Review of Papillary Lesions of the Thyroid

Review of papillary lesions of the thyroid

By: Faten Anwar, BA, MS, MBBCH

We start with the most serious lesion, Papillary carcinoma:

Papillary carcinoma of the thyroid is the most frequently encountered thyroid malignancy. It accounts for 75%-80% of thyroid cancers in the United States. Its peak incidence is in the fourth to fifth decades with a female preponderance. The lesion is often is often multifocal with bilateral foci in 20-30% of the cases. With appropriate therapy, the 10-year survival exceeds 90% (l, 2). The differential diagnosis includes malignant tumors that can acquire papillary architecture such as Hurthle cell and medullary carcinoma. In addition papillary hyperplasia of the thyroid gland as encountered in Grave’s disease can pose difficulty in the diagnostic work-up of thyroid tumors. Papillary carcinoma tends to metastasize via the lymphatic system with cervical metastases occurring in 40-60% of patients at diagnosis. Cervical lymph node metastases have been shown to affect the rate of recurrence but not the rate of the overall survival (3).  Vascular invasion has been reported in 2-14% of thyroid carcinomas. Its presence even within the thyroid gland is associated with more aggressive disease at diagnosis and with a higher incidence of tumor recurrence (1). Distant metastases outside the neck are unusual and represent 5-7% of cases (4). The papillary pattern of growth is not specific for papillary carcinoma, and occasional papillary carcinomas will completely lack completely the papillary pattern of growth.

Differential diagnosis of papillary lesions of the thyroid gland:

I-Papillary carcinoma.

-Papillary hyperplasia in Grave’s disease.

-Papillary change in adenoma or adenomatous follicular nodule.

-Papillary variant of medullary carcinoma.

-Hurthle cell carcinoma with papillary architecture.



I- Cytological features (2):

1-Elongated oval nuclei

2- Nuclear crowding and overlapping

3- Nuclear clearing (the nuclei have an empty look due to margination of the chromatin to the periphery with no nucleoli or if present they are pushed to the nuclear membrane).

4- Pseudonuclear inclusions due to cytoplasmic invaginations.

5-Nuclear grooves usually arranged parallel to the longitudinal axis of the nucleus.

II- Psammoma bodies are a common finding (40-50% of cases); they can be encountered in either the

papillary structures, or the stroma or the adjacent non-tumor thyroid tissue. Although psammoma bodies are almost specific for papillary carcinoma, they can be encountered in other thyroid lesions such as Grave’s disease and Hashimtoto’s thyroiditis (5&6).


III-The formation of true papillae with fibrovascular cores is a prominent feature of the tumor. Most tumors contain variable proportion of follicular and papillary components (7).


IV-The scarring and infiltrating patterns are characteristic; however a subset can show perfect encapsulation.

Differentiating papillary carcinoma from other papillary lesions:

True papillae formation with fibrovascular cores is characteristic of papillary carcinoma and is uncommon in hyperplastic nodules and benign adenomatous nodules. In addition, the cytologic features are lacking in the benign conditions or present in a focal manner (7&2). As for medullary and Hurthle cell carcinomas, the absence of the papillary nuclear features will help the pathologist to reach the actual diagnosis.

Pathogenesis of papillary carcinoma:

Retinoblastoma gene mutations have been shown both by molecular techniques and immunohistochemical techniques to be present in papillary carcinomas (8&9). Somatic mutations of RET proto-oncogene have been documented in papillary carcinoma and are known as RET/PTC. 8 different somatic rearrangement of RET have been reported (10-16).


Grading of papillary carcinoma:

The histologic grading of papillary neoplasm though not a common practice has been shown to correlate with survival and cancer deaths (17).

Genetic abnormalities associated with subtypes of papillary carcinomas:

1-Micropapillary carcinomas are associated with RET/PTC translocation and are associated with excellent prognosis (18).

2- RET-PTC3 translocation has been associated with solid follicular variant of papillary carcinoma arising in children affected by Chernobyl radiation disaster (19).

3- Familial form of the cribriform-morular type is associated with germline alterations of APC gene (20).

4-A subset of familial Papillary carcinoma with hurtle cell features has been associated with abnormalities occurring in a gene mapping to chromosome 19 (21).

Radiation and papillary thyroid cancer:

Duffy and Fitzgerald In 1950 first reported the association between radiation and papillary thyroid carcinoma has been documented. In 1970, Winship and Rosvoll published a series of thyroid carcinomas; 76% of which have had prior radiation to the head and neck area. Also rare cases of thyroid cancer have been reported after I-131 Therapy. In addition multiple reports have documented increased incidence of thyroid neoplasms in children who had prior irradiation to the head and neck area. After 1965 when the use of irradiation to treat benign conditions was abandoned, the incidence of childhood thyroid malignancy has dropped significantly. The study by Nikiforov and Gnepp (22) of 84 post-Chemobyl disaster thyroid carcinomas in children showed increased incidence in the exposed population and 99% of the thyroid tumors were papillary carcinomas.

Varaints of papillary carcinoma of thyroid (23&24)

Tall cell variant:

Initially described by Hawke and Hazard; this entity represents 10-13% of papillary cancers. Pathologically, this entity is characterized by frequent extra thyroidal invasiveness and extensive papillary formation. Columnar cells line the papillae with the height of the cells at least twice as their width. The cytoplasm is oncocytic albeit less granular than Hurthle cell variant. The nuclei show features typical of papillary carcinoma. Follicular differentiation is unusual in that entity. Mitotic figures are commonly encountered in this entity, in contrast to the usual papillary carcinoma. Vascular invasion is seen in 25% of cases, a feature that is unusual in regular papillary carcinomas. As for the clinical profile this lesion tend to affect older population (median age 57 versus 37 for regular type PTC). At time of diagnosis there is extrathyroid extension and the tumors are often larger than 5 cm. The mortality rate approaches 25% for that entity.

As for prognostic markers, the tall cell variant is more often associated with P53 mutation that the regular papillary cell carcinoma.


Columnar cell variant:

Initially described by Evans, this entity occurs predominantly in males. This tumor is usually solid and papillary, usually of large size and extensively invading adjacent thyroid tissues. The component cells are rectangular with basally located nuclei, resembling colonic carcinoma, and occasionally, the cells have clear cytoplasm resembling prostatic carcinoma. The relationship between columnar cell variant and tall cell variant is questionable; at least one case has been reported that combined features of both entities.



Diffuse sclerosing variant:

Originally defined by Vickery et aI, this tumor is commonly found in children and adolescents. It constitutes about 1-3% of papillary carcinomas of thyroid. The patients often present by goiter with or without a discrete mass in the gland. Histologically the tumor is a papillary cancer with extensive squamous metaplasia, numerous psammoma bodies and extensive lymphoid infiltration around the tumor foci. Widespread lymphatic permeation within the gland and in the cervical lymph nodes is often encountered. Distant metastases are present in 25% of cases. Some series reported in the literature indicates that these patients tend to have a guarded prognosis, compared to regular FTC, although other studies failed to confirm this finding.


Diffuse follicular variant:

The cases reported by Sobrinho-Simoes et al showed a female predominance of 7:1. The patients presented with diffusely enlarged gland with hyperthyroidism. The thyroid is diffusely enlarged with or without discrete masses. The tumor consists of follicular Patterned structures with papillary cytologic features. Most patients acquire distant metastases.


Hurthle cell variant:

Several studies included either Hurthle cell follicualr carcinoma with papillary features or tall cell variant in the same entity, and therefore no prognostic implications can be derived from them. The few reports that included legitimate cases of papillary carcinoma with hurthle cell features indicate that their biologic behavior is more or less similar to the regular papillary carcinoma.


Warthin like papillary carcinoma of thyroid:

First described By Apel et al; the authors described 13 tumors of this entity and delineated the main morphologic characteristics in the form of papillary architecture, oxyphilic changes in the cytoplasm of epithelial cells, and dense lymphoid infiltrate. The residual thyroid tissue show evidence of Hashimoto thyroiditis in theses cases which in conjunction with the dense lymphoid infiltrate in the fibrovascular stalk accounts for the better prognosis associated with these cases. Ozaki et al described these tumors as tall cell variant with extensive lymphocytic infiltrate. An approach which should be avoided due to the difference in prognosis between Warthin like papillary carcinoma of thyroid and the tall cell variant and the requirement of the presence of cells with height twice the width to make the diagnosis of tall cell variant. The other important differential diagnosis in this case is Hurthle cell neoplasms, which lack the nuclear features of papillary carcinoma and show large nuclei with vesicular chromatin pattern and prominent nucleoli or hyperchromatic atypical nuclei. The strong expression of RET/PTC by immunohistochemistry also supports their categorization as papillary carcinoma. The RET/PTC is a novel oncogene resulting from the fusion of the tyrosine kinase domain of RET proto-oncogene to the 5′ terminal regions of different genes. The RET proto-oncogene encodes a transmembrane receptor with tyrosine kinase activity which is involved in the development of neural crest derived cell lineages. The RET oncogene is activated in 40% of papillary carcinomas, usually the well-differentiated types and its activation is less frequent in the more aggressive variants of papillary carcinomas.

This entity shows very close resemblance to the hurthle cell variant of papillary carcinoma as defined by Berho et al. In fact the only difference is the presence of the lymphoid infiltrate in the fibrovascular stalk since both entities are associated with chronic lymphocytic thyroiditis.



Solid variant of papillary carcinoma:

Occasional papillary cancers will show a focal solid component representing less than 25% of the tumor volume. This component is more often found in the pediatric population. If the solid pattern represents 75% of the tumor, the tumors tend to have an aggressive clinical course with extensive extra thyroid extension and distant metastases.

Prognostic factors in papillary thyroid carcinomas (25)

Old age at presentation, greater than 4 cm size, gross extrathyroid extension, the presence of distant metastases and certain histologic subtypes are associated with a more aggressive clinical course. The pathologic features that tend to affect the prognosis include psammoma bodies, sclerosis and the presence of squamous metaplasia and lymphatic invasion. The major histopathologic factor that appears to have an impact on survival and prognosis is the subtype of PTC. When compared with the prognosis associated with the usual type of PTC, the encapsulated variant and the micro carcinoma variant seem to have a better prognosis whereas the tall cell variant, columnar variant and diffuse sclerosis variant are associated with worse prognosis. P53 mutation and aneuploidy are associated with worse prognosis, however the stage of disease still is the best factor that correlates with overall survival.





(1) Gardner RE, Tuttle M, Burman KD et al. Prognostic importance of vascular invasion in thyroid carcinoma. Arch Otolaryngol head Neck Surg 2000; 126; 309-12).


(2) Akslen LA, Myking AO, Salvasen H, Varhaug JE. Prognostic Importance of various clinicopathologic features in papillary thyroid carcinoma. Eur J Cancer 1993; 29A: 44- 51.


(3) LiVolsi VA. Surgical pathology of the thyroid in Major problems of pathology, Rorab R, ed. WB Saunders, Philadelphia, PA1990: 136-143.


(4) Mazzaferri EL, Young RL. Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Sem. Onco1 1987; 14:315-32


(5)Klinck GH, Winship T. Psammoma bodies and thyroid cancer. Cancerl959; 12:656- 662.

(6) Dugan JM, Atkinson BF, et al. Psammoma bodies in fine needle aspirate of the thyroid in lymphocytic thyroiditis. Acta Cyto11987; 31 :330-334.

(7) Kini SR. Guides to clinical aspiration biopsy: Thyroid. New York. Igaku-shoin, 1987. (8)Figge J, Bakst G, Weisheit D, solis 0, Ross Js. Image analysis quantitation of immunoreactive retinoblastoma protein in human thyroid neoplasms with a streptavidin- biotin peroxidase staining technique. Am J Patho11991; 139 (6): 1213-9.

(9)Anwar F, Emond MJ, Schmidt Ra, Hwang HC, Bronner MP. Retinoblastoma expression in thyroid neoplasms. Modem Patho12000;13 (5): 562-69.

(10)Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the ret protooncogene and is frequently detected in vivo in human thyroid papillary carcinoma 1990;60:557-563.

(11) Bongarzone I, Monzizni N, Borello MG, et al. Molecular characterization of a thyroid tumor specific transforming sequence formed by the fusion of RET tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell BioI 1993; 13:358-366.

(12) Santoro M, Dathan NA, Berlingieri MT, et al. Molecular characterization of RET /PTC3, a novel rearranged version of the Ret proto-oncogene in a human thyroid papillary carcinoma. Oncogene 1994; 9:509-516.

(13) Fugazzola L, Pierotti MA, Vigan OE, et al. Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELEI genes in a post- Chemobyl papillary thyroid cancer. Oncogene 1996; 13: 1 093-97.



(14) Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chemobyl and analysis of the involved RET-fused gene RFG5 1998; 58:198-203.


(15) Klugbauer S, Rabes HM. The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas. Oncogene 1999; 18:4388-93.

(16) Nakata T, Kitamura Y, and Shinizu K. Fusion ofa novel gene ELKs to RET due to translocation t (10;12) (ql1;p13) in a papillary thyroid carcinoma. Genes Chrom cancer 1999; 25:97-103.


(17)Akslen La, LiVolsi VA. Prognostic significance of histologic grading compared with subclassification with subclassification of papillary thyroid carcinoma. Cancer 2000; 88:1902-8.


(18) Tallini G, santoro M, Helie M, Carlomagno f, et al RET/PTC Oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to

poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res1998; 4:287- 94.


(19) Thomas GA, Bunnell H, Cook HA, et al. High prevalence ofRET/PTC rearrangements in Ukranian and Belarussian post -Chemobyl thyroid papillary

carcinoma: a strong correlation between RET /PTC3 and the solid follicular variant. J Clin Endocrinol Metab 1999; 84:42328.


(20) Harach RH, Williams GT, Williams ED, et al. Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histopathology 1994; 25:549-61.



(21) Harach RH, Leseur F, Amati p, et al. histopathology of familial thyroid tumors linked to a gene mapping to chromosome 19q13.2. 1Patho11999; 189:387-93.

(22) Nikiforov Y, Gnepp DR. Pediatric thyroid cancer after thyroid disaster. Pathomorphologic study of84 cases (1991-1992) from the republic of Belarus. Cancer 1994;74:748-66.


(23) Livolsi V A. Unusual variants of papillary thyroid carcinomas. Advances in Endocrinology and metabolism 1995;6:39-54.


(24) D’antonio a, Chiara AD, santoro M, et al. Warthin-like tumor of the thyroid gland: RET/PTC expression indicates it is a variant of papillary carcinoma. Histopathology 36 (6): 493-498.

(25) Sebastian SO, Rodriguez Gonzalez 1M, Paricio P, et al. Papillary thyroid carcinoma. Prognostic index for survival including the histologic variety. Arch Surg 2000: 135:272- 277.IMG_4626

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s