THYROID Volume 24, Number 8, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/thy.2013.0586
Noninvasive Anaplastic Thyroid Carcinoma: Report of a Case and Literature Review Gregory Dibelius,1 Saral Mehra,2 Jason B. Clain,3 Mark L. Urken,4 and Bruce M. Wenig 5
Anaplastic thyroid carcinoma (ATC) is an uncommon thyroid malignancy. Noninvasive ATC is a rare, surgically resectable variant with only four reported cases. We report a case of an 81-year-old man who presented with a 3.1 cm right thyroid lobe mass that on fine-needle aspiration biopsy was diagnosed as an ATC. Preoperative imaging revealed an encapsulated thyroid tumor without evidence of invasion of surrounding structures and no locoregional and distant metastases. A total thyroidectomy was performed that by histologic and immunohistochemical evaluation was diagnostic for a noninvasive ATC. Given the diagnosis of noninvasive ATC, adjuvant therapy was not administered. At 14 months following diagnosis, the patient remains disease free based on positron emission tomography/computed tomography imaging. A review of the outcomes of similar cases reported in the literature, as well as observations from our case, suggest a favorable prognosis for patients with noninvasive ATC. Noninvasive ATC may represent a distinct subset of resectable ATCs with an improved prognosis. The recently published American Thyroid Association (ATA) Guidelines for Management of Patients with ATC do not include this specific form of ATC. We encourage other authors to report similar cases in order to determine whether noninvasive ATC should be considered as a separate disease entity from the traditional highly lethal form of ATC.
Introduction
A
naplastic thyroid carcinoma (ATC) is a rare form of thyroid carcinoma that is frequently associated with an aggressive clinical course often resulting in rapid patient demise. ATC typically presents with diffuse local invasion and/or metastasis. All ATCs are considered stage IV disease according to the American Joint Committee on Cancer (AJCC) staging system (1). Median overall survival is reported to be as poor as three to five months, with 1- and 10year overall survival reported at 10–20% and less than 5% respectively (2). The American Thyroid Association (ATA) has recently published consensus guidelines for the management of ATC that recommend an aggressive approach to the diagnosis and treatment of this disease (3); these guidelines are based on multiple studies demonstrating an improved survival outcome with complete surgical resection. Accordingly, resectability, as defined by the AJCC Residual Tumor (R) Classification, features prominently in clinical decision making in the management of patients presenting with locoregional disease (3). 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Among ATC patients presenting with locoregional disease, a minority have disease confined to the thyroid (T4a) (3–5). Furthermore these lesions are infrequently discovered after surgical resection of a known well-differentiated thyroid cancer, an entity described as ‘‘incidental ATC’’ (3,6,7). These patients represent a subset of ATC that is highly resectable. Unfortunately, given the small size of this patient population, no meaningful data exist regarding the significance of the extent of thyroidectomy (total or subtotal vs. lobectomy) or the role of surgical resection versus multimodality therapy (3). However, improved survival following complete resection is consistently demonstrated across studies analyzing prognostic factors in ATC (4,6,8–12). There are a small number of reports within the surgical literature that describe a subset of T4a tumors characterized by complete encapsulation of the neoplasm without invasive growth (3,4,13–16). These noninvasive variants of ATC are rare and may portend favorable outcomes, though they are not explicitly recognized or addressed in the ATA guidelines. We describe a case of pathologically proven encapsulated ATC without invasive growth (noninvasive ATC) and review
Otolaryngology, The New York Eye and Ear Infirmary, New York, New York. Otolaryngology—Head and Neck Surgery, Yale School of Medicine, New Haven, Connecticut. Otolaryngology, THANC Foundation, New York, New York. Otolaryngology—Head and Neck Surgery, Beth Israel Medical Center, New York, New York. Pathology, Beth Israel Medical Center, New York, New York.
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the literature pertaining to this less aggressive phenotype. Experience with this entity as described in the clinical literature is limited. With the tracking and reporting of similar cases, and as more experience with and understanding of the biology of this entity is accumulated, it may be useful to consider a sub-classification of noninvasive ATC separately from the traditional highly lethal form of ATC. Case Presentation
An 81-year-old man presented for the evaluation of a 3.1 cm firm right-sided neck mass. He had a remote history of smoking 20 years prior to presentation. His medical history was also significant for multiple skin cancers of the extremities and face for which he received a combination of treatments, including resection by Mohs technique and chemoradiation following surgical resection for right upper cervical nodal metastases arising from a cutaneous squamous cell carcinoma. Specifically, concomitant chemoradiation followed by definitive chemotherapy was completed 44 months prior to presentation. During the course of treatment, 41.4 Gy was delivered to the neck and supraclavicular fossa, after which treatment was coned down to boost the dose to the gross disease in the right upper posterior and right mid-neck (just superior to the right thyroid lobe) to achieve a total of 70.2 Gy in 39 fractions. Concomitant chemotherapy with 100 mg of carboplatin and 130 mg of taxol was administered weekly for three months, followed by three cycles of definitive chemotherapy with 250 mg of carboplatin (AUC = 6) and 400 mg of taxol. Imaging with combined positron emission tomography/ computed tomography (PET/CT) scan showed a hypermetabolic lesion (maximum SUV = 27.0) inseparable from the right thyroid lobe correlating with the clinically identified mass (Fig. 1). No invasion of the aerodigestive tract or carotid sheath was noted. No cervical or thoracic lymph nodes met radiographic criteria for significance. A review of imaging
DIBELIUS ET AL.
dating back to five years prior to presentation revealed the presence of a mass that had been considered extrathyroidal but possibly represents the mass in question, although it was not previously biopsied. It was noted to be hypermetabolic but demonstrated resolution of metabolic activity and decrease in size on post-treatment PET/CT. Ultrasound-guided fine-needle aspiration biopsy (FNAB) of the neck mass revealed a high grade malignancy consistent with an ATC. Gross pathology
A total thyroidectomy was performed, and the specimen was submitted for pathologic analysis. The right thyroid lobe contained a well-circumscribed mass measuring 3.1 cm · 2.8 cm · 2.4 cm that on sectioning appeared yellow to tan with areas of necrosis and a small rim of uninvolved appearing parenchyma. Grossly, there was no evidence of invasion into adjacent thyroid parenchyma and/or outside the thyroid gland proper. Microscopic pathology
At low magnification, the neoplasm was encapsulated without microscopic evidence of invasion (Fig. 2A). The neoplastic proliferation showed lymphoepithelial-like features, including diffuse growth comprised of cells with markedly pleomorphic nuclei, vesicular chromatin, and prominent nucleoli (Fig. 2B). There was increased mitotic activity, including atypical forms, and necrosis. In addition, there were areas of the neoplasm showing angiomatoid features characterized by irregular and anastomosing vascular channels lined by neoplastic cells (Fig. 2C). A sarcomatoid cellular component was not identified. Foci of a differentiated follicular epithelial cell proliferation characterized by colloid-filled follicles, and uniform-appearing nuclei lacking the high-grade histologic features were also present (Fig. 2D). Such differentiated foci
FIG. 1. Positron emission tomography/computed tomography (PET/CT) Imaging showing (A) area of abnormal hypermetabolic activity (maximum SUV = 27.0) in the right neck correlating to a (B) 3.0 · 3.5 cm hypodense neck mass inseparable from the right thyroid lobe on CT. There was no invasion of the aerodigestive tract or carotid sheath noted, and no radiographically significant lymphadenopathy.
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FIG. 2. (A) Low power magnification showing an encapsulated cellular neoplasm focally with identifiable colloid-filled follicles (upper left). The neoplasm was entirely encapsulated without evidence of invasive growth. The residual differentiated thyroid represented a coexisting follicular adenoma. (B) The neoplasm is comprised of diffuse cellular proliferation comprised of epithelioid appearing malignant neoplastic cells lacking evidence of cellular differentiation. The nuclei of the epithelioid appearing malignant neoplastic cells are markedly pleomorphic with vesicular chromatin and prominent eosinophilic nucleoli. Increased mitotic activity is present. (C) In focal areas, the neoplastic proliferation included features of an angiosarcoma characterized by ramifying and interconnecting endothelial-lined vascular spaces; there are pleomorphic and hyperchromatic nuclei as well as tufting. (D) Within the encapsulated neoplasm, there were foci of a differentiated thyroid follicular epithelial proliferation that showed features consistent with a follicular adenoma. (E) Immunohistochemical staining showed the epithelioid appearing undifferentiated malignant cells to be reactive for cytokeratin (CAM5.2). (F) Thyroglobulin staining (cytoplasmic) was present in the foci of residual follicular adenoma (lower) but absent in the undifferentiated malignancy (upper). (G) Thyroid transcription factor 1 (TTF1) staining (nuclear) was present in the foci of residual follicular adenoma (lower) but absent in the undifferentiated malignancy (upper). (H) PAX 8 staining (nuclear) was present in the foci of residual follicular adenoma (lower), as well as in the undifferentiated malignancy (upper). (I) The angiosarcomatous foci were immunoreactive for CD31 (cytoplasmic), a marker of endothelial cell differentiation. represent a residual benign lesion in the context of an encapsulated lesion and is consistent with a follicular adenoma, although the histologic similarity to the adenomatoid nodules in the left thyroid lobe raised the possibility of this differentiated lesion as representing an adenomatoid nodule. The malignant lesion represented approximately 90% of the nodule. The entire tumor was submitted for histologic evaluation and showed no evidence of invasive growth, including capsular invasion, lymphovascular invasion, invasion into the thyroid parenchyma, or extrathyroidal extension. Sections of the left thyroid lobe showed the presence of adenomatoid nodules. Multiple resected central compartment lymph nodes were negative for carcinoma. Immunohistochemical staining
The lymphoepithelial-like carcinoma component showed reactivity for cytokeratins (AE1/AE3, CAM5.2), PAX8, and
vimentin (Fig. 2E–H) but was negative for thyroglobulin, thyroid transcription factor 1 (TTF1), CD5, CD31, Factor 8related antigen, S100 protein, and HBME1. The angiomatoid component showed immunoreactivity for CD31, Factor 8related antigen, and vimentin (Fig. 2I) but was negative for cytokeratins, thyroglobulin, TTF1, PAX8, HBME1, and CD34. An increase proliferation rate of > 50% was seen by Ki67 (MIB1) staining. The differentiated component was immunoreactive for thyroglobulin, TTF1, cytokeratins (AE1/AE3, CAM5.2), PAX8, and HBME1. Numerous foamy (benign) histiocytes were present in association with the neoplastic proliferation, which showed CD68 reactivity. Based on the light microscopic and immunohistochemical findings, a diagnosis of encapsulated (noninvasive) undifferentiated (anaplastic) thyroid carcinoma arising in association with a differentiated follicular epithelial cell lesion was rendered. There was no evidence of extrathyroidal extension.
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The pTNM staging was pT4aN0MX (pT4a representing intrathyroidal anaplastic carcinoma). Treatment and follow-up
This patient underwent a total thyroidectomy without incident. He tolerated that surgery well. He underwent multidisciplinary evaluation, and the decision was made not to administer adjuvant therapy due to the noninvasive nature of this tumor, the absence of regional or distant disease, as well as the prior radiation therapy to the cervical region. At 14 months postoperatively, the patient was doing well, and remained free of disease based on PET/CT imaging. Discussion
The usual clinical scenario for ATC is that of a rapidly enlarging neck mass that is extensively invasive at the time of presentation, directly contributing to its aggressive biology and dire outcome. In this patient’s case, we found a highgrade undifferentiated malignancy that was entirely encapsulated, without invasive growth, arising in association with a differentiated follicular epithelial cell lesion that we felt represented a follicular adenoma. The relatively innocuous clinical presentation and corresponding complete encapsulation, without invasion, are quite unusual for this tumor type. However, there is a recognized subset, albeit rare, of ATC that includes encapsulated tumors (4,13–16) (Table 1). Encapsulation has been documented by a small number of case reports to be associated with an improved outcome for ATC patients. Guimara˜es et al. (14) reported the first case of an improved outcome associated with an encapsulated ATC in 2000. Their report described a 74-year-old man with a 2.6 cm lesion who remained free of disease three years after total thyroidectomy (14). Similarly, Ito et al. (15) reported a
case of a 77-year-old woman with a 7.5 cm encapsulated ATC who underwent a palliative thyroid lobectomy for tracheal deviation and remained free of disease for 57 months at the time of publication. Neither of these patients received adjuvant therapy. Rapkiewicz et al. (13) reported a case of a surgically resectable encapsulated ATC in the setting of a metastatic follicular carcinoma, who at the time of publication was alive but had developed a new pelvic-bone metastasis (13). However, no survival outcomes were reported. Voutilainen et al. (4) reported a series of 33 ATC patients in which the only survivor was a patient with a microscopic focus of ATC within an encapsulated follicular carcinoma. None of the reported cases of encapsulated ATC tumors demonstrated gross capsular invasion. However, these cases differed in the presence or extent of microinvasion of the tumor capsule. This may be a key factor underlying the clinical behavior of these encapsulated lesions. The patient reported by Rapkiewicz et al. (13), had an encapsulated ATC without gross tumor capsule invasion presenting as a metastatic rib lesion; histopathologic analysis subsequently revealed microscopic capsular and lymphovascular invasion, which may have accounted for its more aggressive clinical behavior. The patient described by Guimara˜es et al. (14) also exhibited microinvasion of the tumor capsule, as well as a small extracapsular focus of ATC microscopically invading the glandular capsule. This patient remained free of disease at 35 months. Conversely, the patient reported by Ito et al. (15) had a large (7.5 cm) encapsulated and completely noninvasive lesion, and remained free of disease at 57 months. This is interesting given that large tumor size is typically a poor prognostic indicator on univariate and multivariate analysis of thyroid carcinoma (2,7). These cases were all reported as examples of histologically encapsulated atypical ATC lesions for which prognosis might be expected to be improved.
Table 1. Summary of Literature Review Study
Study type
Tumor size
Capsule invasion
Guimara˜es et al. 2000 (Brazil) (14)
Case report
2.6 cm
Yes
Rapkiewicz et al. 2007 (United States) (13)
Case report
4.1 cm
Yes
Ito et al. 2003 ( Japan) (15)
Case report
7.5 cm
No
Voutilainen et al. 1999 (Finland) (4)
Retrospective review (n = 33)
NR
NR
Note that none of the reported lesions showed gross capsule invasion. FNA, fine-needle aspiration; NR, not reported.
Features 0.8 mm focus of ATC extending through tumor capsule 2.5 mm extracapsular focus partially through glandular capsule FNA: adenocarcinoma Lymphovascular invasion Metastatic disease Background of follicular neoplasm Background of thyroiditis and a limited follicular neoplasm FNA: follicular adenoma ATC focus within encapsulated follicular carcinoma
Outcome Free of disease at 35 months
New metastasis No survival outcomes reported Free of disease at 57 months 1 patient had a focus of ATC within an encapsulated follicular lesion; only survivor of this series at 156 months
NONINVASIVE ANAPLASTIC THYROID CARCINOMA
However, comparison of these reports reveals differences in the microscopic behavior of the described lesions that may more accurately predict their clinical and underlying biologic behavior beyond the commonality of a tumor capsule. There may be more clinical utility in regarding these histologically encapsulated ATC tumors as noninvasive or minimally invasive ATC lesions, as this nomenclature may be more reflective of their true clinical behavior. Our patient’s lesion was found to be an encapsulated, noninvasive ATC for which we might predict an improved prognosis. These case reports and series suggest an improved prognosis in patients with encapsulation as a histologic feature. The presence of a fibrotic capsule may serve to contain disease locally and partially explain observed differences in clinical behavior. Indeed, encapsulation of other thyroid malignancies has been associated with improved outcomes over their nonencapsulated counterparts, including so-called Hu¨rthle cell carcinoma (16), aggressive variants of thyroid papillary carcinoma (17,18), and poorly differentiated (insular) thyroid carcinoma (19,20). Of note, this patient’s thyroid lesion may have been present as early as five years prior to surgical resection. The fact that the tumor in the thyroid may have been ATC at that time, although it was not previously biopsied but was radiographically present five years prior to resection, adds further credence to the contention that this encapsulated variant of ATC has indeed a more favorable outcome. While one may speculate that the course of chemotherapy and radiation may have partially treated the thyroid neoplasm in a neoadjuvant fashion, it would not be considered a curative therapy, as evidenced by the fact that the disease was not eradicated by that therapy and there was no evidence of treatment effect on histologic evaluation when it was resected five years hence. In addition, the fact that it did not spread during that time frame is further evidence of its favorable biology. The majority of ATCs show sarcomatoid histologic features, but there can be a wide histologic spectrum comprised of several morphologic variants including, but not limited to, lymphoepithelial and angiomatoid variants. While the overall pathologic features in this case were those of an ATC, this patient’s neoplasm lacked sarcomatoid features but included an admixture of features that included lymphoepithelial-like carcinoma and angiomatoid variants. Some authorities feel that angiosarcomas of the thyroid represent undifferentiated carcinomas (21). Although angiosarcoma as an independent primary malignancy of the thyroid gland does occur, it may share overlapping clinical and pathologic features with undifferentiated carcinomas. However, from a practical standpoint, trying to distinguish undifferentiated carcinoma from angiosarcoma may be more of an academic matter, as the typical biologic behavior for both tumor types is extremely poor, with patient deaths occurring after short time periods irrespective of treatment (21). ATC typically occurs in association with a pre- or coexisting differentiated thyroid neoplasm that include adenomatoid nodules, follicular adenomas and carcinomas, and papillary carcinomas (3,13,22,23). In this patient’s case, we found a high-grade undifferentiated malignancy arising in association with a differentiated follicular epithelial cell lesion that we felt represented a follicular adenoma. Although the ATA guidelines do not specifically recognize noninvasive (encapsulated) or minimally invasive variants of
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ATC, incidental ATC is probably a related entity. Incidental ATC is defined as a ‘‘small, incidental finding after surgical resection of a predominantly non-anaplastic tumor’’ (3). Some of the cases of noninvasive and minimally invasive ATC described above are included in studies of this category, although others, as in our case, are identified as ATC at the time of FNAB. A large study of 677 patients with ATC treated with surgery with or without chemoradiation demonstrated a one-year cause-specific survival of 18% for common-type ATC, compared to 57% for incidental ATC (7). Whether noninvasive or minimally invasive encapsulated ATC and incidental ATC represent the same biologic continuum requires further analysis. Regardless, both represent groups of patients with initially resectable disease, the importance of which has been consistently demonstrated in the literature. The role of adjuvant therapies in improving locoregional control and/or survival in patients with resectable disease is an area in need of ongoing clinical investigation. While the literature generally supports the use of adjuvant therapies for resectable ATC, a study of 261 ATC patients in the Surveillance, Epidemiology, and End Results (SEER) database showed a survival benefit of radiotherapy for ATC with extrathyroidal extension, but not for patients with intrathyroidal ATC (24). Currently, the guidelines support cautious observation after surgical resection of incidental ATC, although the quality of evidence is low (3). Under the current staging system proposed by the AJCC, all ATC are considered T4 tumors representing stage IV disease (1). The predicted outcomes for noninvasive or minimally invasive variants of ATC may not be adequately described under this staging system. Additionally, it is conceivable that the incidence of these noninvasive or minimally invasive variants and/or incidental variants may increase going forward as the rate of surgery for differentiated thyroid cancer (DTC) increases, further underscoring the imperative for a comprehensive management strategy for resectable ATC. Conclusions
Noninvasive encapsulated ATC is an infrequently identified form of thyroid carcinoma that likely represents both a subset of patients with incidental ATC, as well as a unique pretreatment diagnosis. The few case reports and series describing this disease entity suggest improved survival outcomes as compared with the classic type of ATC. Future study separating noninvasive and minimally invasive ATC from traditional invasive ATC may help to stratify prognostic groups further, which would impact the extent of surgery and need for adjuvant therapy. Author Disclosure Statement
The authors declare that they have no competing interests. References
1. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (Eds) 2010 AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual. Seventh edition. Springer-Verlag, New York, NY. 2. Nagaiah G, Hossain A, Mooney CJ, Parmentier J, Remick SC 2011 Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. J Oncol 2011:1–13. 3. Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, Kebebew E, Lee NY, Nikiforov YE, Rosenthal
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MS, Shah MH, Shaha AR, Tuttle, RM 2012 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22:1104–1139. Voutilainen PE, Multanen M, Haapiainen RK, Leppa¨niemi AK, Sivula AH 1999 Anaplastic thyroid carcinoma survival. World J Surg 23:975–979. Besic N, Hocevar M, Zgajnar J, Pogacnik A, Grazio-Frkovic S, Auersperg M 2004 Prognostic factors in anaplastic carcinoma of the thyroid—a multivariate survival analysis of 188 patients. Langenbecks Arch Surg 390:203–208. Sugino K, Ito K, Mimura T, Nagahama M, Fukunari N, Kubo A, Iwasaki H, Ito K 2002 The important role of operations in the management of anaplastic thyroid carcinoma. Surgery 131:245–248. Sugitani I, Miyauchi A, Sugino K, Okamoto T, Yoshida A, Suzuki S 2012 Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J Surg 36:1247–1254. Haigh PI, Ituarte PH, Wu HS, Treseler PA, Posner MD, Quivey JM, Duh QY, Clark OH 2001 Completely resected anaplastic thyroid carcinoma combined with adjuvant chemotherapy and irradiation is associated with prolonged survival. Cancer 91:2335–2342. Yau T, Lo CY, Epstein RJ, Lam AKY, Wan KY, Lang BH 2008 Treatment outcomes in anaplastic thyroid carcinoma: survival improvement in young patients with localized disease treated by combination of surgery and radiotherapy. Ann Surg Oncol 15:2500–2505. Kihara M, Miyauchi A, Yamauchi A, Yokomise H 2004 Prognostic factors of anaplastic thyroid carcinoma. Surg Today 34:394–398. Passler C, Scheuba C, Prager G, Kaserer K, Flores JA, Vierhapper H, Niederle B 1999 Anaplastic (undifferentiated) thyroid carcinoma (ATC). Langenbecks Arch Surg 384:284–293. Brown RF, Ducic Y 2013 Aggressive surgical resection of anaplastic thyroid carcinoma may provide long-term survival in selected patients. Otolaryngol Head Neck Surg 148: 564–571. Rapkiewicz A, Roses D, Goldenberg A, Levine P, Bannan M, Simsir A 2009 Encapsulated anaplastic thyroid carcinoma transformed from follicular carcinoma: a case report. Acta Cytol 53:332–336. Guimara˘es L, Meneses A, Carrara W, Kefala´s A 2000: Encapsulated anaplastic thyroid carcinoma with three-year disease-free survival. Pathol Res Pract 196:867–870.
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15. Ito Y, Matsuzuka F, Yoshida H, Morita S, Nakano K, Kobayashi K, Yokozawa T, Hirai K, Kakudo K, Kuma K, Miyauchi A 2003 Encapsulated anaplastic thyroid carcinoma without invasive phenotype with favorable prognosis: report of a case. Surg Today 33:277–281. 16. Lopez-Penabad L, Chiu AC, Hoff AO, Schultz P, Gaztambide S, Ordo ez NG, Sherman SI 2003 Prognostic factors in patients with Hurthle cell neoplasms of the thyroid. Cancer 97:1186–1194. 17. Evans HL1996 Encapsulated columnar-cell neoplasms of the thyroid. A report of four cases suggesting a favorable prognosis. Am J Surg Pathol 20:1205–1211. 18. Wenig BM, Adair CF, Thompson LDR, Shmookler BM, Heffess CS 1998 Thyroid papillary carcinoma, columnar cell type: a clinicopathologic study of 16 cases. Cancer 82:740–753. 19. Hiltzik D, Carlson DL, Tuttle RM, Chuai S, Ishill N, Shaha A, Shah JP, Singh B, Ghossein RA 2006 Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer 106:1286–1295. 20. Rivera M, Ricarte-Filho J, Patel S, Tuttle M, Shaha A, Shah JP, Fagin JA, Ghossein RA 2010 Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study. Hum Pathol 41:172–180. 21. Papotti M, Arrondini M, Tavaglione V, Veltri A, Volante M 2008 Diagnostic controversies in vascular proliferations of the thyroid gland. Endocr Pathol 19:175–183. 22. Spires JR, Schwartz MR, Miller RH 1988 Anaplastic thyroid carcinoma. Association with differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg 114:40–44. 23. Nishiyama RH 2000 Overview of surgical pathology of the thyroid gland. World J Surg 24:898–906. 24. Chen J, Tward JD, Shrieve DC, Hitchcock YJ 2008 Surgery and radiotherapy improves survival in patients with anaplastic thyroid carcinoma. Am J Clin Oncol 31:460– 464.
Address correspondence to: Mark L. Urken, MD, FACS Department of Otolaryngology—Head and Neck Surgery Beth Israel Medical Center New York, NY 10003 E-mail: [email protected]
Noninvasive Anaplastic Thyroid Carcinoma: Report of a Case and Literature Review Gregory Dibelius,1 Saral Mehra,2 Jason B. Clain,3 Mark L. Urken,4 and Bruce M. Wenig 5
Anaplastic thyroid carcinoma (ATC) is an uncommon thyroid malignancy. Noninvasive ATC is a rare, surgically resectable variant with only four reported cases. We report a case of an 81-year-old man who presented with a 3.1 cm right thyroid lobe mass that on fine-needle aspiration biopsy was diagnosed as an ATC. Preoperative imaging revealed an encapsulated thyroid tumor without evidence of invasion of surrounding structures and no locoregional and distant metastases. A total thyroidectomy was performed that by histologic and immunohistochemical evaluation was diagnostic for a noninvasive ATC. Given the diagnosis of noninvasive ATC, adjuvant therapy was not administered. At 14 months following diagnosis, the patient remains disease free based on positron emission tomography/computed tomography imaging. A review of the outcomes of similar cases reported in the literature, as well as observations from our case, suggest a favorable prognosis for patients with noninvasive ATC. Noninvasive ATC may represent a distinct subset of resectable ATCs with an improved prognosis. The recently published American Thyroid Association (ATA) Guidelines for Management of Patients with ATC do not include this specific form of ATC. We encourage other authors to report similar cases in order to determine whether noninvasive ATC should be considered as a separate disease entity from the traditional highly lethal form of ATC.
Introduction
A
naplastic thyroid carcinoma (ATC) is a rare form of thyroid carcinoma that is frequently associated with an aggressive clinical course often resulting in rapid patient demise. ATC typically presents with diffuse local invasion and/or metastasis. All ATCs are considered stage IV disease according to the American Joint Committee on Cancer (AJCC) staging system (1). Median overall survival is reported to be as poor as three to five months, with 1- and 10year overall survival reported at 10–20% and less than 5% respectively (2). The American Thyroid Association (ATA) has recently published consensus guidelines for the management of ATC that recommend an aggressive approach to the diagnosis and treatment of this disease (3); these guidelines are based on multiple studies demonstrating an improved survival outcome with complete surgical resection. Accordingly, resectability, as defined by the AJCC Residual Tumor (R) Classification, features prominently in clinical decision making in the management of patients presenting with locoregional disease (3). 1
Department Department 3 Department 4 Department 5 Department 2
of of of of of
Among ATC patients presenting with locoregional disease, a minority have disease confined to the thyroid (T4a) (3–5). Furthermore these lesions are infrequently discovered after surgical resection of a known well-differentiated thyroid cancer, an entity described as ‘‘incidental ATC’’ (3,6,7). These patients represent a subset of ATC that is highly resectable. Unfortunately, given the small size of this patient population, no meaningful data exist regarding the significance of the extent of thyroidectomy (total or subtotal vs. lobectomy) or the role of surgical resection versus multimodality therapy (3). However, improved survival following complete resection is consistently demonstrated across studies analyzing prognostic factors in ATC (4,6,8–12). There are a small number of reports within the surgical literature that describe a subset of T4a tumors characterized by complete encapsulation of the neoplasm without invasive growth (3,4,13–16). These noninvasive variants of ATC are rare and may portend favorable outcomes, though they are not explicitly recognized or addressed in the ATA guidelines. We describe a case of pathologically proven encapsulated ATC without invasive growth (noninvasive ATC) and review
Otolaryngology, The New York Eye and Ear Infirmary, New York, New York. Otolaryngology—Head and Neck Surgery, Yale School of Medicine, New Haven, Connecticut. Otolaryngology, THANC Foundation, New York, New York. Otolaryngology—Head and Neck Surgery, Beth Israel Medical Center, New York, New York. Pathology, Beth Israel Medical Center, New York, New York.
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the literature pertaining to this less aggressive phenotype. Experience with this entity as described in the clinical literature is limited. With the tracking and reporting of similar cases, and as more experience with and understanding of the biology of this entity is accumulated, it may be useful to consider a sub-classification of noninvasive ATC separately from the traditional highly lethal form of ATC. Case Presentation
An 81-year-old man presented for the evaluation of a 3.1 cm firm right-sided neck mass. He had a remote history of smoking 20 years prior to presentation. His medical history was also significant for multiple skin cancers of the extremities and face for which he received a combination of treatments, including resection by Mohs technique and chemoradiation following surgical resection for right upper cervical nodal metastases arising from a cutaneous squamous cell carcinoma. Specifically, concomitant chemoradiation followed by definitive chemotherapy was completed 44 months prior to presentation. During the course of treatment, 41.4 Gy was delivered to the neck and supraclavicular fossa, after which treatment was coned down to boost the dose to the gross disease in the right upper posterior and right mid-neck (just superior to the right thyroid lobe) to achieve a total of 70.2 Gy in 39 fractions. Concomitant chemotherapy with 100 mg of carboplatin and 130 mg of taxol was administered weekly for three months, followed by three cycles of definitive chemotherapy with 250 mg of carboplatin (AUC = 6) and 400 mg of taxol. Imaging with combined positron emission tomography/ computed tomography (PET/CT) scan showed a hypermetabolic lesion (maximum SUV = 27.0) inseparable from the right thyroid lobe correlating with the clinically identified mass (Fig. 1). No invasion of the aerodigestive tract or carotid sheath was noted. No cervical or thoracic lymph nodes met radiographic criteria for significance. A review of imaging
DIBELIUS ET AL.
dating back to five years prior to presentation revealed the presence of a mass that had been considered extrathyroidal but possibly represents the mass in question, although it was not previously biopsied. It was noted to be hypermetabolic but demonstrated resolution of metabolic activity and decrease in size on post-treatment PET/CT. Ultrasound-guided fine-needle aspiration biopsy (FNAB) of the neck mass revealed a high grade malignancy consistent with an ATC. Gross pathology
A total thyroidectomy was performed, and the specimen was submitted for pathologic analysis. The right thyroid lobe contained a well-circumscribed mass measuring 3.1 cm · 2.8 cm · 2.4 cm that on sectioning appeared yellow to tan with areas of necrosis and a small rim of uninvolved appearing parenchyma. Grossly, there was no evidence of invasion into adjacent thyroid parenchyma and/or outside the thyroid gland proper. Microscopic pathology
At low magnification, the neoplasm was encapsulated without microscopic evidence of invasion (Fig. 2A). The neoplastic proliferation showed lymphoepithelial-like features, including diffuse growth comprised of cells with markedly pleomorphic nuclei, vesicular chromatin, and prominent nucleoli (Fig. 2B). There was increased mitotic activity, including atypical forms, and necrosis. In addition, there were areas of the neoplasm showing angiomatoid features characterized by irregular and anastomosing vascular channels lined by neoplastic cells (Fig. 2C). A sarcomatoid cellular component was not identified. Foci of a differentiated follicular epithelial cell proliferation characterized by colloid-filled follicles, and uniform-appearing nuclei lacking the high-grade histologic features were also present (Fig. 2D). Such differentiated foci
FIG. 1. Positron emission tomography/computed tomography (PET/CT) Imaging showing (A) area of abnormal hypermetabolic activity (maximum SUV = 27.0) in the right neck correlating to a (B) 3.0 · 3.5 cm hypodense neck mass inseparable from the right thyroid lobe on CT. There was no invasion of the aerodigestive tract or carotid sheath noted, and no radiographically significant lymphadenopathy.
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FIG. 2. (A) Low power magnification showing an encapsulated cellular neoplasm focally with identifiable colloid-filled follicles (upper left). The neoplasm was entirely encapsulated without evidence of invasive growth. The residual differentiated thyroid represented a coexisting follicular adenoma. (B) The neoplasm is comprised of diffuse cellular proliferation comprised of epithelioid appearing malignant neoplastic cells lacking evidence of cellular differentiation. The nuclei of the epithelioid appearing malignant neoplastic cells are markedly pleomorphic with vesicular chromatin and prominent eosinophilic nucleoli. Increased mitotic activity is present. (C) In focal areas, the neoplastic proliferation included features of an angiosarcoma characterized by ramifying and interconnecting endothelial-lined vascular spaces; there are pleomorphic and hyperchromatic nuclei as well as tufting. (D) Within the encapsulated neoplasm, there were foci of a differentiated thyroid follicular epithelial proliferation that showed features consistent with a follicular adenoma. (E) Immunohistochemical staining showed the epithelioid appearing undifferentiated malignant cells to be reactive for cytokeratin (CAM5.2). (F) Thyroglobulin staining (cytoplasmic) was present in the foci of residual follicular adenoma (lower) but absent in the undifferentiated malignancy (upper). (G) Thyroid transcription factor 1 (TTF1) staining (nuclear) was present in the foci of residual follicular adenoma (lower) but absent in the undifferentiated malignancy (upper). (H) PAX 8 staining (nuclear) was present in the foci of residual follicular adenoma (lower), as well as in the undifferentiated malignancy (upper). (I) The angiosarcomatous foci were immunoreactive for CD31 (cytoplasmic), a marker of endothelial cell differentiation. represent a residual benign lesion in the context of an encapsulated lesion and is consistent with a follicular adenoma, although the histologic similarity to the adenomatoid nodules in the left thyroid lobe raised the possibility of this differentiated lesion as representing an adenomatoid nodule. The malignant lesion represented approximately 90% of the nodule. The entire tumor was submitted for histologic evaluation and showed no evidence of invasive growth, including capsular invasion, lymphovascular invasion, invasion into the thyroid parenchyma, or extrathyroidal extension. Sections of the left thyroid lobe showed the presence of adenomatoid nodules. Multiple resected central compartment lymph nodes were negative for carcinoma. Immunohistochemical staining
The lymphoepithelial-like carcinoma component showed reactivity for cytokeratins (AE1/AE3, CAM5.2), PAX8, and
vimentin (Fig. 2E–H) but was negative for thyroglobulin, thyroid transcription factor 1 (TTF1), CD5, CD31, Factor 8related antigen, S100 protein, and HBME1. The angiomatoid component showed immunoreactivity for CD31, Factor 8related antigen, and vimentin (Fig. 2I) but was negative for cytokeratins, thyroglobulin, TTF1, PAX8, HBME1, and CD34. An increase proliferation rate of > 50% was seen by Ki67 (MIB1) staining. The differentiated component was immunoreactive for thyroglobulin, TTF1, cytokeratins (AE1/AE3, CAM5.2), PAX8, and HBME1. Numerous foamy (benign) histiocytes were present in association with the neoplastic proliferation, which showed CD68 reactivity. Based on the light microscopic and immunohistochemical findings, a diagnosis of encapsulated (noninvasive) undifferentiated (anaplastic) thyroid carcinoma arising in association with a differentiated follicular epithelial cell lesion was rendered. There was no evidence of extrathyroidal extension.
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The pTNM staging was pT4aN0MX (pT4a representing intrathyroidal anaplastic carcinoma). Treatment and follow-up
This patient underwent a total thyroidectomy without incident. He tolerated that surgery well. He underwent multidisciplinary evaluation, and the decision was made not to administer adjuvant therapy due to the noninvasive nature of this tumor, the absence of regional or distant disease, as well as the prior radiation therapy to the cervical region. At 14 months postoperatively, the patient was doing well, and remained free of disease based on PET/CT imaging. Discussion
The usual clinical scenario for ATC is that of a rapidly enlarging neck mass that is extensively invasive at the time of presentation, directly contributing to its aggressive biology and dire outcome. In this patient’s case, we found a highgrade undifferentiated malignancy that was entirely encapsulated, without invasive growth, arising in association with a differentiated follicular epithelial cell lesion that we felt represented a follicular adenoma. The relatively innocuous clinical presentation and corresponding complete encapsulation, without invasion, are quite unusual for this tumor type. However, there is a recognized subset, albeit rare, of ATC that includes encapsulated tumors (4,13–16) (Table 1). Encapsulation has been documented by a small number of case reports to be associated with an improved outcome for ATC patients. Guimara˜es et al. (14) reported the first case of an improved outcome associated with an encapsulated ATC in 2000. Their report described a 74-year-old man with a 2.6 cm lesion who remained free of disease three years after total thyroidectomy (14). Similarly, Ito et al. (15) reported a
case of a 77-year-old woman with a 7.5 cm encapsulated ATC who underwent a palliative thyroid lobectomy for tracheal deviation and remained free of disease for 57 months at the time of publication. Neither of these patients received adjuvant therapy. Rapkiewicz et al. (13) reported a case of a surgically resectable encapsulated ATC in the setting of a metastatic follicular carcinoma, who at the time of publication was alive but had developed a new pelvic-bone metastasis (13). However, no survival outcomes were reported. Voutilainen et al. (4) reported a series of 33 ATC patients in which the only survivor was a patient with a microscopic focus of ATC within an encapsulated follicular carcinoma. None of the reported cases of encapsulated ATC tumors demonstrated gross capsular invasion. However, these cases differed in the presence or extent of microinvasion of the tumor capsule. This may be a key factor underlying the clinical behavior of these encapsulated lesions. The patient reported by Rapkiewicz et al. (13), had an encapsulated ATC without gross tumor capsule invasion presenting as a metastatic rib lesion; histopathologic analysis subsequently revealed microscopic capsular and lymphovascular invasion, which may have accounted for its more aggressive clinical behavior. The patient described by Guimara˜es et al. (14) also exhibited microinvasion of the tumor capsule, as well as a small extracapsular focus of ATC microscopically invading the glandular capsule. This patient remained free of disease at 35 months. Conversely, the patient reported by Ito et al. (15) had a large (7.5 cm) encapsulated and completely noninvasive lesion, and remained free of disease at 57 months. This is interesting given that large tumor size is typically a poor prognostic indicator on univariate and multivariate analysis of thyroid carcinoma (2,7). These cases were all reported as examples of histologically encapsulated atypical ATC lesions for which prognosis might be expected to be improved.
Table 1. Summary of Literature Review Study
Study type
Tumor size
Capsule invasion
Guimara˜es et al. 2000 (Brazil) (14)
Case report
2.6 cm
Yes
Rapkiewicz et al. 2007 (United States) (13)
Case report
4.1 cm
Yes
Ito et al. 2003 ( Japan) (15)
Case report
7.5 cm
No
Voutilainen et al. 1999 (Finland) (4)
Retrospective review (n = 33)
NR
NR
Note that none of the reported lesions showed gross capsule invasion. FNA, fine-needle aspiration; NR, not reported.
Features 0.8 mm focus of ATC extending through tumor capsule 2.5 mm extracapsular focus partially through glandular capsule FNA: adenocarcinoma Lymphovascular invasion Metastatic disease Background of follicular neoplasm Background of thyroiditis and a limited follicular neoplasm FNA: follicular adenoma ATC focus within encapsulated follicular carcinoma
Outcome Free of disease at 35 months
New metastasis No survival outcomes reported Free of disease at 57 months 1 patient had a focus of ATC within an encapsulated follicular lesion; only survivor of this series at 156 months
NONINVASIVE ANAPLASTIC THYROID CARCINOMA
However, comparison of these reports reveals differences in the microscopic behavior of the described lesions that may more accurately predict their clinical and underlying biologic behavior beyond the commonality of a tumor capsule. There may be more clinical utility in regarding these histologically encapsulated ATC tumors as noninvasive or minimally invasive ATC lesions, as this nomenclature may be more reflective of their true clinical behavior. Our patient’s lesion was found to be an encapsulated, noninvasive ATC for which we might predict an improved prognosis. These case reports and series suggest an improved prognosis in patients with encapsulation as a histologic feature. The presence of a fibrotic capsule may serve to contain disease locally and partially explain observed differences in clinical behavior. Indeed, encapsulation of other thyroid malignancies has been associated with improved outcomes over their nonencapsulated counterparts, including so-called Hu¨rthle cell carcinoma (16), aggressive variants of thyroid papillary carcinoma (17,18), and poorly differentiated (insular) thyroid carcinoma (19,20). Of note, this patient’s thyroid lesion may have been present as early as five years prior to surgical resection. The fact that the tumor in the thyroid may have been ATC at that time, although it was not previously biopsied but was radiographically present five years prior to resection, adds further credence to the contention that this encapsulated variant of ATC has indeed a more favorable outcome. While one may speculate that the course of chemotherapy and radiation may have partially treated the thyroid neoplasm in a neoadjuvant fashion, it would not be considered a curative therapy, as evidenced by the fact that the disease was not eradicated by that therapy and there was no evidence of treatment effect on histologic evaluation when it was resected five years hence. In addition, the fact that it did not spread during that time frame is further evidence of its favorable biology. The majority of ATCs show sarcomatoid histologic features, but there can be a wide histologic spectrum comprised of several morphologic variants including, but not limited to, lymphoepithelial and angiomatoid variants. While the overall pathologic features in this case were those of an ATC, this patient’s neoplasm lacked sarcomatoid features but included an admixture of features that included lymphoepithelial-like carcinoma and angiomatoid variants. Some authorities feel that angiosarcomas of the thyroid represent undifferentiated carcinomas (21). Although angiosarcoma as an independent primary malignancy of the thyroid gland does occur, it may share overlapping clinical and pathologic features with undifferentiated carcinomas. However, from a practical standpoint, trying to distinguish undifferentiated carcinoma from angiosarcoma may be more of an academic matter, as the typical biologic behavior for both tumor types is extremely poor, with patient deaths occurring after short time periods irrespective of treatment (21). ATC typically occurs in association with a pre- or coexisting differentiated thyroid neoplasm that include adenomatoid nodules, follicular adenomas and carcinomas, and papillary carcinomas (3,13,22,23). In this patient’s case, we found a high-grade undifferentiated malignancy arising in association with a differentiated follicular epithelial cell lesion that we felt represented a follicular adenoma. Although the ATA guidelines do not specifically recognize noninvasive (encapsulated) or minimally invasive variants of
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ATC, incidental ATC is probably a related entity. Incidental ATC is defined as a ‘‘small, incidental finding after surgical resection of a predominantly non-anaplastic tumor’’ (3). Some of the cases of noninvasive and minimally invasive ATC described above are included in studies of this category, although others, as in our case, are identified as ATC at the time of FNAB. A large study of 677 patients with ATC treated with surgery with or without chemoradiation demonstrated a one-year cause-specific survival of 18% for common-type ATC, compared to 57% for incidental ATC (7). Whether noninvasive or minimally invasive encapsulated ATC and incidental ATC represent the same biologic continuum requires further analysis. Regardless, both represent groups of patients with initially resectable disease, the importance of which has been consistently demonstrated in the literature. The role of adjuvant therapies in improving locoregional control and/or survival in patients with resectable disease is an area in need of ongoing clinical investigation. While the literature generally supports the use of adjuvant therapies for resectable ATC, a study of 261 ATC patients in the Surveillance, Epidemiology, and End Results (SEER) database showed a survival benefit of radiotherapy for ATC with extrathyroidal extension, but not for patients with intrathyroidal ATC (24). Currently, the guidelines support cautious observation after surgical resection of incidental ATC, although the quality of evidence is low (3). Under the current staging system proposed by the AJCC, all ATC are considered T4 tumors representing stage IV disease (1). The predicted outcomes for noninvasive or minimally invasive variants of ATC may not be adequately described under this staging system. Additionally, it is conceivable that the incidence of these noninvasive or minimally invasive variants and/or incidental variants may increase going forward as the rate of surgery for differentiated thyroid cancer (DTC) increases, further underscoring the imperative for a comprehensive management strategy for resectable ATC. Conclusions
Noninvasive encapsulated ATC is an infrequently identified form of thyroid carcinoma that likely represents both a subset of patients with incidental ATC, as well as a unique pretreatment diagnosis. The few case reports and series describing this disease entity suggest improved survival outcomes as compared with the classic type of ATC. Future study separating noninvasive and minimally invasive ATC from traditional invasive ATC may help to stratify prognostic groups further, which would impact the extent of surgery and need for adjuvant therapy. Author Disclosure Statement
The authors declare that they have no competing interests. References
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Address correspondence to: Mark L. Urken, MD, FACS Department of Otolaryngology—Head and Neck Surgery Beth Israel Medical Center New York, NY 10003 E-mail: [email protected]
