Papillary Thyroid Carcinoma (PTC)

 

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy in both the adult and pediatric populations. In adults, it comprises 80%-85%, and in pediatric patients 90% of all thyroid malignancies, defined by a set of distinctive nuclear features, including:

·         Change of nuclear size and shape: nuclear enlargement, elongation and overlapping

·         Chromatin characteristics: chromatin clearing, margination and glassy nuclei

·         Nuclear membrane irregularity: irregular nuclear contour, nuclear groove and nuclear pseudoinclusion

Nuclear pseudoinclusions: always have a color matched with cytoplasm, usually being darker (left), rarely lighter (right) than nucleus (H&E, high power).

 

Exposure to radiation during childhood, is the most extensively studied and well-documented environmental factor in the development of PTC. High levels of dietary iodine have also been implicated in the development of PTC due to the increasing rates in the dietary iodine sufficient regions of the world.

Most PTCs (>90%) are sporadic and approximately 5-10% are familial.

 

Subtypes

·         Classic PTC

·         Encapsulated classic PTC

·         Infiltrative follicular PTC

·         Diffuse sclerosing PTC

·         Solid/trabecular PTC

·         Warthin-like PTC

·         Oncocytic PTC

·         Clear cell PTC

·         Spindle cell PTC

·         PTC with fibromatosis/fasciitis-like/desmoid-type stroma

·         Tall cell PTC

·         Hobnail PTC

·         Columnar cell PTC

 

Location

Anywhere in the thyroid gland in its orthotropic as well as ectopic locations. It can also occur in thyroglossal duct cyst and teratomas including struma ovarii.

 

Clinical features

Painless thyroid nodule with or without associated cervical lymphadenopathy. Dysphagia and stridor due to local compression on trachea and esophagus and voice complaints can be encountered in up to 20% of patients. In most cases of PTC, thyroid function tests are within normal limits.

 

Imagine features

thyroid ultrasound (US) as a solid and hypoechoic nodule with microcalcifications /echogenic foci and ill-defined margins. Cystic elements can occur within a solid nodule. Doppler-US may show disorganized and increased vascularity. US-examination can also confirm cervical lymph node involvement by PTC.

 

 

Molecular profile

The most frequent driver events are either point mutations or gene rearrangements, mostly involving the MAPK pathway. Most common molecular alteration in PTC involve somatic mutations in BRAF and RAS (mainly NRAS) genes and RET fusions. BRAF p.V600E is common in classic PTC and subtypes showing papillary architecture; this is in contrast to RAS mutations and the rare BRAF p.K601E in follicular patterned tumors.

 

Macroscopic Features

Typically, PTC measures greater than 10 to 15 mm, often averaging 20 to 30 mm, although large sized tumors can also occur.

The tumor nodule is usually firm and white in color with an infiltrative appearance. Focal intratumorally calcification is a common feature, however, in some cases it maybe extensive or rarely associated with ossification.

Due to extensive sclerosis, some PTC may grossly resemble a scar.

Cystic formation is not uncommon in PTC.

Necrosis is not a feature of PTC and suggests transformation to poorly differentiated or undifferentiated carcinoma.

Microscopic features

·         Encapsulated PTC (E-PTC)

The E-PTC is defined as classic PTC enveloped by a thick fibrous capsule, which maybe intact or infiltrated by tumor with or without extension into surrounding thyroid parenchyma.

Low magnification showing encapsulated tumor with partial cystic change and papillary architecture

·         Infiltrative Follicular Variant PTC (IFVPTC)

After classic PTC, IFVPTC is the second most common histologic subtype of PTC. It exclusively or almost exclusively shows a follicular growth pattern. Two major forms are known: the infiltrative follicular variant PTC and the encapsulated follicular variant PTC

The neoplastic follicles have the characteristic nuclear features of papillary carcinoma and percolate in between non-neoplastic ones.

·         Oncocytic PTC (O-PTC)

Oncocytic changes can occur in PTC with follicular growth pattern (IF-PTC) as well as in those with a solid pattern. The term O-PTC or pure O-PTC is reserved for those very rare neoplasms composed of well-developed papillae (and rare follicles) all lined by oncocytic cells with nuclear features of papillary thyroid carcinoma.

The tumor is composed of papillae and follicles lined by follicular epithelial cells that have abundant granular eosinophilic cytoplasm and the characteristic nuclear atypia of papillary carcinoma.

·         Warthin-like PTC (WL-PTC)

WL-PTC can present as well circumscribed or infiltrative tumor and share morphologic similarities with Warthin tumor of the salivary gland. It is composed of papillae lined by oncocytic cells with the papillary cores rich in lymphocytes and plasma cells.

Medium power showing papillary structures lined by oncocytic tumor cells and a lymphocytic plasmacytic infiltrate in the core of the papillae.

·         Clear cell subtype

Clear cell changes occur both in benign and in malignant thyroid lesions and are usually associated with other usual features, such as oncocytic changes. Histologically, clear cells can grow in papillae or solid sheets and often show typical PTC nuclei.

·         Diffuse sclerosing PTC (DS-PTC)

Diffuse involvement of a single lobe or the entire thyroid gland with extensive lymphatic permeation, dense sclerosis, numerous psammoma bodies and associated chronic lymphocytic thyroiditis. Tumor appears as solid nests and papillary formations with squamous metaplasia.

The tumor infiltrates throughout the gland in small nests with prominent calcifications and focal squamous metaplasia

·         Solid/trabecular PTC (ST-PTC)

A diagnosis requires presence of solid, trabecular or nested growth pattern in >50% of tumor mass. The stroma separating the tumor sheets and nests usually shows thin and delicate fibrovascular bands, however, some cases may show foci of dense sclerosis. Few well-formed neoplastic papillae and abortive follicular groups can occur.

The tumor cells in the solid nests display the nuclear features of papillary thyroid carcinoma

·         Papillary thyroid carcinoma with fibromatosis/fasciitis-like/desmoid-type stroma

abundant cellular stroma resembling nodular fasciitis, fibromatosis, desmoid or other myofibroblastic processes. The epithelial tumor cells embedded within the stroma usually form cords, tubules, compressed papillae, and show nuclear features of PTC. Varying degrees of squamous metaplasia can occur in these tumors. The stroma can be cellular, show myxoid change or densely collagenous, similar to that seen in scar/keloid and desmoid tumors. The stromal cells do not demonstrate nuclear atypia.

·         Spindle cell PTC

Spindle cell areas may be focal or diffuse in PTC but this subtype is characterized by a predominance (>50%) of spindle cells with nuclear features of PTC. Their presence does not modify the prognosis of the tumor, but a case of spindle cell transformation carrying a poor prognosis has been reported

·         Tall cell PTC (TC-PTC)

By definition, TC-PTC is composed of cells whose height is at least three times their width and show abundant eosinophilic cytoplasm with a prominent cell membrane. The typical nuclear features of PTC, especially intranuclear pseudoinclusions are easily found. Tall cells should represent at least 30% or more of the PTC cells to make the diagnosis of TC-PTC.

The tumor is composed of complex papillary and elongated trabecular formations that have a "tram track" appearance; they are lined by crowded cells that have a height-to-width ratio of at least 3:1.

·         Hobnail PTC (HN-PTC)

HN-PTC is an aggressive subtype of PTC which derives its name from the peculiar feature of its tumor cells having enlarged nuclei that bulge from the apical surface (hobnail appearance).

These tumors usually have a complex papillary or micropapillary architecture.

·         Columnar cell PTC (CC-PTC)

CC-PTC is a rare PTC subtype, composed of columnar cells with pale eosinophilic to clear cytoplasm, and prominent nuclear pseudo-stratification. Subnuclear vacuoles may be present that impart an appearance reminiscent of secretory endometrium. Nuclear clearing and grooves are evident in some tumors, but subtle in others. Pseudo-inclusions are generally absent.  The tumor is hypercellular with areas of crowded elongated follicles admixed with thin papillae.

The tumor is composed of complex papillae lined by crowded elongated pseudostratified epithelial cells.

 

Treatment

 

·         High risk: total thyroidectomy and post operative radioactive iodine therapy

·         Intermediate risk: subtotal / total thyroidectomy; postoperative radioactive iodine therapy should be considered and discussed with the patient

·         Low risk (includes intrathyroidal encapsulated follicular variant and papillary thyroid carcinoma devoid of the aggressive features seen intermediate or high-risk groups): lobectomy alone may be sufficient

·         Very low risk (i.e., papillary microcarcinomas without clinically evident metastasis, local invasion or convincing cytologic evidence of aggressive disease): active surveillance may be considered as an alternative for surgical approach.(1)

References

LiVolsi VA. Papillary thyroid carcinoma: an update. Modern Pathology. 2011;24:S1–9.