiated malignancy and shows loss of INI1 expression, from a poorly differentiated carcinoma with rhabdoid phenotype, in which the protein is expressed.12,24 Our case showed nuclear expression of INI1, which is in keeping with the current experience of other investigators regarding rhabdoid cells in thyroid tumors.23 In summary, the clinicopathologic findings in our case support the diagnosis of ATC. ATC is a rare tumor, and the presence of rhabdoid feature complicates the diagnosis. Tumors with rhabdoid morphology should be considered in the differential diagnosis. Clinical findings coupled with cytologic and histologic analyses, and a broad IHC profile including cytokeratin, PAX-8, and p63 are required to arrive at the correct diagnosis.
References 1. Ordonez N, Baloch Z, Matrias-Guiu X, et al. Undifferentiated (anaplastic) carcinoma. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization Classification of tumours: Pathology & genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. p. 77–80. 2. Are C, Shaha AR. Anaplastic thyroid carcinoma: Biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006;13:453–464. 3. Nagaiah G, Hossain A, Mooney CJ, Parmentier J, Remick SC. Anaplastic thyroid cancer: A review of epidemiology, pathogenesis, and treatment. J Oncol. 2011;2011:542358. 4. Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012;22:1104–1139. 5. Lai ML, Faa G, Serra S, et al. Rhabdoid tumor of the thyroid gland: A variant of anaplastic carcinoma. Arch Pathol Lab Med 2005;129:e55–e57. 6. Rongioletti F, Smoller BR. Unusual histological variants of cutaneous malignant melanoma with some clinical and possible prognostic correlations. J Cutan Pathol 2005;32:589–603. 7. Abbott JJ, Amirkhan RH, Hoang MP. Malignant melanoma with a rhabdoid phenotype: Histologic, immunohistochemical, and ultrastructural study of a case and review of the literature. Arch Pathol Lab Med 2004;128:686–688. 8. Gavino AC, Gillies EM. Metastatic rhabdoid melanoma: Report of a case with a comparative review of the literature. J Cutan Pathol 2008;35:337–342. 9. Srivatsa S, Rhee MK. Metastatic melanoma presenting as a thyroid nodule in a 38-year-old woman. Hosp Physician 2009;45: 39–41. 10. Mehdi G, Maheshwari V, Ansari HA, Sadaf L, Khan MA. FNAC diagnosis of medullary carcinoma thyroid: A report of three cases with review of literature. J Cytol 2010;27:66–68.
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ATC WITH RHABDOID FEATURES 11. Pusztaszeri MP, Bongiovanni M, Faquin WC. Update on the cytologic and molecular features of medullary thyroid carcinoma. Adv Anat Pathol 2013;21:26–35.
18. Chernock RD, El-Mofty SK, Becker N, Lewis JS, Jr. Napsin A expression in anaplastic, poorly differentiated, and micropapillary pattern thyroid carcinomas. Am J Surg Pathol 2013;37:1215–1222.
12. Sato K, Waseda R, Tatsuzawa Y, Soma R, Ueda Y, Katsuda S. Papillary thyroid carcinoma with anaplastic transformation showing a rhabdoid phenotype solely in the cervical lymph node metastasis. Pathol Res Pract 2006;202:55–59.
19. Becker N, Chernock RD, Nussenbaum B, Lewis JS, Jr. Prognostic significance of beta-human chorionic gonadotropin and PAX8 expression in anaplastic thyroid carcinoma. Thyroid 2014;24: 319–326.
13. Miettinen M, Franssila KO. Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma. Hum Pathol 2000;31:1139–1145.
20. Toner M, Banville N, Timon CI. Laryngotracheal presentation of anaplastic thyroid carcinoma with squamous differentiation: Seven cases demonstrating an under-recognized diagnostic pitfall. Histopathology 2014;65:501–507.
14. Puglisi F, Cesselli D, Damante G, Pellizzari L, Beltrami CA, Di Loreto C. Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer Res 2000;20:311–316. 15. Zhang P, Zuo H, Nakamura Y, Nakamura M, Wakasa T, Kakudo K. Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors. Pathol Int 2006;56:240–245. 16. Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R. Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol 2008;21: 192–200. 17. Bishop JA, Sharma R, Westra WH. PAX8 immunostaining of anaplastic thyroid carcinoma: A reliable means of discerning thyroid origin for undifferentiated tumors of the head and neck. Hum Pathol 2011;42:1873–1877.
21. Agarwal S, Sharma MC, Aron M, Sarkar C, Agarwal N, Chumber S. Poorly differentiated thyroid carcinoma with rhabdoid phenotype: A diagnostic dilemma—Report of a rare case. Endocr Pathol 2006; 17:399–405. 22. Rivera M, Sang C, Gerhard R, Ghossein R, Lin O. Anaplastic thyroid carcinoma: Morphologic findings and PAX-8 expression in cytology specimens. Acta Cytol 2010;54:668–672. 23. Agaimy A. The expanding family of SMARCB1(INI1)-deficient neoplasia: Implications of phenotypic, biological, and molecular heterogeneity. Adv Anat Pathol 2014;21:394–410. 24. Ogino S, Ro TY, Redline RW. Malignant rhabdoid tumor: A phenotype? An entity?—A controversy revisited. Adv Anat Pathol 2000;7:181–l90.
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Anaplastic Thyroid Carcinoma With Rhabdoid Features Gong Feng, M.D., William B. Laskin, M.D., Pauline M. Chou, M.D., and Xiaoqi Lin, M.D., Ph.D.*
Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive neoplasm, characterized by complete or partial composition by undifferentiated cells. We report a case of ATC with rhabdoid features in a 68-year-old male, who presented with a rapidly enlarging neck mass. Fine-needle aspiration (FNA) of the thyroid mass showed discohesive, pleomorphic round to polygonal rhabdoid cells with one to multiple eccentric, large, rounded nuclei with a prominent nucleolus, moderate to abundant, globoid cytoplasm which oftentimes harbor a pale para-nuclear inclusion. The cytoplasm of some cells contained variously sized, eosinophilic granules. Rare cells contained neutrophils in their cytoplasm. Mitoses including atypical mitotic figures and necrosis were readily seen. Histologic examination of needle core biopsy (NCB) revealed individual dispersed and sheets of pleomorphic neoplastic cells with similar cytomorphologic features as described above. The tumor extensively infiltrated a myxocollagenous stroma containing lymphocytes and neutrophils, and demonstrated foci of necrosis. Tumor cells were immunoreactive for keratins AE1/AE3, CAM5.2, and CK19; PAX-8, and p63, but negative for S-100, HMB-45, calcitonin, TTF-1, thyroglobulin, CD56, HBME-1, glypican-3, PAX-5, myogenin, CD31, and INI1. The differential diagnosis of this malignant rhabdoid tumor is discussed. Diagn. Cytopathol. 2015;00:000–000. VC 2015 Wiley Periodicals, Inc.
Key Words: anaplastic thyroid carcinoma; fine-needle aspiration; cytology; rhabdoid cells; immunohistochemicstry
Anaplastic (undifferentiated) thyroid carcinoma (ATC) is a rare, highly aggressive subtype of thyroid carcinoma composed completely or partially of undifferentiated cells exhibiting electron microscopic or immunohistochemical
Department of Pathology, Northwestern University, Chicago, Illinois *Correspondence to: Xiaoqi Lin, M.D., Ph.D., Department of Pathology, Feinberg School of Medicine, Northwestern University, 251 E. Huron St., Galter Pavilion 7-132F, Chicago, IL 60611, USA. E-mail: [email protected]. Received 18 September 2014; Revised 25 November 2014; Accepted 17 December 2014 DOI: 10.1002/dc.23254 Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com). C 2015 WILEY PERIODICALS, INC. V
evidence of epithelial differentiation.1 It usually occurs in elderly female patients.1 Clinically, most of patients with ATC present with a rapidly enlarging neck mass with local compressive symptoms.1–3 Both cervical adenopathy and distal metastasis have been documented in more than 40% of patients at the time of diagnosis. Diagnosis of ATC is often made based on the clinical presentation, biochemical profile, radiograph, light microscopic, and immunohistochemical features. The pathologic diagnosis and primary tumor-lymph node-metastasis (TNM) staging of the tumor help physicians to tailor treatment plans for the patients, which often include a combination of radiotherapy, chemotherapy, and surgery. Clinically, the initial diagnosis of ATC is usually made by fine-needle aspiration (FNA), which renders an accurate diagnosis in 90% patients.4 Core biopsy is performed to obtain diagnostic tissue, when FNA fails to provide an adequate specimen, and open biopsy is reserved as the last diagnostic modality. FNA aspirates of ATC are often highly cellular and yield neoplastic cells that are commonly spindled cell, pleomorphic giant cell, or squaPaucicellular and lymphocyte-rich moid.1–4 lymphoepithelioma-like aspirates have also been reported.1,2 In all instances, the cells comprising the tumor show marked nuclear pleomorphism with coarsely clumped chromatin and bizarre nucleoli,1,4 and numerous mitotic figures with presence of atypical forms. In this report, we detail the features of an ATC with rhabdoid features diagnosed on FNA cytology and needle core biopsy (NCB).
Case Presentation Clinical Findings Our patient was a 68-year-old male who presented with a 1-month history of a rapidly progressive anteroinferior neck mass associated with ear pain, sore throat, voice change, dysphagia with solid food and large pills, and Diagnostic Cytopathology, Vol. 00, No 00
1
Diagnostic Cytopathology DOI 10.1002/dc
FENG ET AL.
difficulty breathing when supine. Physical examination revealed a large, firm, fixed thyroid mass, which was mildly tender to palpation. CT scan revealed a 10.5 cm left thyroid mass with focal necrosis, which displaced the trachea toward the right, encased the left common carotid artery, abutted the left subclavian artery and the superior margin of the proximal aortic arch, and extended into the thoracic inlet and anterior mediastinum. There were innumerable small pulmonary metastases (largest, 1.1 cm). Patient’s carcinoantigens, thyroid-stimulating hormone (TSH)-3rd generation, and calcitonin level were within normal range. Patient underwent FNA and NCB. He passed away 1 month after diagnosis.
eccentric, rounded nuclei containing a prominent nucleolus, and moderate to abundant, globoid cytoplasm which oftentimes harbored a pale para-nuclear inclusion (rhabdoid) (Figs. C-1A–C). The cytoplasm of some cells stained dense blue in the center and pale peripherally or pale in the center and dense blue peripherally, and contained variously sized, eosinophilic granules. Rare cells contained neutrophils in their cytoplasm. Mitoses including atypical mitotic figures were readily seen. Abundant neutrophils, myxoid stroma, and necrotic debris were noted in the background. FNA cytology diagnosis was “high grade malignant neoplasm with rhabdoid/plasmacytoid features.”
FNA and Needle Core Biopsy
NCB Histology
An ultrasound-guided FNA biopsy with 25-gauge needles and NCB with 20-gauge needles of the thyroid mass were performed. FNA smears were stained with Diff-Quik stain on-site for specimen adequacy and preliminary diagnosis. Cores were fixed in 10% formalin, processed under standard procedure, and stained with hematoxylin and eosin (H&E) stain.
Histologic examination of NCB revealed individually dispersed and sheets of pleomorphic neoplastic cells with similar cytomorphologic features as described above, notably eccentric round nuclei with coarse chromatin and a central, distinct nucleolus; and abundant cytoplasm with spherical pale paranuclear inclusions (Fig. C-1D). Some neoplastic cells had more delicate cytoplasm or intracytoplasmic neutrophils. The tumor extensively infiltrated an inflammatory myxocollagenous stroma containing lymphocytes and neutrophils. Foci of necrosis were readily identified.
Immunohistochemical Staining Formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, and blocked with methanolic 3% hydrogen peroxide. The immunohistochemical (IHC) stains for keratin AE1/AE3 (M3515, DakoCytomation, Carpinteria, CA), keratin CAM5.2 (349205, BD Biosciences, San Jose, CA), CK19 (M0888, DakoCytomation, Carpinteria, CA), PAX-8 (CP379, Biocare, Concord, CA), p63 (463M-16, Cell Marque, Rocklin, CA), S-100 (7902914, Ventana, Tucson, ZA), HMB-45 (M0634, DakoCytomation, Carpinteria, CA), calcitonin (A0576, DakoCytomation, Carpinteria, CA), thyroglobulin (A0251, DakoCytomation, Carpinteria, CA), TTF-1 (343M-98, Cell Marque, Rocklin, CA), PAX-5 (312R-16, Cell Marque, Rocklin, CA), myogenin (296M-16, Cell Marque, Rocklin, CA), CD56 (NCL-CD56-504, Novocastra, UK), HBME-1 (M3505, DakoCytomation, Carpinteria, CA), glypican-3 (BO134R, BioMosaics, Burlington, VT), CD31 (M0823, DakoCytomation, Carpinteria, CA), and INI-1 (612110, San Jose, CA) were performed in an automated immunostainer with appropriate controls. After incubation with the primary antibodies, the detection was performed with Iview DAB detection kit (Catalog number 760-091, Ventana, Tucson, AZ). Tumor with more than 10% tumor cells showing moderate to strong staining was considered as positive.
Results FNA Cytology FNA smears showed discohesive, pleomorphic, round to polygonal epithelioid cells with one or more, large, 2
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Immunohistochemistry and Chemical (IHC) Staining Tumor cells were immunoreactive for keratins AE1/AE3, CAM5.2, and CK19 (Fig. C-1E); PAX-8 (Fig. C-1F), p63 (Fig. C-1G), and INI-1, but negative for S-100, HMB-45, calcitonin, thyroglobulin, CD56, HBME-1, glypican-3, TTF-1, PAX-5, myogenin (Fig. C-1H), and CD31.
Discussion In this report, we described an ATC with rhabdoid features. In the adult population, the rhabdoid phenotype is considered a morphologic progression of tumors of diverse tissue histotype to a higher grade, more aggressive neoplasms. ATC with rhabdoid features is extremely rare.5 Therefore, the differential diagnosis of such a tumor is broad and includes “dedifferentiated” carcinomas, melanomas, medullary carcinoma of the thyroid, medullary carcinoma of the kidney, and variety of sarcomas. ATC with rhabdoid cells has the potential to mimic sarcomas with rhabdoid features, such as rhabdomyosarcoma, proximal-type epithelioid sarcoma, high-grade synovial sarcomas, and malignant epithelioid peripheral nerve sheath tumor. Although true primary sarcoma of thyroid is extremely unusual,1 blood-borne metastases can occur. Commonly used IHC markers for demonstrating vascular differentiation (CD31 and CD34), muscular differentiation (desmin, myogenin, myo-D1, smooth muscle actin, caldesmon), and peripheral nerve sheath tumor
Diagnostic Cytopathology DOI 10.1002/dc
ATC WITH RHABDOID FEATURES
Fig. C-1. Fine-needle aspiration cytology, needle core biopsy histology, and immunostains of anaplastic thyroid carcinoma. A–C: Fine-needle aspiration cytology, Diff-Quik stain, 2003, 4003, and 4003. D: Needle-core biopsy histology, H&E stain, 4003. E: Immunostain for CK19, 4003. F: Immunostain for PAX-8, 4003. G: Immunostain for p63, 4003. H: Immunostain for myogenin, 4003.
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(S100 and CD57) are powerful tools in distinguishing ATC from sarcomas.1 In our case, IHC studies showed positive staining with epithelial markers, keratins AE1/ AE3, CAM 5.2, and CK19. These keratins can be expressed in synovial sarcoma, epithelioid sarcoma, and epithelioid angiosarcoma, but presence of PAX-8 and p63 militate against these latter diagnoses and favor ATC. Rhabdoid melanoma is a rare variant of malignant melanoma.6–8 In addition, melanoma can show multinucleated giant cells, and pleomorphic epithelioid and spindle cells, further mimicking ATC. Clinically, thyroid is not a common site for melanoma metastasis. The most common initial presentation for metastatic melanoma in thyroid is a solitary nodule or multinodular goiter.9 Cytologically and histologically, the presence of melanin pigment in the tumor cytoplasm is helpful to distinguish melanoma from ATC. Core biopsy and cellblock for histologic examination and IHC studies for melanocyterelated markers (S-100, HMB-45, MART-1/melan A, SOX10, and MITF) and thyroid-related markers (TTF-1, thyroglobin, and PAX-8) are helpful for differential diagnosis,7 especially when tumor is composed almost entirely of rhabdoid cells. In our case, the tumor cells are immunonegative for S-100 and HMB-45, but immunoreactive for PAX-8 and p63. This immunoprofile excludes melanoma. Plasmacytoid features in medullary carcinoma overlap with a rhabdoid tumor. Patient with medullary carcinoma may show hypercalcemia and elevated serum level of calcitonin, or exhibit manifestations of MEN II. In contrast to the nuclei of medullary carcinoma which commonly have stippled chromatin and inconspicuous nucleoli,1,10,11 the nuclei of ATC possess coarse chromatin and have prominent nucleoli. In addition, IHC studies for calcitonin and other less specific neuroendocrine markers,1,10,11 PAX-8, and p63 will be helpful in separating the two entities. Apart from low-molecular-weight keratin and vimentin, which represent the two most commonly expressed proteins in rhabdoid cells of anaplastic thyroid carcinoma,12 immunomarkers TTF-1, PAX-8, and INI1 are especially relevant to the topic under discussion. As more specific markers of thyroid origin, TTF-1 and PAX-8 immunoexpression have been reported in large surgical pathology series in 6–57%, and 0–79% of cases of anaplastic thyroid carcinoma, respectively.13–20 However, these more comprehensive studies did not specifically address thyroid tumors with a rhabdoid phenotype. Agarwal et al. found TTF-1 expression in the rhabdoid component of a poorly differentiated thyroid carcinoma.21 The only report in the English language literature examining PAX-8 immunoexpression in rhabdoid thyroid carcinoma cells failed to identify expression of the transcriptional factor in five cytology specimens tested.22 To our knowledge, we are the first group to report diffuse expression of PAX-8 in a 4
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case of anaplastic thyroid carcinoma with a rhabdoid phenotype. Immunoexpression of SMARCB1 (INI1), the ATPasedependent chromatic remodeling and transcriptional regulating protein complex, is characteristically lost in primary childhood malignant rhabdoid tumors due to bialleic deletions or mutations in INI1 on chromosome 22.23 In adults, the status of INI1 expression helps distinguish composite rhabdoid tumors where a rhabdoid cell component, pathogenetically related to primary childhood malignant rhabdoid tumor, coexists with a more differentiated malignancy and shows loss of INI1 expression, from a poorly differentiated carcinoma with rhabdoid phenotype, in which the protein is expressed.12,24 Our case showed nuclear expression of INI1, which is in keeping with the current experience of other investigators regarding rhabdoid cells in thyroid tumors.23 In summary, the clinicopathologic findings in our case support the diagnosis of ATC. ATC is a rare tumor, and the presence of rhabdoid feature complicates the diagnosis. Tumors with rhabdoid morphology should be considered in the differential diagnosis. Clinical findings coupled with cytologic and histologic analyses, and a broad IHC profile including cytokeratin, PAX-8, and p63 are required to arrive at the correct diagnosis.
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