PTC is the most common malignant epithelial tumor of follicular epithelial origin with characteristic PTC nuclear features. Classic PTC has two basic morphologic features: papillary and infiltrative/PTC nuclear features, with rare nuclear schwannomas and more common sandy calcifications, mainly located in the lymphatics or interstitium. Squamous metaplasia is reported in the literature in 20% to 40% of cases. Lymphovascular invasion is common; vascular invasion is uncommon but can occur. Immunophenotype: TG, TTF1, PAX8, and broad-spectrum CK positive; CK20, CT, and neuroendocrine markers usually negative. The follicular subtype accounts for approximately 40% of PTC and has a predominantly follicular growth pattern with the karyotype of classic PTC.
There are 14 subtypes of PTC, including micro PTC, encapsulated, follicular, diffuse sclerosing, sieve-mulberry, hypercellular, columnar cell, bootstrap, solid/beam, eosinophilic, worsinoma-like, clear cell, spindle cell, and papillary carcinoma with fibromatosis/fasciitis-like interstitium. The hypercellular, spike, columnar cell and solid types are generally considered to be invasive PTC with relatively complex genotypes and poorer prognosis than the classic type.
(1) Diffuse sclerosing type: Most often seen in young female patients with diffusely enlarged bilateral or unilateral thyroid lobe involvement, with serologic features of autoimmune thyroiditis. Morphologic features include significant sclerosis, numerous gravel bodies, a background of chronic lymphocytic thyroiditis, and nests of tumor cells that are often solid with extensive squamous metaplasia, easily invading the intrathyroidal lymphatic ducts and extrathyroidal tissues. Molecular detection of RET rearrangements is common, while BARF mutations are rare. Distant metastases occur in approximately 10% to 15% of cases, most commonly to the lung. Disease-free survival is short, but mortality is not significantly different from that of the common type.
(2) High-cell subtype: ≥30% of cancer cells are more than 2-3 times as tall as their width, with abundant eosinophilic cytoplasm and typical PTC karyotype, often in a single row or parallel arrangement. It is common in older patients, more aggressive than classic type, and more likely to have extrathyroidal invasion and distant metastasis. Most cases have BRAF mutations (60%-95%).
(3) Columnar cell subtype: This rare subtype is composed of pseudostratified columnar cells and often lacks the typical PTC nuclear features. In some cases, immunohistochemical staining is positive for CDX2, and TTF1 is positive to varying degrees. The prognosis may be related to tumor size and extra-glandular spread, but not to the type itself.
(4) Sieve-mulberry-like subtype: This subtype is considered to be a distinct subtype of thyroid cancer, occurring almost exclusively in women, usually associated with familial adenomatous polyposis, with germline mutations in the APC gene, and can also occur in sporadic cases. Sporadic cases are usually solitary and have an excellent prognosis, requiring only lobectomy. Familial cases often have multiple foci and are often associated with colonic polyposis and require APC genetic testing. Tumors are usually encapsulated lesions with a mixture of sieve, follicular, papillary, beam-like, solid, and mulberry-like structures in growth. Envelope/vascular invasion is common. The lumina of the sieve-like structures are large and unrounded and lack intraluminal gel. The nuclei are not particularly clear. Immunostaining is often mottled positive for TTF1. TG is focal or weakly positive. beta-linked protein shows characteristic nuclear positivity. Mulberry-like structures express broad-spectrum CK,21 but not p63, TG, TTF1, ER, β-linked proteins, and CK19.
(5) Bootstrap type: a rare subtype of PTC with aggressive behavior and relatively poor prognosis. The diagnosis requires that at least 30% of the tumor cells exhibit bootstrap-like micropapillary features. The presence of a small number of bootstrap micropapillary structures is also significant and should be noted in the pathology report. Compared to classic PTC, bootstrap PTC often shows extra-glandular spread, lymph node metastases or distant metastases, and responds poorly to radioiodine therapy, resulting in increased mortality. Molecular detection of BARF mutations is predominant.