CLINICAL REVIEW

David W. Eisele, MD, Section Editor

AGGRESSIVE VARIANTS OF PAPILLARY THYROID CARCINOMA Carl E. Silver, MD,1 Randall P. Owen, MD, MS,2 Juan P. Rodrigo, MD, PhD,3,4 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSglasg,5 Kenneth O. Devaney, MD, JD, FCAP,6 Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP5 1

Departments of Surgery and Otolaryngology – Head and Neck Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 2 Department of Surgery, Division of Metabolic, Endocrine, and Minimally Invasive Surgery, Mount Sinai School of Medicine, New York, New York 3 Instituto Universitario de Oncologı´a del Principado de Asturias, Oviedo, Spain 4 Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain 5 Department of Surgical Sciences, ENT Clinic, University of Udine, Azienda Ospedaliero-Universitaria, Piazzale S. Maria della Misericordia, Udine, Italy. E-mail: [email protected] 6 Department of Pathology, Allegiance Health, Jackson, Mississippi

Accepted 21 April 2010 Published online 7 September 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21494

Abstract: A number of histologic variants of well-differentiated papillary carcinoma have been found to be associated with more aggressive tumor behavior. Tall cell, columnar cell, diffuse sclerosing, solid/trabecular, and insular variants of welldifferentiated papillary thyroid cancer are all potentially more aggressive than conventional papillary thyroid cancer. When subjected to multivariate analysis, however, evidence that the histologic subtype of tumor is an independent predictor of outcome is weak. Rather, the aggressive variants tend to present with features recognized by other staging systems as associated with a worse prognosis, including higher histologic grade, extracapsular spread, large tumor size, and the presence of distant metastases. Prognosis is directly related to the presence of these features. The state of our knowledge is limited by the relatively small number of cases that have been studied. The presence of an aggressive variant of papillary carcinoma should alert the surgeon that he is dealing with a potentially aggressive tumor. Clinical treatment decisions should be based on the stage of the disease, influenced by the knowledge that the aggressive variants tend to be associated with higher risk factors. The surgeon must be prepared to perform at the first, or second stage, a total thyroidectomy, central compartment neck dissection, additional lymphadenectomy, and/or resection of invaded surrounding structures, and search for distant metastasis. Postoperative radioactive iodine should generally be administered for these variants as they will generally be intermediate to advanced tumors. The tall cell variant is often refractory to such treatment but may be susceptible to treatment targeted against BRAF mutation. External beam irradiation may be used C 2010 Wiley Periodicals, in cases of incomplete resection. V Inc. Head Neck 33: 1052–1059, 2011

Correspondence to: A. Ferlito This article was written by members of the International Head and Neck Scientific Group (www.IHNSG.com). C 2010 Wiley Periodicals, Inc. V

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Keywords: aggressive variant papillary carcinoma; tall cell; columnar cell; solid trabecular; diffuse sclerosing insular; thyroid cancer

Cancers originating in the thyroid gland have traditionally been categorized as well-differentiated (90%), medullary (5% to 9%), or anaplastic (1% to 2%). Since the 1980s, a fourth category, ‘‘poorly differentiated thyroid carcinoma (PDTC),’’ a heterogeneous group of tumors occupying an area intermediate between welldifferentiated follicular or papillary carcinoma and anaplastic carcinoma, has been recognized.1 With the exception of medullary carcinoma, all other forms of thyroid cancer are epithelial in origin and derived from follicular parenchymal cells. Histologic variants of well-differentiated papillary cancers are well known and have been variously described as either increasing the aggressiveness of the disease or not. Some of these characteristics have also been described in the relatively recent designation of poorly differentiated thyroid cancer and can help fulfill criteria for its diagnosis.2,3 Several different histologic variants of papillary thyroid carcinoma (PTC) have been described in the literature. Tall cell, columnar cell, diffuse sclerosing, and insular variants of PTC have been thought to be more aggressive variants. Oncocytic, solid, and trabecular variants exhibit a variable prognosis. Follicular, macrofollicular, pseudo-Warthin, clear cell, and cancers with lymphocytic stromal reaction are generally thought to have a similar prognoses to conventional forms of PTC. This article will focus on those HEAD & NECK—DOI 10.1002/hed

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variants of PTC generally considered to be more aggressive. Several characteristics of well-differentiated tumors are known to affect prognosis. These are age, size, sex, extracapsular spread, intravascular invasion, and metastasis. Several systems of staging of these tumors for prognostication have been developed, taking into account these various tumor characteristics, including the current TNM classification,4 the Lahey Clinic AMES (age, distant metastases, extent of disease, and size),5 and the Mayo Clinic MACIS score (metastases, age, completeness of surgical resection, extrathyroidal invasion, and size).6 An important question to consider with regard to the prognosis and treatment of these ‘‘aggressive’’ variants of welldifferentiated thyroid cancer is whether the presence of the histologic cell type in itself is an important prognostic factor, or whether the presence of the unusual cell type simply correlates with a higher incidence of the other factors known to influence prognosis unfavorably. Tall Cell Variant. If the conventional PTC is defined by light microscopists as an (usually-predominantly but not always-predominantly papillary) arrangement of polygonal to slightly oblong cells with enlarged nuclei, nuclear grooves, and intranuclear cytoplasmic inclusions, with colloid production, then the cells of a tall cell variant (TCV) tumor differ from those of a PTC in that they are distinctly rectangular, with less colloid production but similar nuclear features to those seen in PTC. The tall or pink cell variant of PTC was originally described by Hawk and Hazard in 1976.7 These authors described a group of PTC with a ‘‘distinctive cell type in a columnar shape with the height of the cell being at least twice the breadth.’’ Subsequently, the TCV has been variously defined as having between 30% and 70% of the follicular thyroid cells at least 2 or 3 times as long as they are wide. The most common definition is that at least 30% of cells are twice as long as they are wide. The definition of TCV by the World Health Organization is that ‘‘it is composed predominantly of cells whose heights are at least 3 times their width.’’8 According to these authors, cytologic features that might differentiate TCV from conventional papillary thyroid carcinoma (CPTC) include ‘‘larger cell size with a large amount of granular cytoplasm, eccentric nuclear location, increased nuclear pleomorphism, and prominent cytoplasmic borders.’’ Its prevalence has been described as between 4% and 19%.9,10 It is also important for pathologists to detect tall cell features correctly by fine-needle aspiration cytology and immunohistochemical study11 (Table 1). In 1976, Hawk and Hazard7 retrospectively reviewed 197 cases of PTC from 1921 through 1960. Seventeen patients (8.6%) died of their disease with a mean follow-up period of 7.3 years. Four of 18 patients (22.2%) with TCV died of disease within 7

Aggressive Variants of Papillary Thyroid Carcinoma

years. Although there was neither statistical analysis performed nor any formal consideration for potential interactions between confounding factors, the authors did mention an association of TCV with more advanced age and larger tumors. The striking increase in disease-related mortality among patients with TCV prompted the authors to consider this variant with some alarm. In 1996, Ostrowski and Merino12 examined a series of 92 specimens of PTC, 11 of which were TCV. They found that there were significant differences in immunoreactivity between the 3 groups. Whereas stains for thyroglobulin, vimentin, keratins, and Leu7 were positive in both groups, Leu M1 and ZC-23 were positive in the TCV group but negative in the usual PTC group. These differences led the authors to conclude that TCV is a distinct type of PTC. In 2004, Sywak et al13 reviewed 209 cases of TCV reported in the literature. The average age was 51, female-to-male ratio was 1.8, tumor diameter 3.1 cm; 67% had extracapsular spread (ECS) of tumor, and 57% had cervical adenopathy. At an average of 61 months of follow-up, 25% showed locoregional recurrence (LRR), 22% developed distant metastases (DM), and 16% had tumor-related mortality. Given the apparently worse prognosis of this tumor type, the authors recommended aggressive surgical treatment to include total thyroidectomy and central compartment neck dissection followed by radioactive iodine and, in some cases, external beam radiation. In the same year, Machens et al14 identified 16 cases of TCV among a cohort of 332 cases of PTC. Nodal and (predominantly pulmonary) distant metastases were identified in 50% and 31%, respectively, of TCV tumors. On univariate analysis, only the association between the TCV and distant metastasis retained statistical significance after adjustment for multiple testing. On multivariate analysis, the presence of distant metastasis increased by more than 4-fold the chances of finding TCV in the primary tumor. The authors concluded that the finding of TCV at surgery warrants an extensive postoperative search for distant metastasis. In 2007, Michels et al15 compared 503 patients with conventional papillary carcinoma to 56 patients with TCV. The 10-year overall survival was 90% and 79%, respectively. On univariate analysis, the presence of TCV impacted prognosis unfavorably; however, on multivariate analysis it did not. Rather, older age, distant metastases, and positive nodes were significant unfavorable prognostic factors. If the MACIS score was used as opposed to its individual components in a multivariate analysis model, it was the most predictive of all variables. Patients with TCV tended to have a higher stage and grade of disease indicating a more aggressive tumor, but stage for stage, TCV did not have a worse prognosis than patients with comparably staged CPTC. Thus, according to their study, TCV would be considered a marker

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Table 1. Tall cell variant of papillary thyroid carcinoma.

Report

No. cases or % of PTC

Hawk and Hazzard7 1976

18/197 (9%)

Pathology 30% of cells 2
as long as they are wide, large cell size, granular cytoplasm, eccentric nuclei, pleomorphism Leu M1 and ZC-23 positive in TCV but not in CPTC

Ostrowski et al12 1996

11/92 (12%)

Sywak et al13 2004

209 cases

67% ECS 57% nodes

16/332 (5%) 56/503 (11%)

50% nodes 31% DM

Machens et al14 2004 Michels et al15 2007

DeLellis et al8 2004 World Health Organization definition of TCV Ghossein and LiVolsi17 2008

Genetic

Comparative mortality PTC 17/197 (8.6%) TCV 4/18 (22.2%)

At 43 months 33% LRR 36% DM 29% mortality At mean 16 years 0 mortality At 5 years 25% LRR 22% DM 16% mortality 10 years CPTC 10% TCV 21%

‘‘Composed predominately of cells whose heights are at least 3
their width’’

Sheu et al20 2009

High prevalence of BRAF somatic mutation High prevalence of BRAF mutation

Abbreviations: PTC, papillary thyroid carcinoma; TCV, tall cell variant; CPTC, conventional papillary thyroid carcinoma; ECS, extracapsular spread; LRR, locoregional recurrence; DM, distant metastases.

of more aggressive disease but not an independent predictor of outcome. They also concluded that TCV and columnar cell variants did not represent a different clinical tumor than the conventional form of PTC, and that treatment should not vary based on this histologic finding alone. In a review of 1108 patients with PTC, Leung et al16 found 14 cases with TCV. They concluded that TCV presents at an older age and at a higher stage with more advanced local disease than does CPTC, and that it has a higher risk of locoregional and distant relapse and a worse overall survival rate. Therefore, they recommended a more aggressive treatment and close follow-up of these patients. In 2008, Ghossein and LiVolsi17 reviewed the papillary thyroid carcinoma TCV and concluded that this tumor is a biologically and clinically aggressive variant of PTC that is still underdiagnosed. TCV is overrepresented in patients with refractory to radioactive iodine disease. It has a high prevalence of BRAF somatic mutation at residue 600 of the BRAF protein (BRAFV600E, BRAF [V600] or ‘‘BRAF’’) mutations, making the latter an attractive target in radioactive iodine refractory cases. Imaging modalities that can detect radioactive iodine refractory disease, such as fluorodeoxyglucose positron emission tomography scanning, are useful in many patients and are required in those with extensive extrathyroid extension. More studies are needed to identify those TCVs

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that become radioactive iodine refractory and to develop effective target therapies against these otherwise incurable carcinomas. In the same year, Ito et al18 noted that patients with TCV showed significantly worse disease-free survival and cause-specific survival rates than those with conventional PTC. They concluded that because patients with some variants show different clinical outcomes from those with conventional PTC, classification of variants might be helpful to predict patient prognosis. BRAF (V600) mutation is the most frequent genetic alteration in PTC.19 Many studies have found this mutation to be associated with those clinicopathologic characteristics of PTC that are conventionally known to predict tumor progression and recurrence, including, for example, old patient age, extrathyroidal invasion, lymph node metastasis, and advanced tumor stages. Direct association of BRAF mutation with the clinical progression, recurrence, and treatment failure of PTC has also been demonstrated.19 As mentioned, a high prevalence of BRAF (V600) mutations have been described in the TCV,17,20 which could explain the higher aggressiveness of this subtype of PTC. However, this association of the TCV with a higher prevalence of BRAF (V600) mutations was not confirmed in other studies,21 suggesting an indirect relationship due to the association of both characteristics with a more aggressive phenotype.

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Table 2. Other variants of papillary thyroid carcinoma. Series

Variant No. (%)

Evans22 1986

CCV 0.15% to 2% of all PTC

Sywak et al13 2004

CCV 41 cases

Fujimoto et al24 1990

DSPTC

Carcangiu and Bianchi29 1989

DSPTC 15 cases

Albareda et al30 1998

7 DSPTC vs 76 CPTC 83 DSPTC vs 183 CPTC

Falvo et al

31

2006

Thompson et al32 2005

DSPTC 22 cases

Sywak et al13 2004

Solid trabecular

Nikiforov34 2006

Solid trabecular 4000 reviewed

Carcangiu et al35 1984

Insular

Akslen & LiVolsi38 2000

Insular 16 focal 17 pre-dominate

Sywak et al13 2004

Insular 213 cases

Pathology

Clinical

Tall cells with elongated hyperchromatic pseudostratified nuclei -lack the cytologic nuclear features of TCV 30% of cells are columnar 27% ECS, 50% nodes

At 43 months 33% LRR 36% DM 29% mortality At mean 16 years, 0 mortality

Dense sclerosis, patchy lymphocytic infiltration, and abundant psammoma bodies Greater incidence of cervical metastases, lung metastases

Cord-like architectural arrangement of typical PTC cells

nests or insulae of tumor cells uniformity, hypercellularity, and scant colloid

44% ECS, 51% nodes

Prognosis

Higher aggressiveness, diffuse intrathyroid growth, and high incidence of nodes and DM Diagnosis of this entity should lead the clinician to aggressively manage these patients 37% of the radiation induced thyroid tumors among survivors of Chernobyl 15 x increase preponderance among Chernobyl survivors Often large tumors May be focal

Tumor

Decreased disease-free survival No difference in outcome

High ECS 83% nodes More aggressive than CPTC Only 15 deaths

Higher number of tumorrelated deaths and DM with the predominantly insular vs focal group Mean 72 months LRR or DM 64% Tumor mortality 32%

Abbreviations: CCV, columnar cell variant; PTC, papillary thyroid carcinoma; TCV, tall cell variant; ECS, extracapsular spread; LRR, locoregional recurrence; DM, distant metastases; DSPTC, diffuse sclerosing variant of papillary thyroid cancer, CPTC, conventional papillary thyroid carcinoma.

Columnar Cell Variant. Columnar cell variant (CCV) was initially described by Evans22 in 1986 (Table 2). It is a rare variant, accounting for 0.15% to 0.2% of all papillary carcinomas, and some authors group it together with TCV.23 Columnar variant thyroid cancer cells are tall cells with elongated hyperchromatic pseudostratified nuclei; these tumor cells differ from TCV cells in that they lack the cytologic nuclear features characteristic of TCV (and PTC). Tumors classified as CCV are required to contain at least 30% columnar cells on thorough sampling of the neoplasm. According to DeLellis et al8 in the World Health Organization Classification of Tumors, ‘‘a variable proportion of pap-

Aggressive Variants of Papillary Thyroid Carcinoma

illary, follicular, trabecular, and solid patterns is seen in most tumors.’’ In 1998, Wenig et al23 studied 16 cases of columnar cell type PTC and concluded that it is a distinct morphologic type but not a distinct clinical type of tumor. He also recommended that it should be treated based on clinical stage, rather than as a function of its histologic classification. In 2004, Sywak et al13 reported on 41 cases of CCV throughout the literature with a mean age of 44, a female-to-male ratio of 1.94, and a mean tumor diameter of 5.3 cm. Twenty-seven percent had extracapsular spread and 50% had cervical metastases. With

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an average of 43 months of follow-up, 33% showed locoregional recurrence, 36% distant metastases, and 29% tumor-related death. The authors conclude that if the tumor showed extracapsular spread than the prognosis was poor, but that CCV in itself did not predict a poor outcome. They recommended no different treatment based on the histologic variant alone. In the study of Ito et al,18 the CCV also showed a worse prognosis, although they accounted for fewer than 1% of cases. The CCV is aggressive, due to its rapid growth, high local recurrence rate, and frequent lung, brain, and bone metastases. Aggressive surgical and medical management are recommended for these neoplasias. However, any recommendation should be viewed in the light of the fact that the current literature mainly consists of case reports, case series, and limited reviews.2

cluded that diffuse sclerosing variant is characterized by its higher aggressiveness, diffuse intrathyroid growth, and high incidence of lymph node and pulmonary metastasis, and that its classification as an autonomous clinical pathologic entity is justified. The same characteristics were reported by Thompson et al32 in their review of 22 cases of DSPTC; they stressed that the diagnosis of this entity should lead the clinician to aggressively manage these patients (total thyroidectomy and lymph node dissection) in an effort to achieve a good long-term clinical outcome. Sywak et al13 noted that the number of cases was too small to draw conclusions about the relative aggressiveness of this variant. However, they recommended that, given the infiltrating nature of the disease and the propensity for lymph node metastases, total thyroidectomy and appropriate lymphadenectomy should be performed for all patients.

Diffuse sclerosing variant of papillary thyroid cancer (DSPTC) ‘‘is characterized by diffuse involvement of one or both thyroid lobes, with dense sclerosis, patchy lymphocytic infiltration, and abundant psammoma bodies.’’24 Although this description was published in 1985 by Vickery et al,25 it is likely that others encountered it previously, but considered it to be the simultaneous occurrence of thyroiditis and PTC.26 Other clinical characteristics include the presence of measurable serum antimicrosomal and antithyroglobulin autoantibodies.27 In a study of the genetic alterations in DSPTC, no BRAF (V600) mutations were found but all the cases showed RET proto-oncogene (RET)/PTC rearrangements. This study confirmed the paradigm of a mutual exclusivity between RET/PTC and BRAF in PTC. Additionally, this study showed that the DSPTC may represent a tumor type susceptible to RET-targeted therapies.28 Among 65 cases reviewed by Sywak et al,13 the mean age was 27 and the female-to-male ratio was 4.88. Extracellular spread was seen in 40% and cervical metastases in 68%. With a mean of 8.2 years of follow-up, 13% had local recurrence, 19% had distant metastases, and 2% had disease-related mortality. Fujimoto et al24 treated 14 patients (all female with a mean age of 20) and found that all patients were alive and disease-free with a mean follow-up of 16 years. Thus, their impression was that this is an eminently curable disease like CPTC. However, Carcangiu and Bianchi29 conducted a pathologic review of 15 cases and found a greater incidence of cervical metastases, lung metastases, and a decreased disease-free survival. The authors concluded that the diffuse sclerosing variety of PTC warranted more aggressive treatment when this diagnosis was recognized. Albareda et al30 compared 7 patients with DSPTC to 76 patients with CPTC and found no difference in outcome. Falvo et al31 reported 83 patients with the diagnosis of DSPTC which they compared with 183 with CPTC; they con-

Solid/Trabecular Variant. The solid/trabecular variant exhibits the usual nuclear cytologic characteristics of PTC, including nuclear grooves, inclusions, and ground glass nuclei. The term ‘‘solid’’ refers to the low-power microscopic architectural pattern of the tumor and is generally seen throughout sections of the tumor examined. ‘‘Trabecular’’ means a cord-like architectural arrangement of typical PTC cells. This form of PTC is commonly seen in patients exposed to radiation and has been identified in 37% of the radiation-induced thyroid tumors among survivors of the Chernobyl accident.13 However, in many radiationexposed patients, the solid changes seen in the tumor can also be seen in the surrounding non-neoplastic thyroid tissue, and many features such as extracapsular extension and vascular changes can be identified as well. Clinical characteristics include a female-to-male ratio of up to 9:1, although the radiation-induced tumors have no sex predilection. In the region affected by the Chernobyl nuclear disaster, radiationinduced cancers began to appear a mean of 5.8 years after the event—much earlier than would generally be expected among patients exposed to low-dose radiation. The age group most affected were children younger than 5 years old.33 Limited data are available regarding the outcome in patients with this variant of disease. Mizukami et al27 followed 30 patients for 10 years, who had a survival rate of 72%, which, on multivariate analysis, was significantly worse than for CPTC patients. The group of 28 patients followed by Carcangiu and Bianchi29 for 6.3 years showed no tumor-related deaths in the solid/ trabecular group leading them to believe that this was not a more aggressive variant. Nikiforov34 reviewed multiple studies on approximately 4000 children and adolescents with thyroid cancer related to the Chernobyl accident, which provided important information about the epidemiologic, clinical, pathologic, and molecular aspects of radiation-induced carcinogenesis in

Diffuse Sclerosing Variant.

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Table 3. Poorly differentiated thyroid carcinoma. Report Volante et al3 2007

Pathology

Genetic

Comparative mortality

Presence of malignant thyroid follicular cells, solid, trabecular and/or insular patterns, absence of typical PTC nuclei throughout, and the presence of either convoluted nuclei, necrosis, or mitoses.

PDTC are genetically homogeneous, RAS mutations being the almost exclusive genetic event.

A significant difference in survival was observed between the PDTC group and the well-differentiated group.

Abbreviations: PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma.

the thyroid gland. Thirty percent of the 4000 cases were of the solid histologic variant—a 15-fold increase from the usual incidence—yet only a total of 15 deaths occurred, indicating no worse prognosis than CPTC. Sywak et al,13 however, found that the solid/trabecular variant seen after Chernobyl had a high propensity for extrathyroidal extension, and cervical lymph node metastases were found in up to 83% of patients. The predominance of opinion seems to be that the solid trabecular variant is more aggressive than CPTC. Therefore, total thyroidectomy with appropriate lymph node dissection is recommended for solid/trabecular variant tumors. Insular Thyroid Carcinoma. The insular variant of PTC was described by Carcangiu et al35 in 1984. Langhans described a similar entity in 1907 which he termed ‘‘wuchernde Struma.’’ Carcangiu et al35 delineated the pathologic criteria for recognition of the insular variant of PTC, which included the presence of well-defined nests or ‘‘insulae’’ of tumor cells with round, dark, and monomorphic nuclei and scant cytoplasm. Cytologic uniformity, hypercellularity, and scant colloid are typical of insular papillary carcinoma, although no psammoma bodies are seen in these tumors. On low-power microscopic examination, these tumors are marked by nests of oval to round cells with some solitary cells. The nuclear to cytoplasmic ratio is high but the nuclear grooves and intranuclear inclusions usually seen in CPTC are generally absent. Insular cell carcinomas are often large tumors, greater than 4 cm, and often exhibit extracapsular spread. The tumors frequently contain a component of conventional papillary or follicular thyroid cancer. A study of 16 patients with focal insular component compared to 17 with a predominant insular component demonstrated a worse prognosis with higher frequency of tumor-related deaths and the development of distant metastases associated with the latter (predominantly insular) group than was observed with the group of patients with only a focal insular component. The authors concluded that a predomi-

Aggressive Variants of Papillary Thyroid Carcinoma

nant insular component PTC is associated with a substantially worse prognosis than focal insular PTC or CPTC.36 An evaluation of 213 patients with insular thyroid cancer revealed a female-to-male ratio of 2.7. Mean tumor diameter was 5.5 cm with 44% showing extracapsular extension, whereas 51% developed cervical metastases. With a mean follow-up of 72 months, locoregional recurrence or distant metastases were seen 64% of the time and tumor-related mortality was 32%.13 These results show that the insular variant of PTC is an aggressive tumor that often presents with numerous risk factors and has a significantly worse prognosis than CPTC. The insular variant meets many of the criteria for poorly differentiated carcinoma, and many believe that it is a precursor to anaplastic or undifferentiated cancer. Recommended treatment is generally aggressive with total thyroidectomy, appropriate lymph node dissection, postoperative radioactive iodine, and external beam radiation in case of incomplete resection. Volante et al3 reported on the consensus meeting held in Turin, Italy, in March 2006, to delineate the criteria for PDTC. As stated above, this is a relatively new designation to classify tumors with prognosis between clinically and pathologically well-differentiated and undifferentiated (anaplastic) thyroid cancer (Table 3). This designation was originally proposed in the early 1980s but by 2 different groups using 2 very different sets of criteria. The Turin proposal brought together pathologists from Japan, Europe, and the United States to agree upon uniform criteria to diagnose PDTC. All invited pathologists read slides from 83 patients in various geographic areas and were blinded to their clinical outcome. They then came together at Turin and agreed upon an algorithm by which PDTC could be diagnosed. The algorithm requires the presence of malignant thyroid follicular cells, the presence of solid, trabecular and/or insular patterns, the absence of typical PTC nuclei throughout, and the presence of either convoluted nuclei, necrosis, or mitoses. Poorly Differentiated Thyroid Cancer.

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With these criteria, a significant difference in survival was observed between the PDTC group and the welldifferentiated group. Molecular data in this group of tumors are extremely heterogeneous, possibly reflecting different inclusion criteria. However, in 1 analysis of 65 cases of PDTC diagnosed after the Turin proposal, RAS mutations in codon 61 were by far the most common genetic alteration in poorly differentiated carcinomas (23% of cases), with all mutations in NRAS except 1 in the HRAS gene. No KRAS, RET/PTC, or PAX8/ PPAR gamma genetic alteration was detected, and only a single BRAF mutation was found in a poorly differentiated carcinoma with a residual component of a TCV of papillary carcinoma. The authors concluded that strictly classified, poorly differentiated carcinomas are genetically homogeneous, RAS mutations being the almost exclusive genetic event.37 Akslen and LiVolsi38 reported on a series of 128 patients with PTC and found that, although histologic variants including tall cell carcinoma seemed to be significant factors on univariate survival analysis, only greatest tumor dimension and histologic grade remained as independent and significant predictors of carcinoma death. Histologic grade was divided into 2 categories. If marked nuclear atypia, tumor necrosis, or vascular invasion was present, then the tumor was considered to be grade 2. If none of these were present, it was considered to be grade 1. Primary tumor extension was of borderline significance (p ¼ .051). ‘‘Histologic category (ie, tall cell) was found to have no independent impact on patient survival.’’ Thus, although tumors that have significant cell populations of the histologic variants considered to represent the aggressive varieties of well-differentiated PTCs are associated with more aggressive behavior and worse prognosis, study of the individual varieties, particularly when subjected to multivariate analysis, indicate that it is the presence of factors previously known to be associated with poor prognosis, large size, extracapsular spread, and higher histologic grade, that predominate in these aggressive varieties, and which are primarily correlated with poor prognosis. The known adverse factor of tumor development at the extremes of age also is correlated with increased presence of aggressive varieties of PTC.

Tumor Grade versus Histologic Variant.

Varying opinions have been expressed by the authors cited here, as to whether the mere presence of 1 of the ‘‘aggressive’’ histologic variants, without other features, should prompt more aggressive treatment, or whether treatment should be based on conventional staging factors alone. Many of the therapeutic recommendations made in the literature were made without knowledge of the results of future multivariate analyses; nevertheless, ‘‘aggres-

Treatment.

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sive variant’’ histology is usually associated with more advanced stage tumors, and most of these tumors do not present as small well-encapsulated lesions. From a practical and therapeutic viewpoint, the histologic variety of PTC and tumor stage, grade, and various other risk factors are often not known, or not fully known, before initial surgical treatment. Knowledge of these features, when available, is helpful in determining the indication for initial or secondary additional treatment, such as completion (contralateral) thyroidectomy, central compartment or lateral neck dissection, postoperative radioiodine treatment, and a search for distant metastasis. Gross invasion of surrounding structures and other features of aggressive malignancy should be dealt with for any thyroid cancer. External beam radiotherapy should be reserved for patients in whom residual disease cannot be resected. It must be borne in mind by the clinician that due to the rarity and recent discovery of these tumors, the issue of what constitutes the best form of treatment for various histologic forms has not been studied conclusively either prospectively or retrospectively. CONCLUSIONS

Tall cell, columnar cell, diffuse sclerosing, solid/trabecular, and insular variants of well-differentiated PTC are all potentially more aggressive than conventional PTC varieties. Nevertheless, evidence that the histologic subtype of tumor is an independent predictor of outcome is weak. Rather, the aggressive variants tend to present with features recognized by other staging systems as associated with a worse prognosis, including higher histologic grade, extracapsular spread, large tumor size, and the presence of distant metastases. On the basis of the state of our knowledge, limited by the relatively small number of cases that have been studied, clinical treatment decisions should be based on the stage of the disease, influenced by the knowledge that the aggressive variants tend to be associated with higher risk factors. The surgeon should be well aware of these histologic variants and be prepared to perform at the first or second stage a total thyroidectomy, central compartment neck dissection, additional lymphadenectomy, and/or resection of invaded surrounding structures, and search for distant metastasis. Postoperative radioactive iodine should generally be administered for these variants as they will generally be intermediate to advanced tumors. External beam irradiation may be used in cases of incomplete resection.

REFERENCES 1. Rosai J, Saxe´n EA, Woolner L. Undifferentiated and poorly differentiated carcinoma. Semin Diagn Pathol 1985;2:123–136.

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