Journal of Head & Neck Physicians and Surgeons

: 2022  |  Volume : 10  |  Issue : 1  |  Page : 30--35

Papillary carcinoma thyroid – Histological subtypes and clinical significance

Hiran Kattilaparambil Ravindran 
 Specialist, Anatomic and Clinical Pathology, Burjeel Hospital, Abu Dhabi, UAE

Correspondence Address:
Hiran Kattilaparambil Ravindran
Burjeel Hospital, Abu Dhabi


Papillary carcinoma thyroid is a very common malignancy of the thyroid having a very good overall prognosis. Among the subtypes of this tumor certain histological subtypes identified are more aggressive than the ones with classic histology. The purpose of this review is to stratify the prognosis concerning papillary thyroid carcinoma patients with different histopathological patterns, their features of identification, and molecular differences. This is a narrative review of various published articles including meta-analysis results. This does not contain any studies with human participants by the author. A general outline of each subtype with histologic descriptions, relevant differential diagnosis, immunohistochemical as well as ancillary studies is discussed in this article. The rarity of the aggressive subtypes of papillary carcinoma and poor understanding of tumor biology can lead to inadequate treatment, and hence, the correct diagnosis is very important, and equally important is the awareness of these entities among the treating physicians.

How to cite this article:
Ravindran HK. Papillary carcinoma thyroid – Histological subtypes and clinical significance.J Head Neck Physicians Surg 2022;10:30-35

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Ravindran HK. Papillary carcinoma thyroid – Histological subtypes and clinical significance. J Head Neck Physicians Surg [serial online] 2022 [cited 2022 Nov 29 ];10:30-35
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Papillary thyroid carcinoma (PTC) is one of the most common malignancies encountered in endocrine clinics. The purpose of this review is to stratify the prognosis concerning PTC patients with different histopathological patterns compared with those with classic PTC as well as features of identification for these subtypes. The molecular studies on these subtypes are also discussed in this review. The aggressive subtypes are given a special emphasis keeping in mind with the impact of such a diagnosis. Sufficient data are still evolving about different histological subtypes and their histology-specific impact on prognosis in reports from different populations.

 Aggressive Histological Subtypes

In the new World Health Organization (WHO) classification of thyroid tumors (5th edition), the term “variant” has been replaced by “subtype” to allow for consistency with other WHO tumor classification schemes and avoid confusion with the molecular diagnostic term “genetic variant (s).”[1] Tall cell, columnar cell, and hobnail subtypes are indisputably aggressive compared to classic PTC.[2],[3],[4],[5] The other subtypes of aggressive outcomes described by various authors include diffuse sclerosing[6] and solid[4] subtypes.

 Aggressive Papillary Thyroid Carcinoma Subtypes

Tall cell subtype

The tall cell variant (TCV) was first described by Hawk and Hazard.[7] The WHO[8] defines TCV as a tumor that is composed of cells that are two to three times as tall as they are wide, and that show abundant eosinophilic (oncocytic-like) cytoplasm. The percentage of tall cells needed to make a TCV diagnosis varies between the studies. Vuong et al.[9] found in a meta-analysis that even PTCs with only 10% tall cells were associated with a poor clinical outcome and suggested that percentages as low as 10% to be included in the report. In contrast, Wong et al.[10] reported that only tumors with >50% of tall cell components had more aggressive behavior. The (WHO-5th edition) recommends that the tall cell areas should account for at least 30% of tumor volume to be diagnosed as a tall cell type. The high expression of Muc1 and type IV collagenase in these tumors may facilitate stromal degradation and increase the invasive potential.[11]

Histologically, the tumor displays “a tram track” appearance which is characteristic for this subtype [Figure 1]. The tall cell subtype is characterized by elongated tall cells with oncocytic cytoplasm, distinct cell borders, conspicuous central nucleoli, multiple inclusions within the same nucleus imparting a “soap bubble appearance,” and a higher frequency of cases with lymphocytic infiltration.[12]{Figure 1}

BRAF V600E is the most common mutation (80%–100%) compared to other subtypes. Telomerase reverse transcriptase (TERT) promoter mutations are seen as a secondary event, especially in cases with more than 50% tall cell components.[10] RET/PTC rearrangements are described in 35.8% of tall cell subtype compared to 17.2% of classic PTC.[13] Other molecular events seen in TC-PTC include loss of heterozygosity for chromosome 1 and TP53 mutations.[14] This variant is also associated with radioactive iodine (RAI) refractoriness.[11]

Columnar cell subtype

Columnar cell subtype is rare and accounts for 0.15%–0.2% of all PTCs.[15] This rare variant is composed of columnar cells with prominent pseudostratification [Figure 2]. The minimum percentage of columnar cells to make a diagnosis of columnar cell variant is not yet defined. Unlike most PTCs, the cells lack the conventional nuclear features of PTC [Figure 3]. Due to morphological resemblance as well Immunohistochemistry (IHC) pattern tumors may resemble endometrial or colonic adenocarcinomas. However, positivity for thyroid transcription factor-1 (TTF-1) and thyroglobulin generally resolve the issue. They are positive for cyclin D1. ER and PR are seen in about a quarter of cases. About 10%–55%[16],[17] of cases show positivity for CDX-2, a homeobox gene that encodes a nuclear transcription factor critical for intestinal embryonic development, relatively specific for intestinal epithelium. The molecular events described with these tumors are BRAF V600E, TERT promoter mutations, and TP53. BRAF V600E is seen in 33% of columnar cell subtype, a figure similar to classic PTC.[18] The prognosis depends more on the encapsulation or infiltrative architecture than on the cytological features. Circumscribed tumors tend to have an indolent biological behavior, whereas those with extensive extrathyroidal extension have a less favorable prognosis.[19] They may not respond well to RAI treatment.[4]{Figure 2}{Figure 3}

Hobnail subtype

Hobnail subtype is a rare, aggressive, and recently described (2010)[3],[20] entity. The WHO recommends that the hobnail cell areas should account for at least 30% of tumor volume to be diagnosed as hobnail cell type. Histologically, hobnail pattern is described as cells having apically placed nuclei [Figure 4]. The cells vary in size with a high nuclear-cytoplasmic ratio, open chromatin showing nuclear pseudoinclusions along with multiple soap bubble-like inclusions and scattered mitotic figures. They also display a loss of cohesiveness, and E-cadherin immunohistochemistry shows patchy lateral/basolateral membrane positivity. They are positive for thyroglobulin, TTF-1, epithelial membrane antigen (EMA), cytokeratin 19, and HBME-1.[21] p53 overexpression (>25% of cells) is seen in 77% of cases. BRAF and TP53 mutations are by far the most common genetic alterations in primary HPTC (72.2% and 55.6%, respectively), followed by hTERT (44.4%).[22] RET/PTC fusion was seen in 20% of cases.[23] Hobnail subtype is associated with RAI refractoriness (33.3% of cases were responsive to RAI[22]), disease progression, and higher mortality.[21]{Figure 4}

Diffuse sclerosing subtype

Diffuse sclerosing subtype accounts for almost 0.7%–66% of all PTC.[24] This lesion often presents as diffuse enlargement of the thyroid gland usually without forming a dominant nodular lesion.[8] A higher prevalence of diffuse sclerosing subtype was noted in pediatric patients and in patients affected by irradiation. They tend to occur more frequently in women and in patients in the third decade of life.

Macroscopically, the diffuse sclerosing subtype involves the thyroid gland extensively without forming a dominant mass. Histological characteristics include marked squamous metaplasia, numerous psammoma bodies [Figure 5], extensive interstitial fibrosis, frequent lymphovascular invasion, and heavy lymphocytic infiltration with the formation of germinal centers.[25] The lack of nuclear pleomorphism and the younger age of the patient helps to differentiate diffuse sclerosing subtype from anaplastic carcinoma.[12]{Figure 5}

Immunohistochemical staining for p63 was positive in 28.6% of cases in areas of squamous metaplasia, p53 was noted in 42.9% in the solid component, but galectin-3 expression was low (16.3%) compared to the conventional PTC. EMA was positive in 40.8%[26] of cases.

Molecular analysis shows RET/PTC1 and RET/PTC3 rearrangements in these tumors, but BRAF mutation is uncommon.[27]

This subtype is associated with a higher incidence of extrathyroidal extension, and of cervical lymph node metastasis, and distant metastasis, primarily to the lung.[28] However, mortality rates are like conventional PTC, possibly because of the favorable effect of younger patients' age.[29] Total thyroidectomy with lymph node excision followed by radioiodine therapy is often recommended.

Solid Subtype

Solid variant is a rare and poorly characterized variant of PTC and comprises approximately 1%–3% of PTCs.[30] This tumor is seen in young age and linked to radiation exposure.[31] The solid subtype of PTC is characterized by a solid/trabecular/nested growth pattern involving all or nearly all the tumor with the preservation of the classic cytologic features of PTC. The proportion of solid areas required for diagnosis varies between authors, 50%[32] to 100%.[8] The new WHO (5th edition) recommends 50% as the cutoff.[1] Care should be taken to differentiate these tumors from poorly differentiated thyroid carcinoma, which is characterized by increased mitosis and necrotic areas. Immunohistochemical staining in the solid subtype usually positivity for thyroglobulin and thyroid transcription factor-1.[33] HBME-1 staining is variable.

Molecular analysis shows frequent association with RET/PTC3 fusions in pediatric and radiation-related cases.[34] ETV6: NTRK3 fusions are also described.

The solid subtype has a slightly worse prognosis than classical PTC,[35] however not all studies have this view.

 Subtypes With Little or No Impact on Prognosis

Oncocytic subtype

This subtype is extremely rare in its pure form and must be distinguished from tall cell subtype.

Clear cell subtype

unusual subtype and is usually seen in combination with oncocytic subtype. This subtype must be distinguished from clear cell medullary carcinoma (positive for synaptophysin and chromogranin), intrathyroidal parathyroid adenoma (positive for synaptophysin, chromogranin, GATA-3, and parafibromin) as well as metastatic renal cell carcinoma (RCC) (positive for EMA and RCC antigen).

Warthin-like subtype

This subtype has oncocytic tumor cells lining the papillae, and the cores of the papillae contain a prominent lymphoplasmacytic infiltrate. Often, the background thyroid shows chronic lymphocytic thyroiditis (Hashimoto's thyroiditis).

Papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma

In rare cases, the stroma of PTC is so abundant and cellular that the tumor resembles nodular fasciitis, fibromatosis, or other proliferative myofibroblastic processes. This unusual tumor has BRAF-mutated PTC-embedded in fibromatosis that has CTNNB1 and nuclear localization of beta-catenin.[1] Because CTNNB1 is not seen in thyroid stroma, the recommendation is to use thyroid carcinoma with desmoid-type fibromatosis.[36]

Spindle cell subtype

They are difficult tumors to distinguish from other spindle cell tumors without the use of ancillary techniques. They are positive for thyroglobulin, TTF-1, Pax-8, CK19, and pancytokeratin.

 Variants/Subtypes Separated from Other Subtypes of PTC in New World Health Organization Classification

Papillary microcarcinoma

Tumors included under this category measure <1 cm in diameter. Overall, the prognosis of papillary microcarcinoma 1 s is excellent. In one series, 93% of the patients were free of disease on follow-up, and there were no instances of distant metastasis. However, there are a group of these tumors with aggressive pathologic features, and hence, they are considered a separate entity and managed in alignment with clinical management guidelines. Tumor size (>5 mm), lower location, no well-defined margin, contact of >25% with the adjacent capsule, display of enlarged lymph nodes, and BRAF mutation were independent predictors of cervical lymph node metastasis in one study.[37]

Follicular variant of papillary thyroid carcinoma

The follicular variant of papillary thyroid carcinoma is subdivided into infiltrative and encapsulated forms with invasion into capsule or blood vessels. The infiltrative form typically exhibits BRAF-like mutations and behaves as PTC-like tumor. The encapsulated form displays RAS-like mutations making it closer to follicular thyroid carcinoma in ontology and behavior.[1]

Cribriform-morular thyroid carcinoma

This tumor can occur as a sporadic form or associated with familial adenomatous polyposis. These tumors characteristically have cribriform components admixed with morulae, display papillae, and exhibit papillary-like nuclear features in some instances and hence were called a cribriform-morular variant of PTC. The cribriform component is negative for PAX8 and thyroglobulin, unlike the follicular-derived tumors. However, TTF-1 is retained. Morulae are positive for cytokeratin5, CDX-2, and CD5 and are negative for p63, p40, TTTF-1, and PAX8[38] and hence may represent divergent ultimobranchial/thymic-like differentiation. Beta-catenin is positive in virtually all cases. Almost all tumors have genetic alterations in Wnt/beta-catenin pathway. APC mutations are common. CTNNB1 mutations are also detected. In contrast, they generally lack BRAF mutations and rarely have RAS or PIK3CA mutations. Considering the molecular and immunohistochemical features, they are reclassified under tumors of uncertain histogenesis.[1]


TNM staging is still an important guideline in determining the postoperative therapy and follow-up. In general, the prognosis is good for aggressive subtypes of intrathyroidal, low-staged (T1/T2) tumors. However, the aggressive variants are more likely to have a gross extrathyroidal extension, nodal/distant metastasis, recurrence, and resistance to RAI therapy. The correct diagnosis of the aggressive subtypes of PTC is also a challenge for histopathologists. The rarity of these tumors and poor understanding of their biology can lead to inadequate treatment. Well-controlled outcome studies will help to assess the independent prognostic value of these subtypes. Novel advances in the molecular pathways may open the way for future targeted therapy.

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