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Aggressive Variants of Papillary Thyroid Carcinoma: Hobnail, Tall Cell, Columnar, and Solid

Nath, Meryl, C.; Erickson, Lori, A., MD

Advances In Anatomic Pathology: May 2018 - Volume 25 - Issue 3 - p 172–179
doi: 10.1097/PAP.0000000000000184
Review Articles

Papillary thyroid carcinomas are the most common endocrine cancer and are usually associated with good survival. However, some variants of papillary thyroid carcinomas may behave more aggressively than classic papillary thyroid carcinomas. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and/or to the clinicopathologic features, an issue that remains controversial. The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension. A papillary thyroid carcinoma is designated as solid/trabecular variant when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance. This tumor must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. New to the fourth edition of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. All of these variants are histologically unique and important to recognize due to their aggressive behavior.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

The authors have no funding or conflicts of interest to disclose.

Reprints: Lori A. Erickson, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: erickson.lori@mayo.edu).

Papillary thyroid carcinoma is the most common endocrine carcinoma. The yearly incidence of thyroid carcinoma in the United States is 13.5 cases per 100,000 population.1 Most papillary thyroid carcinomas are associated with relatively good survival, even in the metastatic setting. Tumor-related deaths in most series are ∼5%.2 Recent studies have suggested that tumors previously regarded as noninvasive follicular variant of papillary thyroid carcinoma may be better classified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features to better reflect the indolent biological course of this group of tumors.3 However, at the other end of the spectrum, some papillary thyroid carcinomas are associated with aggressive behavior such as the recently described hobnail variant as well as the tall cell variant, the columnar variant, and the solid variant.

New to the fourth edition of the WHO Classification Tumours of Endocrine Organs (2017), the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality.1,4,5 The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been attributed to the histologic subtype and/or to the clinicopathologic features, an issue which remains controversial.6–8 The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension.9,10 The solid/trabecular variant of papillary thyroid carcinoma must be distinguished from poorly differentiated thyroid carcinoma which has a similar growth pattern, but lacks nuclear features of papillary thyroid carcinoma and may show necrosis and prominent mitotic activity.1 The term solid/trabecular variant of papillary thyroid carcinoma is used when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance.1 All of these variants are histologically unique and important to recognize due to their aggressive behavior.

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HOBNAIL VARIANT OF PAPILLARY THYROID CARCINOMA

The hobnail variant of papillary thyroid carcinoma is a recently described aggressive type of papillary thyroid carcinoma (Table 1).4,5,11–24 The features have also been described as micropapillary.23 The histologic features of this variant include papillary and micropapillary structures closely lined by cells containing eosinophilic cytoplasm and apically located nuclei with prominent nucleoli (Fig. 1).1 The cells that line these complex papillary structures have increased nuclear to cytoplasmic ratios and apically placed nuclei that produce a surface bulge (hobnail). In 2010, a study from Mayo Clinic identified 8 cases of papillary thyroid carcinoma with prominent hobnail features.5 Two were consultation cases and 6 were in the files of the Mayo Clinic of 2,534 papillary thyroid carcinomas from 1955 to 2004. The patients ranged in age from 28 to 78 years (mean, 57.6 y), and 6 were female and 2 were male.5 The tumors ranged in size from 1 to 4 cm (mean, 2.5 cm) and were often multifocal. The criteria used to identify these cases were: nonsolid type of papillary thyroid carcinoma, ≤10% tumor tall/columnar or diffuse sclerosing, loss of polarity/cohesiveness with hobnail features in ≥30%, and available clinical data and follow-up.5 The tumors have complex papillary structures lined by cells with increased nuclear to cytoplasmic ratios and apically placed nuclei that produce a surface bulge (hobnail) (Fig. 1).5 The tumors were positive for thyroglobulin, thyroid transcription factor-1 (TTF1), p53, B-catenin, E-Cadherin (intact, membranous staining), and Ki67 2% to 20% (mean, 10%). BRAF mutation was identified in 4 of 7 cases (57%).5 With a mean follow-up of 77 months, 5 of 8 had distant metastases, 4 of 8 died of disease (mean follow-up, 43 mo), 2 were alive with disease (at 4 and 87 mo) and 2 were alive without disease (120 and 236 mo follow-up).5 The authors concluded that papillary thyroid carcinoma with a prominent hobnail pattern is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality.5

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

In a subsequent extended study of 24 papillary thyroid carcinomas with prominent hobnail features, the patients ranged in age from 28 to 78 years (mean, 57 y) and had a mean follow-up of 106 months (4 to 274 mo).4 The tumors were associated with aggressive features: 71% vascular invasion, 61% with lymph node metastases, and 44% with distant metastases. There was no difference in the aggressive histologic features between the tumors with <30% or >30% hobnail component. Of the 24 cases, 12 tumors had <30% hobnail component and 12 had tumors had >30% hobnail component. Of the tumors with <30% hobnail component, 58.3% (7/12) were American Joint Committee on Cancer pathological tumor, regional node, distant metastases stage I or II and 41.6% were stage III or IV at presentation. Of those with >30% hobnail component 16.7% (2/12) were stage I or II and 83.3% (10/12) were stage III or IV at presentation. Of the 12 patients with tumors with >30% hobnail component at last follow-up, 6 had died of disease (mean, 44.8 mo), 3 were alive with extensive disease (mean, 32.3 mo), and 3 were alive with no disease (mean, 125.3 mo). Of the 12 patients with tumors with <30% hobnail component at last follow-up, 2 had died of disease (21 and 163 mo), 9 were alive with extensive disease (mean, 162 mo), and 1 had died of other causes (155 mo). Interestingly, 1 of the 2 patients with <30% hobnail component who died of disease had a tumor with <10% hobnail component.4 Although the cutoff of 30% hobnail component is used in the recent (fourth edition, 2017) WHO Classification Tumours of Endocrine Organs for the hobnail variant, even tumors with <10% hobnail component can behave aggressively.

The hobnail variant of papillary thyroid carcinoma is often associated with other aggressive histologic types of thyroid carcinoma. A study from Massachusetts General Hospital, Boston, MA included 12 cases of the hobnail variant of papillary thyroid carcinoma with >30% hobnail component.18 In total, 40% of these tumors also had components of tall cell papillary thyroid carcinoma (comprising <50% of the tumor), and 2 had foci (<5%, 1%) of anaplastic thyroid carcinoma.18 In a study from Washington University in St. Louis, Missouri, a hobnail component (>10% of the tumor) was identified in 1.3% (6/478) papillary thyroid carcinomas.11 Hobnail features were often associated with other aggressive histologic variants of papillary thyroid carcinoma, including tall cell, columnar cell, and solid variant.11 Four of 18 (22%) poorly differentiated carcinomas studied had a component of hobnail features, and 1 of 26 (3.8%) anaplastic thyroid carcinomas had a component of hobnail features.11

The hobnail variant of papillary thyroid carcinoma is associated with aggressive features including high stage, older age, vascular invasion, and lymph node and distant metastases. These tumors often present at a high pathological tumor, regional node, distant metastases stage with 25% to 87.5% presenting with stage III or IV disease.4,5,15,16,18 These tumors often occur in patients in their fifth and sixth decade, but can occur over a wide age spectrum (21 to 86 y).4,5,11,12,15,16,18,25 Vascular invasion is common, occurring in 41.7% to 71.4% of cases.4,18,25 Lymph node metastases are identified at presentation in up to 75% of cases18 and distant metastases are identified in up to 43.5% of cases.4

The hobnail variant of papillary thyroid carcinoma shows immunopositivity for TTF1 and thyroglobulin.4,5 These tumors show increased expression of p53 (>25% of the neoplastic nuclei).4 E-cadherin expression and B-catenin expression are usually intact (membranous).4,18 Ki67 is often moderately increased (mean, 10%; range, 2% to 20%) 4 Hobnail papillary thyroid carcinomas are usually large tumors with studies reporting mean tumor sizes of 2.5 to >10 cm with a wide range in size.4,5,12,15,16,18

BRAF V600E mutation is commonly identified in papillary thyroid carcinoma. Studies report 33.3% to 83.3% of hobnail papillary thyroid carcinomas have BRAF mutation.5,11,12,15,16,18,19 Of 64 cases studied for BRAF mutation in the literature, 44 (68.8%) had BRAF mutation.5,11,12,15,16,18,19 Of the 12 cases of hobnail variant of papillary thyroid carcinoma with >30% hobnail component reported from Massachusetts General Hospital, 8 of the 10 cases evaluated had BRAF V600E mutation, including 3 without a tall cell component.18 Two of 12 cases studied had RET/PTC1 mutation (both of which were BRAF wild-type).18 A recent somatic mutation profiling study of 18 cases of hobnail variant of papillary thyroid carcinoma (containing >30% hobnail component) and 4 lymph node metastases found mutations in BRAF in 72.2%, TP53 in 55.6%, hTERT in 44.4%, PIK3CA in 27.8%, CTNNB1 in 16.7%, EGFR in 11.1%, AKT1 in 5.5%, and NOTCH1 in 5.5%.19 A similar mutation pattern was identified in primary tumors and in metastases.19 An increased mortality risk was associated with BRAF mutation and with BRAF mutation associated with TP53 and/or PIK3CA mutations.19

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TALL CELL VARIANT OF PAPILLARY THYROID CARCINOMA

The tall cell variant of papillary thyroid carcinoma was described in 1976 by Hawk and Hazard.26 The tall cell variant is the most common aggressive variant of papillary thyroid carcinoma (Table 2). Depending on the report, the tall cell variant comprises 1% to 19% papillary thyroid carcinomas. These tumors usually occur in older patients who present with a neck mass or other symptoms, and the tumors are large in size.26 The incidence of the tall cell variant of papillary thyroid carcinoma is increasing. A study utilizing the surveillance, epidemiology, and end results program (SEER) database from 1988 to 2008 identified 573 tall cell variants and 42,904 classic papillary thyroid carcinomas.27 Over this time period the incidence of tall cell variant increased 158%, with classic papillary thyroid carcinoma increasing 61%.27 This has been attributed to increased detection of thyroid carcinoma overall and increased attention to the tall cell variant of papillary thyroid carcinoma.27 The tall cell variant of papillary thyroid carcinoma is usually treated by resection, lymph node dissection, I131 for systemic disease (but 20% are refractory), and external beam therapy.

TABLE 2

TABLE 2

The tumors have been described as composed of prominent papillary structures lined by cells 2 or 3 times as tall as they are wide, depending on the study. The tumor cells have abundant eosinophilic (oncocytic-like) cytoplasm and cytologic features classic of papillary thyroid carcinoma (Fig. 1). The most recent WHO Classification of Tumours of Endocrine Organs describes them as having typical nuclear features of papillary thyroid carcinoma and being “composed of cells that are 2 to 3 times as tall as they are wide, and that show abundant eosinophilic (oncocytic-like) cytoplasm.”1

How much of the tumor needs to be tall cell for the tumor to be regarded as tall cell variant of papillary thyroid carcinoma? In the original description by Hawk and Hazard was ≥30%, but the subsequent literature has varied from 10% to 75%. The third edition (2004) of the WHO Classification of Tumours of Endocrine Organs listed ≥50%, which was the cutoff in some studies.28,29 In a study of 125 tall cell papillary thyroid carcinomas (enriched with 57 cases with adverse outcome) tumors with >10% tall cell component were associated with advanced tumor stage and lymph node metastases.30 A tall cell component of >10% was the only significant factor for overall, tumor-specific, and relapse-free survival by multivariable analysis. The authors suggested that papillary thyroid carcinomas with at least 10% tall cell component are associated with adverse outcome and this feature should be included in the pathology report. Others have suggested that any foci of tall cells should be noted in pathology reports regardless of percentage.31

In a study from Memorial Sloan Kettering Cancer Center, 288 papillary thyroid carcinomas with <30% tall cell component, 31 carcinomas with 30% to 49% tall cell component, and 134 carcinomas with ≥50% tall cell component were compared.32 The tumors were all ≥1 cm, diagnosed from 1985 to 2005, and had mean follow-up of 9.3 years. Tumor size increased as percentage of tall cell component increased. The tumor size increased from those with <30% tall cell component to those with 30% to 49% to those ≥50% tall cells having the largest mean tumor size. Tumors in groups 30% to 49% tall cells and ≥50% tall cells were associated with higher pT stage, increased extensive extrathyroidal extension, increased margin positivity, increased patient age, and decreased disease-specific survival (91% for tumors with 30% to 49% tall cell component and 96% for tumors with ≥50% tall cell component) compared with papillary thyroid carcinomas with <30% tall cell component (100% disease-specific survival). Also, 2.5% (4/165) cases with 30% to 49% and with ≥50% tall cell component had poorly differentiated or anaplastic carcinoma in recurrences. None of the 288 cases with <30% tall cell component were associated with poorly differentiated or anaplastic carcinoma. By multivariable analysis, >5 positive lymph nodes was prognostically significant for neck recurrence, and extranodal extension was prognostically significant for distant recurrence-free survival. As tumors with 30% to 49% and ≥50% tall cell component had similar features and survival and were more aggressive than those <30% tall cell component, the authors recommend 30% cutoff for classification as tall cell variant.32 In a review of the literature published in 2016, >30% tall cell component is most often used as the cutoff for the classification.33 The most recent (fourth edition, 2017) of the WHO Classification of Tumours of Endocrine Organs notes that “tall cells must account for ≥30% of all tumor cells for the diagnosis of the tall cell variant.”1

The tall cell variant of papillary thyroid carcinoma is more aggressive than classic papillary thyroid carcinoma and the follicular variant of papillary thyroid carcinoma. A recent retrospective study of 6282 papillary thyroid carcinomas treated with total or near-total thyroidectomy, neck dissection, and postsurgical I131 ablation as needed clinically from The Cancer Genome Atlas included and 26 centers included 4702 (74.8%) classic papillary thyroid carcinomas, 1126 (17.9%) follicular variant of papillary thyroid carcinomas, and 239 (3.8%) tall cell variant of papillary thyroid carcinomas.34 The median age was 44 years, and 4799 females and 1483 males were included. The follow-up was 37 months. High risk parameters [extrathyroidal invasion, lymph node metastasis, stages III/IV, recurrence, mortality, and the use (need) of radioiodine] were increasingly identified from follicular variant of papillary thyroid carcinoma to classic papillary thyroid carcinoma to tall cell variant of papillary thyroid carcinoma. Recurrence and thyroid cancer–specific death also increased from follicular variant of papillary thyroid carcinoma (9.1% recurrence, 0.6% thyroid cancer–specific death) to classic papillary thyroid carcinoma (16.1% recurrence, 2.5% thyroid cancer–specific death) to tall cell papillary thyroid carcinoma (27.3% recurrence, 6.7% cancer-specific death).34

In a literature review of 843 tall cell papillary thyroid carcinomas, the tall cell variant was associated with a relatively increased prevalence in males, older age, and more frequent aggressive features at diagnosis than classic papillary thyroid carcinoma.33 A relatively increased prevalence in males (26% male, 74% female) was identified as compared classic papillary thyroid carcinoma.33 Age at diagnosis 41 to 66 years (mean, 50.1 y) for tall cell variant was older than those with classic papillary thyroid carcinoma 34 to 53 years (mean, 45.7 y). Similarly, a SEER study found mean age at diagnosis for the tall cell variant (55.3 y) to be older than that for classic papillary thyroid carcinoma (47.1 y).35 In the literature review of 843 tall cell papillary thyroid carcinomas, aggressive features were identified at presentation more often in the tall cell cases than in the classic papillary thyroid carcinomas.33 The tall cell variant was multifocal in 45.7% (in classic it was multifocal 32.7%), had extrathyroidal extension in 63.9% (classic 33.5%), had lymph node involvement in 59.3% (classic 33.7%), and had distant metastases in 8.6% (classic 3%).33

Why is the tall cell variant of papillary thyroid carcinoma more aggressive than conventional papillary thyroid carcinoma? The tall cell variant is more often associated with increased recurrence and decreased survival than classic papillary thyroid carcinoma. Some studies have suggested that the tall cell variant may have a worse prognosis due to older patient age, larger tumor size, and higher frequency of extrathyroidal extension, whereas others have found the tall cell variant without aggressive features (ie, extrathyroidal extension) to be more aggressive than classic papillary thyroid carcinoma independent of age, sex, and tumor size.

Studies have suggested the histologic type—tall cell—independently affects recurrence6–8 and survival.27 In a study of 183 papillary thyroid carcinomas, including 19 tall cell variant, multivariate analysis showed tall cell histology, age, and tumor size were significant predictors of recurrence.7 A study from Memorial Sloan Kettering Cancer Center evaluated 62 tall cell papillary thyroid carcinomas without extrathyroidal extension and 83 classic papillary thyroid carcinomas without extrathyroidal extension, and no statistical difference was identified between the tall cell and classic types in relation to age, sex, tumor size, risk stratification, therapy, or follow-up.6 The tall cell cases showed more capsular invasion and more frequent lymph node metastases at presentation than the classic tumors.6 By multivariate analysis, the only independent factor associated with lymph node metastases was histologic subtype (tall cell vs. classic). They concluded that in tumors without extrathyroidal extension, tall cell variant is more biologically aggressive than classic papillary thyroid carcinoma independent of age, sex, and tumor size.6 However, in a subsequent larger study from Memorial Sloan Kettering Cancer Center, multivariate analysis showed the only independent prognostic factors of neck and distant recurrence-free survival were >5 positive lymph nodes and extranodal extension, respectively.32 A SEER-based study of 278 tall cell papillary thyroid carcinomas and 2522 classic papillary thyroid carcinomas found 5-year disease-specific survival for tall cell variant worse than other papillary thyroid carcinomas (81.9% vs. 97.8%).35 Tall cell variant of papillary thyroid carcinoma was worse compared with matched classic papillary thyroid carcinomas—matched for age, sex, extent of extrathyroidal extension, regional and distant metastases, and surgical and adjuvant therapy. Another SEER-based study found patients with papillary thyroid carcinoma with tall cell histology had shorter 5-year overall survival (80.6% vs. 93.5%) after adjustment for other factors.27

Other studies have found tall cell histology not to be an independent risk factor for recurrence and death. By multivariate analysis, age, extrathyroidal extension, and TNM stage have been reported to be most relevant factors.36–38 In a study of 128 papillary thyroid carcinomas, tumor size and histologic grade (nuclear atypia, necrosis, vascular invasion), not subtype, were significant independent prognostic markers.36 A study of 56 tall cell papillary thyroid carcinomas found that histologic subtype did not have an effect on clinical outcome after multivariate analysis.38 Rather, tall cell variant was considered more aggressive because of higher stage and grade compared with the 503 classic papillary thyroid carcinomas in the study. In a study of 24 cases tall cell variant of papillary thyroid carcinoma, no relationship was found between tall cell variant histology and recurrence or mortality.37 In the study that included 165 papillary thyroid carcinomas with >30% tall cell component and 288 classic papillary thyroid carcinomas from Memorial Sloan Kettering Cancer Center multivariate analysis showed the only independent prognostic factors of neck and distant recurrence-free survival were >5 positive lymph nodes and extranodal extension, respectively.32

In the most recent fourth edition (2017) of the WHO Classification of Tumours of Endocrine Organs, the aggressive behavior of tall cell variant of papillary thyroid carcinoma is ascribed to a variety of features that have been described in the literature.1,28,32,35 The study by Morris et al35 is cited reporting tall cell to be associated with older patient age and considered aggressive because tumors show extrathyroidal extension and metastases more frequently than conventional papillary thyroid carcinoma.1 Also noted are the studies by Ghossein and Livolsi28 and Ganly et al32 that showed the prognosis of tall cell variant remains less favorable in cases with no extrathyroidal extension or only focal tall cell areas.1 The WHO also addresses the issue of the tall cell variant accounting for many radioiodine-refractory thyroid carcinomas.39

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COLUMNAR VARIANT OF PAPILLARY THYROID CARCINOMA

The columnar variant of papillary thyroid carcinoma is uncommon and occurs over a wide age range. This variant of papillary thyroid carcinoma can be aggressive, and may not respond to I131 or chemotherapy (Table 3). The columnar cell variant is composed of at least 30% of elongated cells with nuclear stratification and scant cytoplasm.1 The nuclear stratification and scant cytoplasm differentiate it from the tall cell variant of papillary thyroid carcinoma (Fig. 1). The columnar variant also lacks psammoma bodies except if it is associated with classic papillary thyroid carcinoma. The neoplastic cells lack conventional nuclear features of papillary thyroid carcinoma. These are hypercellular neoplasms with thin papillae or glandular-like spaces lined by pseudostratified epithelium. The cells have elongated nuclei, hyperchromasia, supranuclear, and/or subnuclear cytoplasmic vacuolization reminiscent of endometrioid or intestinal adenocarcinoma. Tumors may be circumscribed or encapsulated, and those with diffuse and infiltrative growth pattern and extrathyroidal extension may behave more aggressively.9,10 Mitotic activity is usually increased, with a mitotic rate of 2 to 13 per 10 high power fields. Ki67 is often 20%, but may be even higher in aggressive tumors. These tumors are positive for TTF1 and thyroglobulin, and B-catenin is intact. Interestingly, these tumors may occasionally be positive for CDX2.40

TABLE 3

TABLE 3

The columnar variant of papillary thyroid carcinoma variable behavior but can be aggressive and can metastasize widely. These are uncommon tumors. Of 5174 papillary thyroid carcinomas from 3 institutions, only 9 cases of columnar variant of papillary thyroid carcinoma were identified.10 Of the 9, 4 occurred in females and 5 in males. The mean age was 57 years (range, 32 to 90 y). Eight of the 9 patients presented with a neck mass, whereas 1 case was identified incidentally at autopsy. The tumors were treated with resection (1 with laryngotracheal resection) postoperative I131 in 7, and external radiation in 3 cases. The tumors had increased expression of cyclin D1, increased Ki67, weak nuclear p53, retained B-catenin (membranous), necrosis (2/9), and increased estrogen and progesterone receptor expression. Three of the 9 tumors had BRAF V600E mutation (2 of which were identified in aggressive cases). Of the 9 cases, 4 were associated with an indolent course, whereas 5 were associated with aggressive disease. In the indolent group of 4 cases, 3 occurred in females and 1 in a male. Of the 5 cases in the aggressive group 1 occurred in a female and 4 in males. The mean age for the indolent group was younger (49 y; range, 32 to 90 y) than that of the aggressive group (63 y; range, 5 to 81 y). Patients in the indolent group were either asymptomatic or had a painless mass, whereas those in the aggressive group had a clinical mass and 2 were symptomatic (shortness of breath, hoarse, stridor, hemoptysis, adenopathy, tracheal deviation, dysphagia). The tumors in the indolent group were smaller (2.1 cm; range, 1.3 to 4 cm) than those in the aggressive group (6.7 cm; range, 4 to 11 cm). Importantly, tumors in the indolent group were either encapsulated or circumscribed with 2 having minimal capsular invasion and no extrathyroidal invasion was present. Tumors in the aggressive groups were diffusely infiltrative, had extrathyroidal extension, laryngotracheal invasion, cervical lymph node metastases, or distant metastases. American Joint Committee on Cancer stage was I or II for the indolent group and III or IV for aggressive group. Those in the indolent group were alive without disease (mean follow-up, 59 mo). Patients with aggressive tumors either died of disease (3 patients, 17 to 45 mo) or were alive with disease (2 patients). The authors reviewed 48 cases of columnar variant of papillary thyroid carcinoma in the literature and found 20 of the cases to be associated with indolent behavior and 28 with aggressive disease. Those associated with indolent behavior were more common in females (18 females and 2 males in indolent group, 10 females and 13 males in aggressive group), younger (mean age, 45 y in indolent group, 56 in aggressive group), and smaller tumors (mean, 3.6 cm in indolent group, 6.0 cm in aggressive group). Eighteen of 19 patients with follow-up in indolent group were alive without disease, whereas among the 20 in the aggressive group 13 died of disease and 5 were alive with disease.10

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SOLID/TRABECULAR VARIANT OF PAPILLARY THYROID CARCINOMA

The solid/trabecular variant of papillary thyroid carcinoma is uncommon, accounting for ∼2.6% (20/758) papillary thyroid carcinomas diagnosed at Mayo Clinic in Rochester, Minnesota from 1962 to 1989.41 This variant comprises ∼1% to 3% adult papillary thyroid carcinoma, but is more common in young patients and with history of exposure to ionizing radiation. Approximately 37% of papillary thyroid carcinomas associated with the Chernobyl nuclear disaster were solid variant of papillary thyroid carcinoma. RET/PTC3 rearrangement is associated with pediatric and radiation-associated solid variant of papillary thyroid carcinoma, but not those in other settings (Table 4). The solid variant of papillary thyroid carcinoma has a higher frequency of distant metastases (lung) and less favorable prognosis than classical papillary thyroid carcinoma.41 The mortality rate for this tumor in adults is up to 10%.

TABLE 4

TABLE 4

Historically, criteria for classification of solid variant of papillary thyroid carcinoma included >70% solid growth, cytologic features of papillary thyroid carcinoma, and no necrosis (Fig. 1). The recent fourth edition (2017) WHO Classification of Tumours of Endocrine Organs states: “The term solid variant should be used when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance.”1

The solid variant of papillary thyroid carcinoma must be distinguished from follicular carcinoma with a solid growth pattern and from poorly differentiated thyroid carcinoma. Poorly differentiated thyroid carcinoma has been referred to as insular carcinoma, trabecular carcinoma, among others terms. The classification of poorly differentiated thyroid carcinoma itself has been controversial. According to the fourth edition (2017) of the WHO Classification of Tumours of Endocrine Organs, poorly differentiated thyroid carcinoma “is a follicular cell neoplasm that shows limited evidence of follicular cell differentiation and is morphologically and behaviorally intermediate between differentiated (follicular and papillary) carcinomas and anaplastic carcinoma.”1 The fourth edition (2017) WHO Classification then refers readers to the Turin consensus proposal for the histopathologic diagnostic criteria of poorly differentiated thyroid carcinoma.1,42 The Turin criteria include: “(1) presence of a solid/trabecular/insular pattern of growth, (2) absence of the conventional nuclear features of papillary carcinoma, and (3) presence of at least one of the following features: convoluted nuclei; mitotic activity ≥3×10 HPF, and tumor necrosis.”42 Poorly differentiated thyroid carcinomas have the same growth pattern as solid/trabecular variant of papillary thyroid carcinoma. Poorly differentiated thyroid carcinomas may arise in a synchronously or metrachronously with a papillary thyroid carcinoma or a follicular thyroid carcinoma or it may arise de novo.1 Poorly differentiated thyroid carcinomas have a growth pattern similar to that of the solid/trabecular variant of papillary thyroid carcinoma. Follicular thyroid carcinomas may also show a solid growth pattern, but the cells in follicular thyroid carcinoma and poorly differentiated thyroid carcinoma lack nuclear features of papillary thyroid carcinoma. The convoluted nuclei that may be seen in poorly differentiated carcinoma may reflect dedifferentiated nuclear features of papillary thyroid carcinoma.1 Poorly differentiated thyroid carcinomas may also show tumor necrosis and/or high mitotic activity. The fourth edition (2017) of the WHO Classification of Tumours of Endocrine Organs states that aggressive forms of papillary or follicular carcinomas “should not be included in the poorly differentiated category if their distinctive features of differentiation (papillary carcinoma nuclei, papillae or follicles) are retained throughout the tumor.”1,42 The authors of the Turin proposal suggest a diagnostic algorithm.42 When evaluating a folliculogenic thyroid tumor, one may start by considering a follicular or papillary thyroid carcinoma. If the tumor shows solid, trabecular, or insular growth, then one would consider solid variant of papillary thyroid carcinoma, a follicular carcinoma with a solid growth pattern, and a poorly differentiated thyroid carcinoma. The solid variant of papillary thyroid carcinoma would show typical cytologic features of papillary thyroid carcinoma throughout. Follicular thyroid carcinoma with a solid growth pattern and poorly differentiated thyroid carcinoma would lack the classic cytologic features of papillary thyroid carcinoma. By the Turin criteria, poorly differentiated thyroid carcinomas would have at least one of the following criteria: convoluted nuclei or necrosis or increased mitotic activity.42 The presence of even 10% of poorly differentiated component in a well-differentiated thyroid carcinoma may be prognostically significant and worth including in the pathology report.1,43 Thus, careful histologic evaluation and sampling of these tumors is important to the most appropriate classification.

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CONCLUSIONS

The variants of papillary thyroid carcinoma are interesting pathologic entities, and some variants may behave more aggressively than classic papillary thyroid carcinoma. Thus, it is important to be aware of these variants and their significance. New to the fourth edition (2017) of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is an uncommon but very aggressive variant of papillary thyroid carcinoma. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and to the clinicopathologic features. The columnar variant of papillary thyroid carcinoma can also be aggressive, particularly in older patients, with larger tumors, presenting symptomatically, and showing a diffusely infiltrative growth, and extrathyroidal extension. The solid/trabecular variant of papillary thyroid carcinoma must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. These variants are histologically unique and important to recognize due to their aggressive behavior.

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REFERENCES

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Keywords:

papillary thyroid carcinoma; tall cell; columnar; hobnail; solid; variant of papillary thyroid carcinoma

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