The contribution of molecular pathology to the classification of thyroid tumors

Significant molecular advances have been undertaken for the past two decades in the field of thyroid follicular neoplasms, including a detailed genomic profile of papillary thyroid carcinoma (PTC) by The Cancer Genome Atlas (TCGA) project. These molecular discoveries led to a better understanding of the pathogenesis of thyroid neoplasms and resulted in reclassification of certain types of thyroid tumors. This review discusses how, 1) the molecular profiles of follicular-patterned lesions led to the reclassification of the follicular variant of PTC into non-invasive follicular thyroid neoplasm with papillary like nuclei, 2) the genotyping of Hürthle cell neoplasm provided the rationale to classify these tumors independently from follicular adenomas and carcinomas, and 3) BRAF and RAS molecular signatures have the potential of subclassifying PTC and poorly differentiated thyroid carcinoma into clinically relevant molecular subtypes.     

Sonographic and cytologic differences of NIFTP from infiltrative or invasive encapsulated follicular variant of papillary thyroid carcinoma

We reclassified 179 cases of the follicular variant (FV) of papillary thyroid carcinoma (PTC) into 72 (40.2%) noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP), 37 (20.7%) encapsulated FVPTC with invasion (EFVPTC), and 70 (39.1%) infiltrative FVPTC (IFVPTC) without a capsule. In the NIFTP group, 5.6% cytology were hypercellular and the remainder low to moderate cellularity. PTC nuclei were absent in 18%, focally present in 37.5%, and diffusely present in 44.4%. In the EFVPTC group, 8.1% cytology were hypercellular and the reminder low to moderate cellularity. PTC nuclei were absent in 24.3%, focally present in 29.7% and diffusely present in 45.9%. In IFVPTC group, 24.3% cytology were hypercellular and the reminder low to moderate cellularity. PTC nuclei were diffusely present in 88.6% and focally present in 11.4%. The ultrasound findings for NIFTP and minimally invasive EFVPTC typically demonstrated a circumscribed oval/round nodule with a hypoechoic rim, and the Doppler was mostly hypervascular. The ultrasound findings for overtly invasive EFVPTC typically showed a round/oval nodule with irregular margins and the Doppler was mostly hypervascular. The ultrasound findings for IFVPTC group showed at least one of the malignant gray‐scale features: markedly hypoechoic, taller‐than‐wide, microcalcifications or blurred margins. The Doppler in this group was mostly avascular. An algorithm is proposed to triage thyroid FNA based on different scenarios of the sampled cells, interpreted in the context of ultrasound features with histology outcomes. Five composite ultrasound‐cytology‐histology figures illustrate NIFTP, IFVPTC, and IFVPTC with intratumoral fibrosis, microfollicular EFVPTC and normofollicular EFVPTC. Diagn. Cytopathol. 2017;45:533–541. © 2017 Wiley Periodicals, Inc.     

Diagnosis of "follicular neoplasm": a gray zone in thyroid fine-needle aspiration cytology.

The thyroid fine-needle aspiration (FNA) diagnosis of "follicular neoplasm" does not differentiate between a benign and malignant tumor. Often cases diagnosed as "follicular or Hürthle-cell neoplasm" undergo surgical excision for further characterization. The aim of this study was to identify clinical features that may help in predicting malignancy in patients with an FNA diagnosis of follicular neoplasm. One hundred eighty-four cases in 167 patients were diagnosed as "follicular neoplasm" among 1,024 thyroid FNA evaluated with on-site interpretation from 1998-2000. The cases were evaluated for the following variables: histologic diagnosis, age, sex, and size of the nodule. One hundred thirty-nine patients were female, and 28 were male (age range, 23-80 yr). Among 122 patients (67%) undergoing surgical excision (lobectomy, 96; total thyroidectomy, 26), malignancy was identified in 37 cases (31%). Nonpapillary (follicular/Hürthle) carcinoma was diagnosed in 11 (9%), follicular variant of papillary carcinoma in 25, and medullary carcinoma in 1 case. The risk of malignancy was greater in males (47% vs. 29%, P < 0.0004) than females, in nodules measuring 3 cm or more (55% vs. 23%, P < 0.0001), than in nodules measuring less than 3 cm, and in patients 40 or more yr old (20% vs. 10%, P = 0.0001) than in patients younger than 40 years. The diagnosis "follicular neoplasm" is indeterminate, and the majority of cases (70% in the current study) are benign. However, clinical features, including gender, nodule size, and age, can be a part of the decision analysis in selecting patients for surgery.     

Adenomatoid nodules are the main cause for discrepant histology in 234 thyroid fine-needle aspirates reported as follicular neoplasm

According to several large studies, the surgical pathologist renders a non-neoplastic diagnosis in ～20-40% of thyroid fine-needle aspiration (FNA) cases reported as follicular neoplasm. This study analyzes the cause of this poor correlation between cytology and histology. Cases consisting of oncocytic (Hurthle) cells were excluded from study. During the study period from January 1996 to April 2010, histologic follow-up was available for 234 of 670 cases (34.9%) reported as follicular neoplasm on ultrasound-guided thyroid FNA. Sonographic and Doppler data were available in all cases and included nodule location, size, echogenicity, and vascularity. Of the 234 aspirates with follow-up, surgical pathology reported 130 cases (55.6%) of follicular adenoma, 15 cases (6.4%) of follicular carcinoma, 14 cases (6.1%) of follicular variant of papillary carcinoma, and 75 cases (32.3%) of nodular goiter. Recuts of those index nodules reported as nodular goiter were examined independently by two pathologists using the 2× objective lens. Adenomatoid nodule was defined as an insufficiently encapsulated "blue" nodule of increased nuclear density when compared with the surrounding thyroid. Of the 75 cases reported as nodular goiter, 60 index nodules (80%) fulfilled the described criteria for adenomatoid nodule, while 15 did not. In conclusion, adenomatoid nodules are the main cause of poor histologic correlation with follicular neoplasm reported by FNA. If "increased nuclear density at scanning magnification" were adopted by surgical pathologists as the major diagnostic criterion for follicular adenoma rather than encapsulation, noncorrelated cases would be reduced from 32 to 6.4%.     

Familial non-medullary thyroid cancer: an update on the genetic and pathologic features

Well differentiated thyroid carcinoma is one of the most increasingly prevalent cancers, and while many are sporadic, some are inherited. These heritable thyroid cancers are grouped as familial non-medullary thyroid carcinoma (FNMTC) and represent approximately 5–10% of non-medullary thyroid carcinomas. While the group of FNMTC is quite heterogeneous, an ever increasing number of attributable genetic changes have been described. In addition to the classic, non-syndromic FNMTC there are also several well defined and characterized genetic syndromes with thyroid cancer as a component. This review will provide an update on the current molecular understanding of both syndromic and non-syndromic heritable thyroid cancer.     

Incidence of neoplasia in Hashimoto's thyroiditis: A fine-needle aspiration study

There is a recognized association between Hashimoto's thyroiditis (HT) and thyroid neoplasms. We reviewed fine-needle aspirations (FNAs) from 90 patients with HT to assess the contribution of this procedure. For seven patients, FNA showed HT and follicular neoplasm (n = 6) or HT and papillary carcinoma (n = 1). Eighteen patients underwent thyroid resection. Three patients had follicular adenomas which were not detected by FNA, one patient had papillary carcinoma confirmed, and six patients with follicular neoplasm by FNA were negative for tumor. Thus, 4% of our patients had confirmed neoplasms, an incidence lower than usually reported. One reason for the lower rate of neoplasia in our series was misinterpretation of follicular neoplasia in the background of HT. The cytologic changes in the hyperplastic follicular and metaplastic oncocytic epithelium are similar to those seen in follicular neoplasm. Our study suggests that these processes may be indistinguishable, and thus, in the presence of HT, the diagnosis of follicular neoplasm probably should not be rendered. Diagn Cytopathol 1996;14:38–42. © 1996 Wiley-Liss, Inc.     

Update on follicular variant of papillary thyroid carcinoma with an emphasis on new terminology: noninvasive follicular thyroid neoplasm with papillary-like nuclear features

The most common papillary thyroid carcinoma (PTC) variant is the follicular variant, representing ∼30% of all PTCs. The tumour is most common in middle aged (4th – 5th decades) women, who usually present with a single dominant nodule (about 3 cm). By definition, follicular architecture must be the dominant finding, while demonstrating the nuclear features of PTC. Papillary structures are <1% of volume, while necrosis, increased mitoses (>3/10 high power fields) and psammoma bodies are absent. The tumour category is divided into “encapsulated/well demarcated” and “invasive” types. The nuclear features include enlarged, elongated and overlapping nuclei; membrane irregularities (irregular contours, grooves and pseudoinclusions); chromatin clearing, margination and glassy nuclei. When the tumour is encapsulated/well demarcated without invasion, demonstrating the other inclusion and exclusion criteria, the new name of “Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features” (NIFTP) is used, a tumour that requires no additional treatment.     

The triage efficacy of fine needle aspiration biopsy for follicular variant of papillary thyroid carcinoma using the Bethesda reporting guidelines

Diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) by ultrasound-guided fine-needle aspiration (FNA) is challenging. In this retrospective review, we evaluated triage efficacy (i.e., potential for triggering surgical intervention) in 44 archived FNA biopsies of surgically confirmed FVPTC obtained between December 2006 and December 2008. We compared the original FNA diagnoses with reclassified diagnoses based on 2007 National Cancer Institute (NCI)/Bethesda recommendations, and reviewed FNA cytologic features. Original FNA diagnoses included colloid nodule (7%, 3/44), atypical follicular cells (5%, 2/44), follicular lesion (11%, 5/44), follicular neoplasm (16%, 7/44), suspicious for malignancy/PTC (27%, 12/44), and papillary thyroid carcinoma (34%, 15/44). Reclassified diagnoses included indeterminate (5%, 2/44), colloid nodule (7%, 3/44), atypical cells of undetermined significance [ACUS] (7%, 3/44), Hurthle cell neoplasm (2%, 1/44), follicular neoplasm (7%, 3/44), suspicious for malignancy/PTC (25%, 11/44), and PTC (48%, 21/44). Triage efficacy was 77% (34/44) for original diagnoses versus 82% (36/44) for reclassified FNA diagnoses. We frequently observed cytologic features of PTC, such as nuclear grooves and fine chromatin; conversely, intranuclear inclusions, though present in 77% cases, were scant. Our review findings suggest that lack of characteristic cytologic features of PTC,coexistence with other thyroid lesions, and small tumor size arethe major obstacles to FNA diagnosis of FVPTC. Reclassification of thyroid FNA diagnoses does not significantly improve triage efficacy. Furthermore, FNA diagnoses of follicular neoplasm and suspicious for malignancy are valuable in patients with FVPTC because they trigger triage toward surgical intervention.     

Follicular variant of papillary carcinoma of the thyroid: Fine-needle aspirates with histologic correlation

Crile and Hazard reported in 1953 a follicular pattern of papillary thyroid carcinoma. Little has been said about this pattern in the cytologic literature. From more than 8,000 thyroid aspirates in our files, we reviewed all those diagnosed as “follicular variant of papillary carcinoma,” “suspect follicular variant of papillary carcinoma,” and “follicular neoplasm vs. follicular variant of papillary carcinoma.” Also, we reviewed all aspirates in which a diagnosis of follicular variant of papillary carcinoma had been made on surgically excised glands, regardless of the cytologic diagnosis; 63 aspirates from 45 patients were collected. All smears were air-dried and stained with Diff-Quik. Most smears were very cellular (“tumor cellularity”), and the neoplastic follicular cells formed empty follicles, rosettes, tubules, and papillary structures. Nuclei were twice the size of red blood cells, had smooth contours, were hyperchromatic, and varied in shape but not much in size. Nuclear overlapping was common. Some nuclei had one small and almost pointed end, thereby resembling arrowheads. Intranuclear inclusions, multinucleated histiocytes, and psammoma bodies were uncommon. Pink-stained colloid was frequent. Diagn. Cytopathol. 16:207–213, 1997. © 1997 Wiley-Liss, Inc.     

筛状-桑椹状型甲状腺乳头状癌1例报道及文献复习

目的 探讨筛状-桑椹状型甲状腺乳头状癌的病理特征。方法 复查1例女性患者的临床资料及病理切片行免疫组化标记,选用的一抗有CKpan、CK19、EMA、TG、TTF1、CD99、CT、SYN和CgA,并复习文献。结果 肿瘤位于甲状腺右叶。大体为淡白色卵圆形孤立实性肿块。组织学表现为乳头状、筛状、桑椹状、滤泡状、小梁状、肉瘤样、实性的结构伴囊性变和组织细胞反应,未见砂粒体。免疫组化显示肿瘤性的乳头状上皮、筛状和肉瘤梭形细胞表达CKpan和CK19。结论 甲状腺乳头状癌中的乳头状、筛状-桑椹状肿瘤细胞和肉瘤样的梭形细胞具有表达上皮性细胞的特征,该肿瘤是乳头状癌的一种罕见的变型。