Return to: Papillary Thyroid Carcinoma

Overview

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid, contributing to over 70% of thyroid cancers (Lloyd 2011). These tumors are diagnosed using characteristic nuclear morphology; however, within the classification of "papillary thyroid carcinoma," there exist several distinct architectural and cytologic subtypes. About 50% of PTC are of the classical subtype, while the other 50% are made up of less common histologic variants (Yu 2013). Conventional, or classical, papillary thyroid carcinoma (C-PTC), seen below, is characterized by papillary architecture with fibrovascular cores (black arrows) and psammoma bodies (yellow arrows) and tumor cells containing enlarged, overlapping nuclei (yellow box) with nuclear clearing ("Orphan Annie cells") and nuclear grooves and nuclear membrane irregularities (green arrow). While papillary thyroid carcinoma tends to have an excellent prognosis, certain histologic variants have been shown to have more aggressive clinical courses. As such, determining the microscopic subtype of a papillary thyroid cancer is an important step in determining prognosis. Described below are the presentation, pathologic features, and prognostic indications of several of the more common variants of papillary thyroid carcinoma (Lloyd 2011, Khanafshar 2011, Robinson 2010, Baloch 2014).

Papillary thyroid microcarcinoma​

• Clinical presentation: "Papillary thyroid microcarcinoma" refers to all papillary thyroid carcinoma measuring smaller than 1 cm in size (see image below). These tumors are often found incidentally in autopsies and thyroidectomy specimens, with a recent increase in clinical identification and biopsy attributed to the increased utilization of ultrasound. 
• Microscopic features:
  • These tumors tend to be located near the thyroid capsule and are frequently non-encapsulated.
  • Because papillary microcarcinomas are classified based on size (<1 cm), these tumors do not exhibit a distinctive morphology. Rather, they can have features of any larger papillary carcinoma subtype.
• Immunohistochemistry & molecular markers: Both RET rearrangements and BRAF mutations are common findings, with BRAF mutations confering a worse prognosis.
• Prognosis: The majority of papillary microcarcinomas exhibit a relatively benign disease course, with 28% with metastatic nodes and <1% with extra nodal metastases. Lack of encapsulation of the presence of extensive sclerosis may confer a more aggressive disease course (Lloyd 2011). High risk disease has been associated with male gender, tumors larger than 5 mm, bilateral or multifocal lesions, location in lower third of the thyroid lobe, lymph node metastasis, capsule invasion/extrathyroidal extension, BRAF mutation, and stromal fibrosis (Lloyd 2011, Khanafshar 2011, Robinson 2010).

Tall Cell Variant (TCV)

• Clinical presentation: These tumors tend to present in older patients (greater than 50 years of age) and are generally more bulky in size than conventional PTCs, often with extension beyond the thyroid capsule. The majority of cases present with metastases to the lymph nodes or even distant metastases (Baloch 2014).
• Microscopic features:
  • Due to the larger size of these tumors, they are more likely to be necrotic and exhibit mitotic activity as well as extrathyroidal extension, microcalcifications, and macrocalcifications.
  • This tumor is defined by cells whose height measures at least 2-3 times that of their width (yellow arrows). These cells have abundant eosinophilic cytoplasm and nuclear features characteristic of conventional/classical PTC (white box).
• Immunohistochemistry & molecular markers: Varied prevalence in BRAF(V600) mutations have been reported, with the aggressive behavior of TCV PTC attributed to these mutations. Other mutations associated with TCV PTC include loss of heterozygosity for chromosome 1 and the p53 gene, as well as RET/PTC3 rearrangement and RAS mutations.
• Prognosis: These tumors present in older patients are are more bulky with a greater propensity for extrathyroidal extension, and thus have a more aggressive course than conventional PTC, including increased likelihood for lymph node metastases and higher overall mortality. Some cases have also been found to be refractory to radioactive iodine treatment, conferring a worse prognosis (Baloch 2014, Roman 2013).

Columnar Cell Variant (CCV)

• Clinical presentation: These tumors are rare. They are frequently symptomatic, or present as an enlarging neck mass (as in the case below, in which there is invasion into the laryngeal soft tissue and cartilage) and are clinically indistinguishable from classical PTC.
• Microscopic features:
  • Low power: These tumors are made up of pseudostratified columnar cells arranged in papillary structures, often resembling endometrial or colonic adenocarcinomas. Solid growth patterns can coexist within the tumor (Robinson 2010, Baloch 2014).
  • High power: In contrast to the majority of PTC variants, these cells do not exhibit the typical nuclear features. Instead, they may have supranuclear and subnuclear cytoplasmic vacuoles, and thus can easily be mistaken for metastatic adenocarcinoma. The nuclei exhibit palisading along the thick fibrovascular cores (yellow line), are elongated, and hyperchromatic (white arrow). In contrast to traditional PTC, the cystoplasm is not eosinophilic and may contain super- or subnuclear vacuoles (Robinson 2010, Baloch 2014).
• Immunohistochemistry & molecular markers: Due to cytologic similarities between columnar cell variant PTC and adenocarcinoma, immunohistochemistry is useful in making diagnosis. These tumor cells are often positive for TTF-1 and may also be positive for thyroglobulin.
• Prognosis: A rare and aggressive variant of PTC, CCV has been associated with widespread metastasis and poor prognoses, particularly if presenting as an infiltrating mass. Better outcomes are seen in tumors that are completely encapsulated (Robinson 2010, Baloch 2014, Bongiovanni 2017).

Follicular Variant (FV)

• Clinical presentation​: These tumors grossly resemble follicular carcinoma, with mean tumor size falling between that of C-PTC and folliculary thyroid carcinoma (FTC) (Yu 2013).
• ​Microscopic features​:
  • The cytologic features of PTC are needed to distingush FV-PTC from a follicular neoplasm. This tumor should have cellular features of a papillary tumor (yellow box), including enlarged, overlapping irregular/ovular nuclei, nuclear clearings described as "Orphan Annie Eyes," nuclear grooves, and pink cytoplasmic invaginations (Lloyd 2011).
  • These tumors are made up of follicles that vary in size and are filled with colloid that can be distinguished as darker and more eosinophilic (yellow arrows) than that of adjacent non-neoplastic follicles (black arrows). The colloid may also exhibit the scalloped borders characteristic of papillary carcinoma. This is often is a well-circumscribed or encapsulated tumor (dashed lines), making the distinction between FV-PTC and follicular adenoma difficult and controversial.
• Immunohistochemistry & molecular markers: Because of difficulty in distinguishing follicular variant PTC from follicular neoplasms, the use of immunohistochemical and molecular markers can be helpful in the diagnosis of difficult cases. A recent study by Rivera, et al, revealed that encapsulated FV-PTCs had a molecular profile similar to that of FTC, with a high rate of RAS and absence of BRAF mutations, while infiltrative FV-PTCs tended to have an opposite molecular pattern, more closely mimicking that of PTC (high rate of BRAF mutations and low rate of RAS) (Rivera 2010).
• Prognosis: The prognosis of follicular variant PTC is similar to that of typical PTC, with the exception of diffuse or multinodular follicular variant, which confers a worse prognosis. Tumors that are completely encapsulated and do not invade have a very low risk of adverse outcome - these tumors are classified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP), thereby avoiding unnecessary surgical treatment and the emotional consequences of a cancer diagnosis (Nikiforov 2016). 

Images scanned from selected slides from University of Iowa Department of Pathology.

References

Lloyd RV, Buehler D, Khanafshar E. Papillary Thyroid Carcinoma Variants. Head and Neck Pathology. 2011;5(1):51-56. doi:10.1007/s12105-010-0236-9.

Khanafshar E, Lloyd RV. The spectrum of papillary thyroid carcinoma variants. Advanced Anatomic Pathology. 2011;18(1):90-7. doi:10.1097/PAP.0b013e3182026da6.

Robinson (2010). Thyroid and Parathyroid. In Robinson, Head and Neck Pathology, Atlas for Histologic and Cytologic Diagnosis. P 276-283. Lippincott Williams publishing.

Baloch ZW, LiVolsi VA. Special types of thyroid carcinoma. Histopathology. 2014;72:40-52. doi:10.111/his.13348.

Ganly I, Ibrahimpasic T, Rivera M, Nixon I, Palmer F, Patel SG, Tuttle RM, Shah JP, Ghossein R. Prognostic implications of papillary thyroid carcinoma with tall-cell features. Thyroid. 2014;24(4):662-669. doi:10.1089/thy.2013.0503.

LiVolsi VA. Papillary carcinoma tall cell variant (TCV): A review. Endocrine pathology. 2010;21:12-15. doi:10.1007/s12022-010-9106-y.

Roman S, Sosa J. Aggressive variants of papillary thyroid cancer. Current Opinion in Oncology. 2013;25(1):33-38. doi: 10.1097/CCO.0b013e32835b7c6b.

Bongiovanni M, Mermod M, Canberk S, Sglietti C, Sykiotis GP, Pusztaszeri M, Ragazzi M, Mazzucchelli L, Giovanella L, Piana S. Columnar cell variant of papillary thyroid carcinoma: Cytomorphological characteristics of 11 cases with histological correlation and literature review. Cancer Cytopathology. 2017;125(6):389-397. doi: 10.1002/cncy.21860.

Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol.2016;2(8):1023–1029. doi:10.1001/jamaoncol.2016.0386

Yu XM, Schneider DF, Leverson G, Chen H, Sippel RS. Follicular variant of papillary thyroid carcinoma is a unique clinical entity: a population-based study of 10,740 cases. Thyroid. 2013;23(10):1263-8.

Rivera M. Ricarte-Filho J. Knauf J. Shaha A. Tuttle M. Fagin JA. Ghossein RA. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs. infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. 2010;23:1191–1200.