Papillary carcinoma is the most common malignant neoplasia of the thyroid gland, representing about 80% of thyroid cancer. It is more frequent in females in their III- IV decades of life and it is the most frequent thyroid cancer in the paediatric population. A familiar form of papillary carcinoma is frequent, but papillary carcinoma is rarely associated with familial syndromes such as familial adenomatous polyposis or Cowden syndrome.
Papillary carcinoma takes the name from its most frequent growth pattern: making papillae. The diagnosis of papillary carcinoma is however based on typical nuclear alterations. Papillary carcinoma generally has a good prognosis with long disease- free survival and high probability of healing. The mortality rate ranges from 5 to 17%. Negative prognostic factors are older age at time of diagnosis, large size, male sex, extension to extrathyroidal tissues (in particular to stripe muscles) and, finally, presence of distant metastases. Some authors consider variants of papillary carcinoma (e.g. tall cells or hobnail variants) as negative prognostic factors. Papillary carcinoma can indeed show variable clinical behaviour: few variants of papillary carcinoma are very aggressive and may result in distant metastases and sometimes causing fatal out comes. Papillary carcinoma usually metastasizes lymphatically., Vascular invasion can more rarely be observed, especially in follicular variants or tall cell variants of papillary carcinoma. The most important etiological cause of papillary carcinoma is the exposure to ionizing radiation during childhood and adolescence. Dramatic cases were the nuclear accidents of Chernobyl in 1986 and the more recent one of Fukushima, in which the massive emissions of radioactive elements, in particular of radioiodine131 (I131), increased the incidence of papillary carcinoma by more than 100 times. Other evidence is the use of radiotherapy in the head and neck and in the mediastinum regions (in the past used for acne or tinea capitis or thymic hyperplasia in children and adolescents). The risk of cancer has a strong inverse correlation with age at exposure.
The molecular alterations of papillary carcinoma are numerous, of which one of the most important is the V600E mutation of the BRAF gene, also considered a diagnostic marker for papillary carcinoma.
Other mutations of the BRAF gene have been described, in particular the K601E mutation of BRAF has been reported in follicular variants of papillary carcinoma and sometimes in follicular adenomas.
Other important gene alterations are the rearrangements involving the RET gene (called RET/ PTC) alongside a series of other genes, the most frequent being RET/ PTC1 and 3. Their frequency is extremely variable in the different study cases and could be due to a high heterogeneity of papillary carcinoma. Other important gene alterations of papillary carcinoma are the point mutations of RAS genes; these mutations are located at several specific sites, which are codons 12, 13, 61 of the N- , H- , K- RAS genes. Rearrangements of the NTRK1 gene, also called TRK rearrangement, can be present in papillary carcinoma with a frequency of about 10%. It is important to underline that almost all these mutations are mutually exclusive, and are capable of activating the mitogen- activated protein kinase (MAPK) pathway regulating cell growth, differentiation, and survival.
Morphology
At gross examination, papillary carcinoma can show different aspects and sizes, and usually arises as a white- grey, irregular area with central scar formation; or as completely solid nodule; or as a solid and partially cystic nodule; or sometimes as a totally cystic lesion. The size of papillary carcinoma can change from only a few millimetres to numerous centimetres, forming voluminous masses with extension in the extrathyroidal tissues and sometimes in closer structures and organs. At microscopic examination papillary carcinoma can show different growth patterns: the most frequent growth pattern, the papillary pattern, shows exclusively papillary structures with a central fibro- vascular core lined by tumour cells. The papillary carcinoma tumour cells are very peculiar. Accordingly with the WHO, the histological and cytological diagnosis of papillary carcinoma must be made only in presence of typical nuclear alterations.
The papillary carcinoma cells are oval or elongated with ir regular, large nuclei. These have a clear appearance with a very marked and pronounced nuclear membrane on account of chromatin clearing and lateralization along the nuclear membrane. The nuclei of papillary carcinoma show nuclear grooves, generally arranged in parallel to the long axis of the nucleus, resulting in a typical coffee bean shape. The nuclei of papillary carcinoma can also show nuclear pseudoinclusions that are cytoplasmatic intranuclear inclusions similar to bubbles (see Figure1). Papillary carcinoma can present psammoma bodies that are calcific, lamelled, and concentric structures. They are the result of cyclical depositions of calcium on tumoural death cells and they are particularly frequent in classical variants of papillary carcinoma.
Fig1. Nuclear features of papillary carcinoma: carcinoma cells are oval or elongated with irregular, large nuclei. The nuclei have a clear appearance with a marked nuclear membrane, show nuclear grooves, usually arranged in parallel to long axis of the nucleus, obtaining a typical coffee bean shape and they can show also nuclear pseudo- inclusions that are cytoplasmatic intranuclear inclusions.
other Variants of Papillary carcinoma
Papillary carcinoma can present different histological variants. They are numerous and very different for their aspect and sometimes for their clinical behaviour. The histological variants are described on the basis of cell type, cell size and shape, architecture, and stroma. It is important to repeat that the diagnosis of papillary carcinoma must be made only in the presence of the typical nuclear alterations, independent of variants or growth patterns.
Follicular Variant of Papillary carcinoma
The follicular variant is the most common following the classical variant. As underlined by its name, it is characterized by the exclusive presence of follicular structures lined with cells with nuclear alterations of papillary carcinoma (see Figure2). The follicular growth pattern can be micro, macrofollicular, or mixed.
Fig2. Follicular variant of papillary carcinoma: exclusive presence of follicular structures lined by cell with the typical nuclear alterations of papillary carcinoma.
The follicular variant of papillary carcinoma can show an infiltrative attitude and lacks a fibrous capsule. Instead, its most frequent form presents a complete fibrous capsule, with no kind of infiltration or invasion. This form has an extremely low (quite absent) malignant potential.
Recently, a task force of thyroid pathologists and molecular pathologists, together with clinicians, has declassified the completely encapsulated follicular variant of papillary carcinoma in Non- invasive follicular thyroid neoplasm with papillary- like nu clear features (named by its acronym NIFT- P).
Tall cell Variant of Papillary carcinoma
The tall cell variant of papillary carcinoma is a typical variant of older age and male gender. It commonly shows papillary or solid growth patterns. The papillary or solid structures are lined with very particular elongated cells, the so- called tall cells, with a height two or three times the width and with the typical nuclear features of papillary carcinoma. The clinical behaviour of this variant is normally more aggressive than that of the classical variant, showing larger dimensions at the time of tumour diagnosis, with high likelihood of extrathyroidal infiltration and vascular invasion, and a high prob ability of recurrences and distant metastases. Disease- free survival is usually shorter than that of the classic variant and the mortality rate can reach 25% and more.
oncocytic Variant of Papillary carcinoma
The oncocytic variant of papillary carcinoma is a rare variant. It is formed by large cells with wide eosinophilic cytoplasm and nuclear features of papillary carcinoma. The growth pattern is generally papillary, with a very low infiltrative behaviour. The clinical outcome is very similar to that of the classical variant.
Hobnail Variant of Papillary carcinoma
The hobnail variant of papillary carcinoma is a rare variant showing a papillary or micropapillary growth pattern, but rarely presents follicular or clustered structures. These structures are lined by cells with a wide eosinophilic cytoplasm and with apically located nuclei (see Figure 3). The nucleus cytoplasm ratio is decreased and the cells lose cellular cohesion. This variant has an aggressive be haviour and presents frequent necroses, mitoses, lymphatic invasion, extrathyroidal extension, distant metastases, and recurrences.
Fig3. Hobnail variant of papillary carcinoma: papillary or micropapillary structures lined by cell with a wide eosinophilic cytoplasm and with apically located nuclei.
Solid Variant of Papillary carcinoma
The solid variant of papillary carcinoma is a rare variant, representing about 1% of adult papillary carcinoma. It is more common in children and adolescents or in patients exposed to ionizing radiations. The solid variant should be taken into consideration when all the other variants are not represented inside the tumour. It shows a solid, trabecular, or nested growth pattern. This variant has an aggressive behaviour showing distant metastases (in particular in the lung) and higher mortality rates than those of the classical variant.
Other rarer variants are: Warthin’s- like variant, morphologically very similar to Warthin’s- like tumour of salivary gland; the columnar cell variant, that can be very aggressive and that is characterized by a papillary growth pattern with nuclear overlapping and stratification; the cribriform variant associated with familiar adenomatous polyposis; papillary carcinoma with nuclear fasciitis- like stroma in which papillary carcinoma is almost completely substituted by spindle cells arranged in irregular fascicles in a background of fibro- myxoid stroma (see Table 1 for complete list of variants of papillary carcinoma).
Table1. List of papillary carcinoma variants
