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Papillary carcinoma of the thyroid is the most common malignant tumor of the thyroid gland, accounting for 80% of all thyroid cancers in the United States. Overall, it accounts for 1% of all cancers. These tumors may arise at any age but are most common between the 3-5th decades and twice as common in women. These tumors usually have a good prognosis but may invade the lymphatics leading to metastases to the regional lymph nodes and occasional spread beyond the neck in 5-7% of cases. Poor prognostic factors associated with this tumor include:

Male sex
Older age >45 yrs
Large tumor size
Extrathyroidal growth
Less differentiated or solid areas of growth
Vascular invasion
Aneuploid cell population (as measured by flow cytometry)
Rearrangements of the ret oncogene

There are several risk factors associated with the tumor.

Iodine Most common malignant tumor of the thyroid in countries with iodine-sufficient or iodine-excess diets
EXTERNAL RADIATION Variable delay after exposure
May show aggressive features

Risk of thyroid carcinoma in a female population after radiotherapy for breast carcinoma.

Huang J, Walker R, Groome PG, Shelley W, Mackillop WJ.

The Radiation Oncology Research Unit, Department of Oncology, Queen's University, Kingston Regional Cancer Center, Kingston, Ontario, Canada.

Cancer 2001 Sep 15;92(6):1411-1418 Abstract quote

BACKGROUND: There is increasing concern regarding the risk of developing a second primary tumor in adjacent organs as a result of scattered radiation among patients who have undergone radiotherapy (RT) for breast carcinoma. Previous studies have focused mainly on the possible increase in the incidence of contralateral breast carcinoma. To the authors' knowledge, the risk of thyroid carcinoma among these women has not been explored to date.

METHODS: In this population-based, retrospective cohort study, the authors identified 194,798 women who were diagnosed with invasive breast carcinoma (exclusive of those with distant metastasis) between 1973 and 1993, and ascertained subsequent cases of thyroid carcinoma utilizing data from the Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. Poisson regression was used to calculate the age-standardized incidence ratio (SIR) of thyroid carcinoma and to model the influence of RT on the relative risk (RR) between the RT cohort (48,495 women) and the non-RT cohort (146,303 women).

RESULTS: A total of 28 women in the RT cohort and 112 women in the non-RT cohort subsequently developed thyroid carcinoma. The distribution of thyroid carcinoma histologies in both the RT cohort and the non-RT cohort was similar to that in the female general population. Overall, there was no significant increase in the risk of thyroid carcinoma in either the RT cohort or the non-RT cohort compared with the general population; the SIR was 1.1 (95% confidence interval [95% CI], 0.8-1.6) for the RT cohort and 1.2 (95% CI, 1.0-1.4) for the non-RT cohort. When the RT cohort was compared with the non-RT cohort, the RR of thyroid carcinoma was 1.0 (95%CI, 0.7-1.5).

CONCLUSIONS: The risk of radiation-associated thyroid carcinoma after initial RT for breast carcinoma was so low as to be undetectable in the current large population-based study. Continued monitoring of these women will be required to document that these findings are maintained with even longer follow-up periods. However, with 10,895 women having been followed for > 10 years at the time of last follow-up in the current study, these findings should be reassuring to women considering RT for their breast carcinoma. Therefore, women who have received RT for breast carcinoma require no special surveillance for their thyroid gland. Furthermore, previous breast radiation need not be a factor in determining the optimal management of thyroid nodules arising in women who received RT for breast carcinoma.


AUTOIMMUNE DISEASES Questionable association between Grave's disease and Hashimoto's thyroiditis
GENETIC SYNDROMES Gardner's syndrome
Cowden's syndrome



The tumor has a variable appearance on cut sections, usually averaging 2-3 cm. They are usually white with some calcifications and may resemble a scar. Other tumors may form cysts with


GENERAL Under the microscope, the tumor is composed papillae with a central fibrovascular core lined by oval nuclei, many of which have an optically clear nucleus, sometimes referred to as Orphan Annie-eye nuclei. Psammoma bodies, characterized by lamellated calcifications, are usually common. Nuclear grooves are also common. These tumors may invade the glandular lymphatics resulting in spread within the gland itself leading to multifocal tumors.
COLUMNAR CELL Usually >6 cm
Papillae lined by tall columnar cells with hyperchromatic nuclei and stippled chromatin
Mitoses common
Extrathyroidal extension and distant mets common
Poor prognosis with death within 5 years
Somatic but Not Germline Mutation of the APC Gene in a Case of Cribriform-Morular Variant of Papillary Thyroid Carcinoma José Cameselle-Teijeiro, etal.

Am J Clin Pathol 2001;115:486-493 Abstract quote

We report a case of cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) in a 27-year-old woman. In addition to conventional cytologic features of typical PTC, the fine-needle aspirate showed numerous epithelial cells with abundant, eosinophilic, very elongated cytoplasm.

Microscopically, the tumor was encapsulated and highly cellular and exhibited a mixture of cribriform, follicular, papillary, trabecular, solid, and spindle cell patterns of growth, with morular foci showing peculiar nuclear clearing (biotin-rich nuclei). The cells were cuboidal or tall, with frequent nuclear pseudostratification and abundant eosinophilic cytoplasm. The nuclei were usually hyperchromatic, with grooving, pallor, and pseudoinclusions. Angioinvasion and foci of capsular invasion were observed. Immunohistochemically, the neoplastic cells showed reactivity for thyroglobulin, epithelial membrane antigen, low- and high-molecular-weight cytokeratins, vimentin, neuron-specific enolase, CD15, estrogen and progesterone receptors, and bcl-2 protein. Molecular genetic analysis of the APC gene revealed a mutation in exon 15 at codon 1309 in tumoral tissue but not in peripheral lymphocytes.

These findings support a relationship between the morphologic pattern of the C-MV of PTC and the APC gene and the existence of this variant as a sporadic counterpart of familial adenomatous polyposis–associated thyroid carcinoma.

DIFFUSE SCLEROSIS Common in children and young adults, may present with bilateral goiter
Frequent local recurrence
Frequent extrathyroidal extension with distant and nodal mets
More aggressive than usual papillary CA
FOLLICULAR VARIANT Architectural growth pattern of a follicular tumor with cytologic features of papillary carcinoma, including psammoma bodies
Same prognosis as ordinary variants but may have greater risk to metastasize outside of the neck and to have vascular invasion
May be subdivided into a diffuse follicular variant which is aggressive with lymph node and distant mets and an encapsulated variant which has an excellent prognosis
  Total encapsulation of tumor
Good prognosis

Am J Clin Pathol 2002;117:16-18

(1) Nuclei are ovoid rather than round
(2) Nuclei are crowded, often manifesting as lack of polarization in the cells that line a follicle
(3) Nuclei show a clear or pale chromatin pattern (nuclear clearing should not be confined to the central portion of the tumor, where artifactual bloating of the nuclei is common due to delayed fixation), or they exhibit prominent grooving
(4) Psammoma bodies are found.

If 1 of these 4 features is lacking, 4 or more of the following subsidiary features have to be present for a diagnosis of encapsulated follicular variant PTC to be made: (1) presence of abortive papillae, (2) predominantly elongated or irregularly shaped follicles, (3) dark-staining colloid, (4) presence of rare nuclear pseudoinclusions, and (5) multinucleated histiocytes in lumens of follicles.



(Occult papillary carcinoma)

Measure 1-1.5 cm or less with majority measuring 4-7 mm.
Lymph node mets have been documented in tumors as small as 5 mm
May have prominent sclerosis
TALL CELL Usually >6 cm with frequent extrathyroidal extension, increased mitotic figures, and vascular invasion
More frequent in older patients
Histology of cells which are twice as tall as it is wide, these cells should comprise >30% of the tumor
SOLID Common in childen
Solid areas must be >50% of the tumor
May be more aggressive

Solid Variant of Papillary Thyroid Carcinoma Incidence, Clinical–Pathologic Characteristics, Molecular Analysis, and Biologic Behavior

Yuri E. Nikiforov, M.D. , Ph.D. ; Lori A. Erickson, M.D. ; Marina N. Nikiforova, M.D. ; Christy M. Caudill, B.S. ; Ricardo V. Lloyd, M.D. , Ph.D.

From the Department of Pathology and Laboratory Medicine (Y.E.N., M.N.N., C.M.C.), University of Cincinnati, Cincinnati, Ohio; and the Department of Laboratory Medicine and Pathology (L.A.E., R.V.L.), Mayo Clinic, Rochester, Minnesota, U.S.A.

Am J Surg Pathol 2001;25:1478-1484 Abstract quote

Solid variant is a rare and poorly characterized variant of papillary thyroid carcinoma. In this study we analyzed 20 primary cases of the solid variant of papillary carcinoma found in a series of 756 papillary carcinomas operated at the Mayo Clinic between 1962 and 1989. The criteria for classification included predominantly (>70%) solid growth pattern of primary tumor, retention of cytologic features typical of papillary carcinoma, and absence of tumor necrosis.

For each case of the solid variant, a control case of classical papillary carcinoma matched by age, sex, tumor size, and length of follow-up was selected. The follow-up ranged from 6 to 32 years. Two patients with the solid variant of papillary carcinoma (10%) died from disease 7 and 10 years after initial surgery, while another two patients (10%) are alive with lung metastases. In contrast, the control group had no cases with distant metastases or death from disease. Molecular analyses showed a similar prevalence of RET /PTC rearrangements in both groups.

In conclusion, the solid variant of papillary carcinoma is associated with a slightly higher frequency of distant metastases and less favorable prognosis than classical papillary carcinoma. However, it should be distinguished from poorly differentiated thyroid carcinoma, which has a reported lower survival rate compared with the solid variant of papillary carcinoma.


Spindle Cell Metaplasia of the Thyroid Arising in Association With Papillary Carcinoma and Follicular Adenoma

JoAnne Vergilio, MD, Zubair W. Baloch, MD, PhD, and Virginia A. LiVolsi, MD

Am J Clin Pathol 2002;117:199-204 Abstract quote

Spindle cell proliferations of the thyroid have been described in association with reactive processes and aggressive malignant neoplasms.

We describe spindle cell proliferations in 10 patients arising in association with papillary carcinoma and follicular adenoma. The spindle proliferations were 0.3 to 3.0 cm in size, constituted from 1% to 95% of the primary neoplasm, and were either admixed with the neoplastic elements or peripherally located within the primary tumor.

Cytologically, these proliferations showed bland-appearing spindle cells with fine chromatin and subtle nucleoli. Mitoses were rare, and inflammation was minimal. Immunostains showed reactivity with thyroglobulin, indicating their follicular origin. We believe it is important to recognize these metaplastic proliferations and distinguish them from aggressive malignant neoplasms.


Special stains  

Hyalinizing Trabecular Adenoma and Papillary Carcinoma of the Thyroid Gland Express Different Cytokeratin Patterns

Mitsuyoshi Hirokawa, M.D., Ph.D.; J. Aidan Carney, M.D., Ph.D.; Yuji Ohtsuki, M.D., Ph.D.

From the Department of Pathology, University of Tokushima School of Medicine, Tokushima, Japan (M.H.); Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A. (J.A.C.); and Second Department of Pathology, Kochi Medical School, Kochi, Japan (Y.O.).

Am J Surg Pathol 2000;24:877-881 Abstract quote

It has recently been suggested that hyalinizing trabecular adenoma of the thyroid is an encapsulated variant of papillary carcinoma because of certain similarities of their histology, the occasional occurrence of both tumors in the same gland, and their similar pattern of expression of cytokeratins, including staining for cytokeratin 19.

To investigate this notion further, we examined immunocytochemically the expression of a series of cytokeratins in 12 hyalinizing trabecular adenomas and six papillary carcinomas. Hyalinizing trabecular adenoma showed no or minimal reactivity for cytokeratin 19, whereas papillary carcinoma was almost always strongly reactive. Also, hyalinizing trabecular adenoma showed no staining for high-molecular-weight (HMW) cytokeratin, whereas papillary carcinoma was strongly positive.

Thus, there are different patterns of cytokeratin 19 and HMW cytokeratin expression in hyalinizing trabecular adenoma and papillary carcinoma. The findings do not support the suggestion that hyalinizing trabecular adenoma is an encapsulated variant of papillary carcinoma.

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

Carol C. Cheung, etal.

Mod Pathol 2001;14:338-342 Abstract quote

In thyroid, the diagnosis of papillary carcinoma (PC) is based on nuclear features; however, identification of these features is inconsistent and controversial. Proposed markers of PC include HBME-1, specific cytokeratins (CK) such as CK19, and ret, the latter reflecting a ret/PTC rearrangement.

We applied immunohistochemical stains to determine the diagnostic accuracy of these three markers. Formalin-fixed, paraffin-embedded tissue from 232 surgically resected thyroid nodules included 40 hyperplastic nodules (NH), 35 follicular adenomas (FA), 138 papillary carcinomas (PC; 54 classical papillary tumors and 84 follicular variant papillary carcinomas [FVPC]), 4 follicular carcinomas (FC), 6 insular carcinomas (IC), 7 Hürthle cell carcinomas (HCC), and 2 anaplastic carcinomas (AC). HBME-1 and ret were negative in all NH and FA; some of these exhibited focal CK19 reactivity in areas of degeneration. Half of the FC and AC exhibited HBME-1 staining but no positivity for CK19 or ret. In PC, 20% of cases stained for all three markers.

Classical PC had the highest positivity with staining for HBME-1 in 70%, CK19 in 80%, and ret in 78%. FVPC were positive for HBME-1 in 45%, for CK19 in 57%, and for ret in 63%; only 7 FVPC were negative for all three markers. The six IC exhibited 67% staining for HBME-1 and 50% positivity for CK19 and ret. The seven HCC had 29% positivity for HBME-1 and CK19, and 57% positivity for ret.

This panel of three immunohistochemical markers provides a useful means of diagnosing PC. Focal CK19 staining may be found in benign lesions, but diffuse positivity is characteristic of PC. HBME-1 positivity indicates malignancy but not papillary differentiation. Only rarely are all three markers negative in PC; this panel therefore provides an objective and reproducible tool for the analysis of difficult thyroid nodules.

Cytokeratin 19 Immunoreactivity in the Diagnosis of Papillary Thyroid Carcinoma A Note of Caution

Sunati Sahoo, MD
Syed A. Hoda, MD
Juan Rosai, MD
Ronald A. DeLellis, MD

Am J Clin Pathol 2001;116:696-702 Abstract quote

To evaluate the expression of cytokeratin (CK) 19, we stained sections obtained from formalin-fixed, paraffin tissue blocks of 35 thyroid tumors (follicular adenoma [FA], 20; papillary thyroid carcinoma [PTC], 10 follicular variant [FV] and 5 usual type) and scored the extent of staining as follows: 1+ (<5% positively stained cells), 2+ (5%-25% positively stained cells), 3+ (25%-75% positively stained cells), and 4+ (>75% positively stained cells).

All 15 PTCs (including 10 FV-PTCs) were CK19 positive: 14 were 4+ and 1 (FV-PTC) was 2+. All 20 FAs also were CK19 positive: 15 were 1+, 1 was 2+, 4 were 3+, and none were 4+. In the FAs that were scored 1+, reactivity usually was confined to follicular cells lining cystically dilated atrophic follicles that lacked the typical nuclear features of PTC. The remaining FAs showed more diffuse reactivity, which was, however, less intense than that observed in the PTCs.

Thus, immunoreactivity for CK19 is not specific for PTC, although we acknowledge that the extent and intensity of staining are considerably greater in this tumor than in FA. There were no significant differences in staining for CK19 between nonneoplastic follicles adjacent to PTCs and those adjacent to FAs.


Benign conditions which may result in papillary hyperplasia, mimicking papillary carcinoma. These changes are usually diffuse and preserve the glandular architecture with normal nuclei.

Rare lesions composed of circumscribed nodules with a microscopic appearance of papillary growth with edematous stalks containing follicles

These nodules show none of the cytologic features of papillary carcinoma and have been termed papillary hyperplasia in follicular nodules. Some investigators have also used the term papillary adenomas, a term that is in disfavor since it has also been applied to encapsulated papillary carcinomas which are malignant

Untreated Grave's disease
Congenitial errors of thyroid metabolism
Hyperfunctioning foci in goitrous glands

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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