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Background
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 oncogeneOUTLINE
EPIDEMIOLOGY CHARACTERIZATION AGE
*Department of Anatomic Pathology daggerUnit of Otorhinolaryngoiatry double daggerUnit of Pediatric Oncology, Istituto Nazionale Tumori, Milan, Italy.
Papillary thyroid carcinomas (PTCs) in pediatric age show an excellent outcome, independently of sex, stage at diagnosis, occurrence of relapse, and type of treatment.
Our aim was to study the biologic behavior and the impact on survival of PTC subtypes in childhood. From 1968 to 2002, 42 sporadic pediatric PTCs were subclassified into PTC, not otherwise specified and PTC variants. In all cases, sex, age at diagnosis, age of menarche, side, size, TNM/pTNM classification, neoplastic microfoci, vascular invasion, status of the non-neoplastic parenchyma, and treatment (surgery and nonsurgical therapies) were registered. Follow-up was carried on up to May 2005. PTC, solid/trabecular variant was the most frequent subtype. Both extrathyroid local invasion (P<0.04) and distant metastases (P<0.01) at onset were significantly associated with PTC, not otherwise specified. After a median follow-up of 16 years, for the whole series overall survival and progression-free survival (PFS) rates were 100% and 77%, respectively. The solid/trabecular variant was at a significantly increased risk of relapse (PFS 50%, P<0.01). The occurrence of poorly differentiated tall cell morphology did not influence survival. Sensitivity to hormonal manipulation was maintained over time.
In conclusion, although overall survival was not influenced by PTC subtypes, the solid/trabecular variant of PTC was at a significantly higher risk of relapse. At variance with adults, presence of the tall cell morphology did not carry a worst prognostic significance.RISK FACTOR DESCRIPTION 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 featuresRisk 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.
PATHOGENESIS CHARACTERIZATION GENERAL
- Correlation Between Genetic Alterations and Microscopic Features, Clinical Manifestations, and Prognostic Characteristics of Thyroid Papillary Carcinomas.
Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW, Nikiforov YE.
From the Departments of *Pathology and Laboratory Medicine, daggerOtolaryngology-Head and Neck Surgery, and double daggerSurgery, University of Cincinnati, Cincinnati, OH; and section signDepartment of Pathology, University of Michigan Medical School and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI.
Am J Surg Pathol. 2006 Feb;30(2):216-222. Abstract quote
Papillary carcinoma is the most common type of thyroid malignancy. It has been recently shown that these tumors commonly have one of three genetic alterations: BRAF point mutations, RET/PTC rearrangements, or RAS point mutations.
In this study, we analyze the relationship between these alterations and the microscopic features of papillary carcinomas, their clinical features, and prognostic characteristics. Ninety-seven papillary carcinomas were studied; in all cases, frozen tissue was available for nucleic acid extraction.
Of 96 unselected cases, 42% were positive for BRAF, 18% for RET/PTC, and 15% for RAS mutations. Morphologic features were evaluated in detail in 61 cases and 6 characteristic nuclear features and 3 additional microscopic features were assessed quantitatively. At least 4 nuclear features were found in each tumor, with nuclear pseudoinclusions being the least frequent finding in all mutation groups. BRAF mutations were associated with older patient age, typical papillary appearance or the tall cell variant, a higher rate of extrathyroidal extension, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at younger age and had predominantly typical papillary histology, frequent psammoma bodies, and a high rate of lymph node metastases.
Tumors with RAS mutations were exclusively the follicular variant of papillary carcinoma and correlated with significantly less prominent nuclear features and low rate of lymph node metastases. These findings demonstrate that BRAF, RET/PTC, and RAS mutations are associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.BRAF
- Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma.
Rosenbaum E, Hosler G, Zahurak M, Cohen Y, Sidransky D, Westra WH.
[1] 1Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA [2] 2Department of Otolaryngology/Head and Neck Surgery (Division of Head and Neck Cancer Research), The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Mod Pathol. 2005 Jul;18(7):898-902. Abstract quote
Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age.
We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T) --> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector((R)) assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (>20 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR=13.3, 95% confidence interval (CI)=3.4-56.5; P<0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals=1.80 CI=1.33-2.44; P<0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients.
The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma.
- BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.
Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M, Fagin JA, Nikiforov YE.
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
J Clin Endocrinol Metab. 2003 Nov;88(11):5399-404. Abstract quote
Activating point mutations of the BRAF gene have been recently reported in papillary thyroid carcinomas.
In this study, we analyzed 320 thyroid tumors and six anaplastic carcinoma cell lines and detected BRAF mutations in 45 (38%) papillary carcinomas, two (13%) poorly-differentiated carcinomas, three (10%) anaplastic carcinomas, and five (83%) thyroid anaplastic carcinoma cell lines but not in follicular, Hurthle cell, and medullary carcinomas, follicular and Hurthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T-->A transversion at nucleotide 1796. In papillary carcinomas, BRAF mutations were associated with older age, classic papillary carcinoma or tall cell variant histology, extrathyroidal extension, and more frequent presentation at stages III and IV.
All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well-differentiated and dedifferentiated components.
These data indicate that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. They are associated with distinct phenotypical and biological properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.EPSTEIN-BARR VIRUS
Expression of Epstein-Barr virus in thyroid carcinoma correlates with tumor progression.
Shimakage M, Kawahara K, Sasagawa T, Inoue H, Yutsudo M, Yoshida A, Yanoma S.
Clinical Research Institute and Department of Pathology, Osaka National Hospital, Japan.
Hum Pathol. 2003 Nov;34(11):1170-7. Abstract quote
There have been few studies regarding cancer progression from differentiated thyroid carcinoma to the undifferentiated one. To examine the possible involvement of Epstein-Barr virus (EBV) in this progression, 10 papillary carcinomas and 11 undifferentiated carcinomas were subjected to mRNA in situ hybridization, indirect immunofluorescence staining, polymerase chain reaction (PCR), and reverse-transcriptase PCR. mRNA in situ hybridization using a BamHIW probe revealed signals in all of the examined samples, although the signal strength was weaker in the papillary carcinomas than in the undifferentiated carcinomas. EBV nuclear antigen-2 (EBNA2) in situ hybridization produced almost the same results; however, the signals were detected less frequently in the papillary carcinomas. Indirect immunofluorescence using anti-EBNA2, anti-latent membrane protein-1 (LMP1), and anti-BZLF1 antibodies also showed positive results with high frequency and with more prominent fluorescence in undifferentiated carcinomas than in papillary carcinomas.
An examination of thyroid carcinoma cell lines also confirmed these findings. EBV infected all of the thyroid carcinomas irrespective of the degree of pathological differentiation. The expression of EBV, especially of EBNA2 and LMP1 (both of which are oncogene products of EBV), was stronger in the undifferentiated carcinomas than in the papillary carcinomas.
These results suggest that increased expression of EBV may be involved in the progression of thyroid papillary carcinoma to undifferentiated carcinoma.PAX8-PPAR-GAMMA
PAX8-PPAR? Rearrangement in Thyroid Tumors: RT-PCR and Immunohistochemical Analyses
Marina N. Nikiforova, M.D.; Paul W. Biddinger, M.D.; Christy M. Caudill, B.S.; Todd G. Kroll, M.D., Ph.D.; Yuri E. Nikiforov, M.D., Ph.D.
Am J Surg Pathol 2002; 26(8):1016-1023 Abstract quote
A PAX8-PPAR? rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors.
We report here the analyses of PAX8-PPAR? in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPAR? antibody. PAX8-PPAR? was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three).
Strong, diffuse nuclear immunostaining with the PPAR? antibody correlated with the presence of PAX8-PPAR? detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPAR? were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPAR? had trabecular growth pattern and thick capsule, but no invasion, and thus may represent "pre-invasive" follicular carcinomas.The absence of PAX8-PPAR? rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.
p53
Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto's thyroiditis: A stem cell hypothesis of papillary carcinoma oncogenesis.
Burstein DE, Nagi C, Wang BY, Unger P.
Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York, USA.
Hum Pathol. 2004 Apr;35(4):465-73. Abstract quote
Most models suggest that the cell of origin of papillary carcinoma is the mature thyroid follicular epithelial cell. In a recent study, p63 was detected in papillary carcinoma, Hashimoto's thyroiditis, and in squamoid aggregates and solid cell nests (SCNs), embryonic remnants found sporadically in the fully developed thyroid.
In the present study, the relationship between solid cell nests and papillary carcinoma was investigated further. Four-micrometer sections from 88 routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid pH 6.0 for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained with a streptavidin-biotin kit and diaminobenzidine as chromogen and were counterstained with hematoxylin. Squamoid aggregates or SCNs were noted in 21 specimens. Several morphologic variants of SCNs were found, all of which displayed p63 positivity. These included undifferentiated SCNs and those displaying commitment toward squamoid and ciliated glandular differentiation. Small, morphologically inconspicuous aggregates of p63-positive cells were commonly found in Hashimoto's thyroiditis.
Commitment of p63-positive undifferentiated cells toward thyroid follicular epithelial differentiation was occasionally noted. One SCN variant, also associated with Hashimoto's thyroiditis, was a floretlike arrangement of p63-positive cells with fusiform nuclei. p63 staining was strong and uniform in some SCNs, but in other SCNs it was compartmentalized and homologous to stem cell-staining patterns in normal squamous or bronchial epithelia. Stem cell-like staining, associated with compartmentalized p63 staining or p63-positive undifferentiated cells, was noted in 7 of 27 papillary carcinomas. p63 immunostaining is a highly sensitive means of detecting SCNs. p63 expression patterns in SCNs and a subset of papillary carcinomas are closely homologous to stem cell-associated p63 staining patterns that have been described elsewhere in squamous and bronchial epithelia.
We propose a stem-cell-associated model of papillary carcinoma oncogenesis that suggests that (1) p63-positive embryonal remnants rather than mature follicular cells are the cells of origin of a subset of papillary carcinomas; (2) these p63-positive cells are pluripotent and may stay undifferentiated or undergo benign squamoid or glandular maturation, may undergo thyroid follicular epithelial differentiation, may undergo oncogenic change leading to papillary carcinoma, or may trigger an immune reaction, resulting in lymphoid infiltration and Hashimoto's thyroiditis; and (3) Hashimoto's thyroiditis and papillary carcinoma may therefore be linked etiologically, because both disorders may be initiated by the same population of pluripotent p63-positive embryonal stem cell remnants.ras MUTATIONS Molecular Profile and Clinical-Pathologic Features of the Follicular Variant of Papillary Thyroid Carcinoma
An Unusually High Prevalence of ras Mutations
Zhaowen Zhu, MD, PhD, Manoj Gandhi, MD, Marina N. Nikiforova, MD, Andrew H. Fischer, MD, and Yuri E. Nikiforov, MD, PhDAm J Clin Pathol 2003;120:71-77 Abstract quote
The follicular variant (FV) of papillary thyroid carcinoma is characterized by a follicular growth pattern and cytologic features of papillary carcinoma. ret/PTC rearrangements are common in classic papillary thyroid carcinoma (PTC) and PAX8-PPARg and ras mutations in follicular thyroid carcinoma. Their prevalence in FV has not been established.
We studied these genetic alterations and clinical-pathologic features in 30 FV cases and compared those with 46 non-FV papillary carcinomas. FV cases revealed 1 ret/PTC rearrangement (3%) and 13 ras mutations (43%). Non-FV cases harbored 13 ret/PTC (28%) (P = .006) and no ras mutations (P = .0002). No PAX8-PPARg was found in either group. FV cases demonstrated a significantly higher prevalence of tumor encapsulation, angiovascular invasion, and poorly differentiated areas and a lower rate of lymph node metastases.
These data indicate that the FV of papillary carcinoma has a distinct set of molecular alterations and is characterized by a high frequency of ras point mutations.RET/PTC
Prevalence of RET/PTC Rearrangements in Hashimoto's Thyroiditis and Papillary Thyroid Carcinomas.Nikiforova MN, Caudill CM, Biddinger P, Nikiforov YE.
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
Int J Surg Pathol 2002 Jan;10(1):15-22 Abstract quote The relationship between Hashimoto's thyroiditis (HT) and follicular cell-derived thyroid cancer remains unclear. Recently, 2 studies reported a 95% prevalence of RET/PTC rearrangements in histologically benign tissue affected by HT, suggesting that multiple occult tumors exist in HT patients with high frequency.
We tested the prevalence of RET/PTC rearrangements in 26 HT, in 6 papillary carcinomas arising in the background of HT, and in 27 papillary carcinomas not associated with HT. We detected no RET/PTC rearrangements in HT or papillary carcinomas arising in the background of HT, in contrast to a 33% prevalence among papillary carcinomas not associated with HT. However, the expression of wild-type RET was found in more than half of papillary carcinomas.
These results suggest that, if the association between HT and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement.
HISTOLOGICAL TYPES CHARACTERIZATION 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. CYTOLOGY
1Division of Cytopathology, Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
No single cytologic feature is specifically diagnostic for papillary thyroid carcinoma. We report herein the presence of swirl-like cellular aggregates in fine needle aspirates of papillary thyroid carcinoma but not in other thyroid entities. Cellular swirls are defined as concentrically organized aggregates of tumor cells in which many of the most peripherally situated cells have ovoid rather than round nuclei that are oriented perpendicular to the radius of the swirl.
One hundred Papanicolaou- and/or Diff-Quik-stained FNAs of the thyroid diagnosed as papillary carcinoma, including seven fine needle aspirates of cervical lymph nodes showing metastatic papillary carcinoma, with or without cell blocks, were reviewed for the presence of cellular swirls. An additional 100 thyroid FNAs, similarly stained and prepared, diagnosed as nodular goiter, Hashimoto's thyroiditis and follicular neoplasm were also reviewed for the presence of cellular swirls. Cellular swirls were easily observed at screening magnification and confirmed at high magnification.
Seventeen of 100 FNAs (17%) of papillary carcinoma contained cellular swirls. No cases diagnosed as nodular goiter, Hashimoto's thyroiditis or follicular neoplasm contained these structures. Thirteen cases with swirls had histologic follow-up. These comprised seven papillary carcinomas with classical histopathology, two designated 'differentiated papillary carcinoma,' two with follicular variant histopathology; one with a minor component of follicular variant histopathology; one papillary carcinoma metastatic to a cervical lymph node with classic histopathology. Swirls occurred in cases with relatively little pleomorphism, or in well-differentiated regions of papillary carcinoma that also displayed less well-differentiated components.
Cellular swirls are a finding that is highly specific to papillary thyroid carcinoma. They are easily seen at screening magnification. Their presence in a FNA specimen may be helpful in cases where classic criteria for papillary thyroid carcinoma are scarce, particularly in well-differentiated papillary thyroid carcinoma.
While the size and scope of this study are insufficient to conclude that cellular swirls alone are diagnostic of papillary thyroid carcinoma in the absence of other criteria, we believe these structures should be added to the list of diagnostic criteria.
- Fine-needle aspiration of papillary thyroid carcinoma: distinguishing between cases that performed well and those that performed poorly in the College of American Pathologists Nongynecologic Cytology Program.
Renshaw AA, Wang E, Haja J, Wilbur D, Henry MR, Hughes JH; Cytopathology Committee, College of American Pathologists.
Department of Pathology, Baptist Hospital of Miami, Miami, FL 33176-2197, USA.
Arch Pathol Lab Med. 2006 Apr;130(4):452-5. Abstract quote
CONTEXT: Although the cytologic features of papillary thyroid carcinoma in fine-needle aspiration specimens are well known, the correlation of these features with the ability of cytologists to identify this tumor has not been well studied.
OBJECTIVE: To compare the cytologic features of cases of papillary thyroid carcinoma that performed poorly with those of cases that performed well.
DESIGN: The cytologic features of 13 cases of papillary thyroid carcinoma from the College of American Pathologists Nongynecologic Cytology Program that performed poorly were compared with those of 15 cases that performed well.
RESULTS: Compared with cases that performed well, cases that performed poorly were significantly more likely to lack marked nuclear enlargement (38% vs 100%, P < .001), lack pale chromatin (8% vs 47%, P = .04), and lack intranuclear inclusions (8% vs 53%, P = .02). The differences between the 2 groups in staining, type of preparation, nuclear grooves, nuclear crowding, colloid, cellularity, nuclear pleomorphism, and Hurthle cell change were not significant.
CONCLUSIONS: Cases of papillary thyroid carcinoma that lack marked nuclear enlargement, pale chromatin, and intranuclear inclusions are significantly more difficult to recognize than cases that have these features. Increased awareness of these types of cases might improve the performance of thyroid fine-needle aspiration in clinical practice.Focal Features of Papillary Carcinoma of the Thyroid in Fine-Needle Aspiration Material Are Strongly Associated With Papillary Carcinoma at Resection
Andrew A. Renshaw, MDAm J Clin Pathol 2002;118:208-210 Abstract quote
The cytologic features of papillary carcinoma of the thyroid in fine-needle aspiration material have been well described. The significance of finding these features in only a small population of cells is not well characterized. I reviewed the results of 28 thyroid fine-needle aspirates processed as direct smears and cell blocks in which only a small population (<20 cells) showed features of papillary carcinoma.
Papillary carcinoma was considered in 142 (8.98%) of 1,581 aspirates, and in 28 cases (1.77%), 20 cells or fewer showed features of papillary carcinoma and follow-up was available. Papillary carcinomas greater than 1 cm were identified in 11 cases (39%; 3 follicular variants), papillary carcinomas less than 1 cm were identified in 4 cases (14%), and benign lesions in the remaining 13 cases (46%). The background material (either scant or abundant benign epithelium) did not correlate significantly with the result of resection.
Identifying features of papillary carcinoma in a small population of cells in either a scant or an abundant thyroid aspirate are associated with a high rate of papillary carcinomas at resection, only a minority of which represent either the follicular variant or incidental tumors.VARIANTS CLEAR CELL 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 yearsCRIBRIFORM 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 CAELASTOSIS
- Stromal elastosis in papillary thyroid carcinomas.
Kondo T, Nakazawa T, Murata S, Katoh R.
Hum Pathol. 2005 May;36(5):474-9. Abstract quote
Summary Stromal elastosis, defined as dense aggregations of elastic fibers, is found in some neoplastic tissues especially in malignant tumors of the breast and lung. Although also found in thyroid tissue, stromal elastosis in thyroid neoplasms have received little attention.
To clarify the histopathological significance of stromal elastosis in the thyroid, we examined neoplastic (n = 223) and hyperplastic (n = 82) thyroid tissues in conjunction with cancer tissues (n =193) of various other organs. Stromal elastosis was observed as deposits of pale homogeneous material in hematoxylin and eosin stain, and distinctively highlighted by elastic-van Gieson's stain.
On immunohistochemical examination, elastin and tropoelastin were confirmed in these deposits. Stromal elastosis was found in 66% of papillary thyroid carcinomas (PTCs), although it was not identified in other histological types of thyroid neoplasms. In PTCs, deposits of elastic fibers varied in size and shape, and were more frequently distributed in the periphery of the tumor tissue. The histological subtypes of PTC varied in prevalence of elastosis with the follicular variant's (9%) prevalence being significantly lower than that of the classical type (72%). The frequency of stromal elastosis in PTCs was very similar to the frequencies in breast and lung adenocarcinomas, and higher than the frequencies in carcinomas of other organs.
In conclusion, our results suggest that stromal elastosis is a characteristic histological finding of PTCs, presumably associated with their growth pattern and/or histological architecture. It is, therefore, reasonable to propose that stromal elastosis is an ancillary feature in the histopathological diagnosis of PTCs.FASCIITIS-LIKE STROMA 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 prognosisTotal encapsulation of tumor
Good prognosisObserver Variation in the Diagnosis of Follicular Variant of Papillary Thyroid Carcinoma.
Lloyd RV, Erickson LA, Casey MB, Lam KY, Lohse CM, Asa SL, Chan JK, DeLellis RA, Harach HR, Kakudo K, LiVolsi VA, Rosai J, Sebo TJ, Sobrinho-Simoes M, Wenig BM, Lae ME.
*Departments of Laboratory Medicine and Pathology and Statistics, Mayo Clinic, Rochester, MN; daggerDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario; double daggerDepartment of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong; section signDepartment of Pathology and Laboratory Medicine, Brown Medical School, Providence, RI; paragraph signService of Pathology, Dr. A. Onativia Hospital, Salta, Argentina; Department of Pathology, Wakayama Medical University, Wakayama City, Japan; **Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA; daggerdaggerDepartment of Pathology, National Tumor Institute, Milano, Italy; double daggerdouble daggerInstitute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; and section sign section signDepartment of Pathology and Laboratory Medicine, Beth Israel Medical Center, New York, NY.
Am J Surg Pathol. 2004 Oct;28(10):1336-1340. Abstract quote
The histopathologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Recent reports have suggested that this neoplasm may be frequently overdiagnosed by pathologists. We examined the observer variation in the diagnosis of FVPCA in 87 tumors by 10 experienced thyroid pathologists.
The criteria that the reviewers considered most helpful for making a diagnosis of FVPCA were also assessed. A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. In this series, 24.1% of the patients had metastatic disease (n = 21). In the cases with metastatic disease, a diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 66.7%, and 7 of the reviewers made a diagnosis of FVPCA with a cumulative frequency of 100%. The most important criteria used to diagnose FVPCA included the presence of cytoplasmic invaginations into the nucleus (pseudo-inclusions), abundant nuclear grooves, and ground glass nuclei.
These results suggest that although the diagnosis of FVPCA is variable even among experienced thyroid pathologists, most reviewers agreed on this diagnosis for patients with metastatic disease. The use of well-defined histopathologic features should improve the consistency in diagnosing FVPCA. Since most cases with metastatic disease had obvious invasion, caution should be used in making a diagnosis of FVPCA in the absence of the major histopathologic features or clear-cut invasive growth.
Macrofollicular variant of papillary carcinoma of the thyroid: a histologic, cytologic, and immunohistochemical study of 3 cases and review of the literature.
Lugli A, Terracciano LM, Oberholzer M, Bubendorf L, Tornillo L.
Arch Pathol Lab Med. 2004 Jan;128(1):54-8. Abstract quote
CONTEXT: The macrofollicular variant of papillary carcinoma of the thyroid is a rare entity described by J. Albores-Saavedra and colleagues in 1991. It is characterized histologically by a predominance of macrofollicles and clinically by a low incidence of metastasis. This entity may represent a source of diagnostic error, since it can be easily misinterpreted as a macrofollicular adenoma or nodular goiter.
DESIGN: In this study, we describe 3 cases of papillary carcinoma of the thyroid with a macrofollicular growth pattern and review the literature.
RESULTS: The fine-needle aspiration biopsies in 2 cases showed large cells with optically clear nuclei and nuclear grooves, suggestive of papillary carcinoma of the thyroid. In one case, the cytology showed no signs of malignancy. In all cases, the tumors showed a combination of the conventional follicular variant of papillary carcinoma of the thyroid and macrofollicles (diameter, >250 microm) occupying more than 50% of the cross-sectional area. Cytologic features were large, cuboidal cells with optically clear, ground-glass nuclei with smooth outlines, a fine chromatin pattern, nuclear grooves, and pseudoinclusions. The colloid was dense and more eosinophilic than in adjacent normal follicles. In 2 cases, there was capsular or blood vessel infiltration, and one tumor had metastasized to a cervical lymph node. One tumor recurred 1 year later as an anaplastic carcinoma. Immunohistochemical staining showed a positivity of the tumor cells for cytokeratins 7, 17, and 19, thyroid transcription factor-1, and galectin-3 and a negativity for cytokeratin 20 and p53.
CONCLUSIONS: Although it has been suggested that this tumor is a highly differentiated variant with a favorable prognosis, our study shows that its biologic behavior is not conclusive because metastases and recurrences with dedifferentiation may occur.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.
LIPOMATOUS STROMA MYXOID OXYPHILIC (HURTHLE CELL) PAPILLARY MICROCARCINOMA
(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
Microscopic papillary thyroid carcinoma compared with clinical carcinomas by loss of heterozygosity mutational profile.Hunt JL, LiVolsi VA, Baloch ZW, Barnes EL, Swalsky PA, Niehouse L, Finkelstein SD.
Am J Surg Pathol 2003 Feb;27(2):159-66 Abstract quote The clinical significance of microscopic papillary thyroid carcinoma (PTCa) is controversial. Many authors think that microscopic PTCa (<1 cm) have the same pathogenetic origin as clinically sized papillary carcinomas (>1 cm). Despite the fact that all clinical risk prognostication schemes have the size of the tumor as a primary category, small tumors do have malignant potential and can metastasize. There is growing evidence that small PTCa have the molecular translocations between the proto-oncogene RET and various activating partner genes that are characteristic of clinically sized PTCa.
This study used a microdissection and genotyping assay to study the patterns of loss of heterozygosity of tumor suppressor genes in microscopic and clinically sized PTCa.
Our results indicate that all PTCa harbor mutations with similar frequencies and distribution patterns, regardless of the size of the tumor. These data are further evidence that microscopic and clinically sized PTCa are pathogenetically related.
SARCOMATOID
Spindle cell transformation of papillary carcinoma: an aggressive entity distinct from anaplastic thyroid carcinoma.
Brandwein-Gensler MS, Wang BY, Urken ML.
Department of Pathology, The Mount Sinai School of Medicine, The Mount Sinai New York University Medical Center, New York, NY 10029, USA.
Arch Pathol Lab Med. 2004 Jan;128(1):87-9. Abstract quote
Spindle cells are not routinely encountered in the context of thyroid pathology and are most often present in anaplastic thyroid carcinoma, medullary thyroid carcinoma, and benign conditions such as Riedel struma or de Quervain granulomatous thyroiditis. Only a few publications have reported papillary thyroid carcinoma admixed with a prominent spindle cell component.
While these tumors are clearly distinct from anaplastic thyroid carcinoma, prognostication as to their oncologic potential is not yet established. We describe a unique case of spindle cell transformation of papillary thyroid carcinoma. The blandness of the spindle cells was so impressive as to dissuade us from a malignant diagnosis on preoperative biopsies. However, this patient unfortunately died shortly after transformation of this papillary thyroid carcinoma.
We conclude that this peculiar and rare spindle cell transformation should be regarded as a potentially lethal variant of papillary thyroid carcinoma.SOLID Common in childen
Solid areas must be >50% of the tumor
May be more aggressive
- A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma.
Trovisco V, Soares P, Soares R, Magalhaes J, Sa-Couto P, Sobrinho-Simoes M.
Hum Pathol. 2005 Jun;36(6):694-7. Abstract quote
Summary BRAF gene mutations have been frequently detected in papillary thyroid carcinoma (PTC). Moreover, there is a close association between the type of mutation and the PTC histotype: BRAF V600E is associated with conventional PTC and with histological variants of PTC displaying a prominent papillary growth pattern, whereas BRAF K601E is associated with the follicular variant of PTC.
We report the detection of a novel BRAF triplet deletion in a case of PTC displaying a predominantly solid growth pattern. The deletion leads to the replacement of a valine and a lysine by a glutamate in the BRAF activation segment (BRAF VK600-1E ), thus mimicking partially the 2 BRAF mutations previously described.
Our study reinforces the existence of a close relationship between the occurrence of some types of BRAF mutation and some PTC histotypes. The genetic study of more cases of the solid variant of PTC is necessary to find whether there exists a significant association between the occurrence of BRAF VK600-1E and such PTC histotype.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 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.
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
Department of Pathology, Centre Francois Baclesse, 14016 Caen Cedex 05, France.
The aim of this study was to assess the prevalence, prognostic factors, and long-term outcome of tall cell variant (TCV) in comparison with the conventional forms of papillary thyroid carcinoma (PTC). A total of 945 patients with thyroid cancer were treated and followed up from 1960 to 1998.
Pathologic review was performed in 778 patients (84%) of the cohort. Of these, 674 had PTC: 503 (74%) had conventional form (CF); 56 (8%), TCV; and 155 (17%), other variants of PTC. Tall cell variant was associated with tumors of larger size (P < .001), bilaterality (P < .02), multifocality (P < .04), and extrathyroidal invasion (P < .001). Treatment was similar in both groups, but neck dissection was performed more frequently in patients with TCV (P < .04).
The 10-year overall and event-free survival rates were, respectively, 90% and 85% in the CF versus 79% and 67% in the TCV group (P < .001). Histologic subtype did not have an effect on clinical outcome after multivariate analysis, the most relevant factors being age, involved nodes, or the "Metastasis, Age, Completeness, Invasion, Size" classification after multivariate analysis.
In this large cohort of patients, TCV represents 8.3% of PTC, and it is a more aggressive form of PTC than CF because of the higher stage and increased grade.
CHARACTERIZATION CYTOKERATIN
Cytokeratin 19 immunolocalization in cell block preparation of thyroid aspirates. An adjunct to fine-needle aspiration diagnosis of papillary thyroid carcinoma.Khurana KK, Truong LD, LiVolsi VA, Baloch ZW.
Department of Pathology, State University of New York Upstate Medical University Hospital, Syracuse 13210, USA.
Arch Pathol Lab Med 2003 May;127(5):579-83 Abstract quote CONTEXT: Immunohistochemical staining for cytokeratin 19 (CK-19) is a useful ancillary technique for diagnosing papillary thyroid carcinoma (papillary carcinoma) in histologic specimens. Although similar results have been obtained on aspirate smears, to our knowledge the utility of CK-19 immunolocalization in cell block preparations as an adjunct to fine-needle aspiration diagnosis of papillary carcinoma has not been examined.
OBJECTIVE: The purpose of this study was to determine whether CK-19 immunostaining of cell block preparations of thyroid aspirates is a useful ancillary technique for diagnosing papillary carcinoma.
MATERIALS AND METHODS: Using a monoclonal antibody to CK-19 and a standard avidin-biotin complex technique, immunostaining was performed on paraffin-embedded cell blocks of 57 cases with the following cytologic diagnoses: (a) papillary carcinoma (20 cases); (b) atypical cytology, cannot exclude papillary carcinoma (19 cases); and (c) nonneoplastic thyroid (18 cases). The staining reaction in each case was graded on the basis of percentage of epithelial cells stained (1+, <10%; 2+, <10%-50%; 3+, >50). Tissue follow-up was available in all cases.
RESULTS: Nineteen (95%) of 20 cases with an unequivocal diagnosis of papillary carcinoma were positive for CK-19 (3+). Tissue follow-up confirmed papillary carcinoma in all 20 cases. Of the 19 cases with a diagnosis of atypical cytology, cannot exclude papillary carcinoma, 7 (37%) cases displayed 3+ immunostaining and subsequent excision confirmed papillary carcinoma in all 7 cases. The remaining 12 cases with 1+ immunostaining included surgically confirmed goiter (6 cases), adenoma (2 cases), lymphocytic thyroiditis (3 cases), and papillary carcinoma (1 case). The follicular cells in 18 cases with a cytologic diagnosis of nonneoplastic thyroid showed 1+ immunostaining. Histologic follow-up of these cases confirmed the nonneoplastic cytologic diagnoses.
CONCLUSIONS: Cytokeratin 19 immunostaining of cell block preparations of thyroid aspirates serves as a useful tool for the diagnosis of papillary carcinoma. Strong immunostaining (3+) for CK-19 aids in accurate diagnosis of malignancy in cytomorphologically equivocal cases of papillary carcinoma.
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, MDAm 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.
p75 NEUROTROPHIN RECEPTOR
- The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma.
Rocha AS, Risberg B, Magalhaes J, Trovisco V, de Castro IV, Lazarovici P, Soares P, Davidson B, Sobrinho-Simoes M.
IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
Hum Pathol. 2006 May;37(5):562-8 Abstract quote.
Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation.
Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls.
We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC.
No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern.
This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.
TREATMENT AND PROGNOSIS CHARACTERIZATION PROGNOSIS GENERAL
Thyroid Carcinomas With Distant Metastases: A Review of 111 Cases With Emphasis on the Prognostic Significance of an Insular Component
Myriam Decaussin, M.D.; Marie Hélène Bernard, M.D.; Patrice Adeleine, Ph.D.; Isabelle Treilleux, M.D., Ph.D.; Jean Louis Peix, M.D., F.R.C.S.; Michel Pugeat, M.D.; Jacques Tourniaire, M.D.; Nicole Berger, M.D.
Am J Surg Pathol 2002; 26(8):1007-1015 Abstract quote
Distant metastases (DM) are rare in well-differentiated thyroid carcinomas and correlate with a poor survival. Among the histologic subtypes, insular carcinoma has an intermediate prognosis that lies between well and undifferentiated carcinomas. To assess the characteristics that could predict a worse prognosis, we reviewed the initial thyroid cancer slides from patients with DM. We achieved a comparative statistical analysis with a control group without DM. Among 1230 differentiated carcinomas treated from 1960 to 1999, 9% developed DM. In this group the mean age was 53 years, with a 73% rate of death. The histologic slides were available in 80 cases. The primary thyroid tumors were classified as papillary (51 cases), follicular (25), and pure insular carcinomas (4).Extrathyroidal extension was present in 47% of papillary carcinomas. The mean tumor size was above 5 cm for all the histologic subtypes, and at least a vascular invasion was found in 69%. Fifty-four percent of these tumors had an insular component compared with only 6.5% in the control group. The statistical analysis confirmed by univariate and multivariate logistic regression that the risk of DM was highly elevated in the presence of insular carcinoma.
Our study indicates that elevated age, large tumor size, vascular invasion, and extrathyroidal extension are important prognostic factors in well-differentiated carcinomas. We also demonstrate that the presence of an insular component in an otherwise differentiated carcinoma is a strong independent poor prognostic factor.
CYCLIN D1
Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma.Khoo ML, Beasley NJ, Ezzat S, Freeman JL, Asa SL.
Department of Pathology, University Health Network, Toronto, Ontario, Canada.
J Clin Endocrinol Metab 2002 Apr;87(4):1814-8 Abstract quote Lymph node metastasis in papillary thyroid carcinoma increases the morbidity of treatment and the risk of local regional relapse and may also affect cure rates and survival. Factors that predict lymph node metastasis are, however, unclear.
We analyzed 125 patients with papillary thyroid carcinoma for factors that predict lymph node metastasis. On univariate analysis, age, extrathyroidal extension, tumor focality, overexpression of cyclin D1, and underexpression of p27 predicted lymph node metastasis, whereas patient gender and tumor size did not. On multivariate analysis, extrathyroidal extension, overexpression of cyclin D1, and underexpression of p27 proved to be strong independent predictors of lymph node metastasis.
We suggest that immunohistochemistry for cyclin D1 and p27 will prove valuable in identifying papillary thyroid carcinomas with metastatic potential.
METASTASES
Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid.Sivanandan R, Soo KC.
Department of Surgery, Singapore General Hospital, Singapore.
Br J Surg 2001 Sep;88(9):1241-4 Abstract quote INTRODUCTION: The management of cervical metastases from papillary thyroid carcinoma ranges from selective removal (berry picking) to a formal comprehensive neck dissection. Without a clear understanding of the distribution of nodes at risk, the formulation of strategies on how best to manage the clinically positive neck is difficult. This study reports on observations made in patients who underwent a therapeutic comprehensive neck dissection for metastatic papillary thyroid carcinoma by defining lymph node involvement with respect to neck level.
METHODS: The clinical records and pathological reports of 75 consecutive patients who underwent a neck dissection for cervical metastases from papillary thyroid carcinoma over a 10-year period were reviewed. All dissections were therapeutic in nature, being performed in patients with clinically positive neck nodes. Eighty neck dissection specimens were obtained and analyses were divided into three groups by virtue of the type of dissection performed: a bilateral comprehensive neck dissection, unilateral radical neck dissection and unilateral comprehensive neck dissection. The relative involvement of cervical nodes was analysed with reference to node levels I-V.
RESULTS: Patients in the anterolateral group (levels II, III and IV) were at greatest risk of metastatic disease, with level III nodes consistently the most frequently involved, across all treatment groups. Only three patients exhibited level I involvement, all of whom had extensive neck disease involving all or almost all neck levels.
CONCLUSION: The majority of patients present with multiple level node disease, with the anterolateral group at greatest risk. A comprehensive neck dissection is recommended for all patients with palpable cervical lymphadenopathy.
RECURRENCE
Prognosis after lymph node recurrence in papillary thyroid carcinoma depends on age.Voutilainen PE, Multanen MM, Leppaniemi AK, Haglund CH, Haapiainen RK, Franssila KO.
Department of Surgery, Helsinki University Central Hospital, Finland.
Thyroid 2001 Oct;11(10):953-7 Abstract quote Papillary thyroid carcinoma (PTC) is a malignancy that has good prognosis especially among patients up to 45 years of age; about half of the patients are female and of childbearing age. Lymph node recurrence (LNR) occurs in 10%-14% of patients but is considered to be associated with relatively good prognosis.
The purpose of this study was to estimate the association between patient age at primary operation, and the behavior of the disease after LNR. Between 1967 and 1994, 495 patients underwent surgery for primary PTC at the Department of Surgery, Helsinki University Central Hospital. There were 391 (79.0%) women and 104 (21.0%) men with a mean age of 44.5 years (range, 10.8-85.4 years).
Fifty-eight patients in whom LNR was the first clinical sign of persistent disease after complete clinical response to primary treatment were included in this series. At the time of primary operation, 37 (64.3%) of the 58 patients who developed LNR were younger than 45 years of age and 21 patients were older. The mean times to LNR in these groups were 42.0 months (range, 3.0-194.5 months) and 49.0 months (range, 3.6-209.0 months) respectively. Carcinoma-specific 5-year survival after LNR was 100% (95% confidence interval [CI] 88.8%-100.0%) in patients ages up to 45 years and 61.1% (40.5%-82.8%) in older patients; 10-year survival rates were 100%, and 41.3% (p < 0.0001), respectively. Relative survival at 10 years was 98.6% for patients ages up to 45 years and 42.6% for older patients (p = 0.0014). Using the Cox model it was shown that development of LNR after primary treatment has an independent highly significant negative effect on survival (p < 0.001) in patients over 45 years of age.
Prognosis of PTC even after LNR on patients ages up to 45 years at the time of the primary operation is almost parallel to the normal reference population, but in patients over 45 years of age the prognosis is relatively poor.
RET PROTO-ONCOGENE
Expression of the RET proto-oncogene in papillary thyroid carcinoma and its correlation with clinical outcome.Kjellman P, Learoyd DL, Messina M, Weber G, Hoog A, Wallin G, Larsson C, Robinson BG, Zedenius J.
Department of Molecular Medicine, Endocrine Tumour Unit, Karolinska Hospital, Stockholm, Sweden
Br J Surg 2001 Apr;88(4):557-63 Abstract quote BACKGROUND: In papillary thyroid carcinoma (PTC), presence of the oncogenes RET/PTC has been described, but their correlation with prognosis is debated. The aim of this study was to investigate the expression of the RET proto-oncogene (RET) and correlate it with clinical outcome.
METHODS: Sixty-one PTCs were analysed for expression of RET and the oncogenes RET/PTC1-4 by polymerase chain reaction of complementary DNA.
RESULTS: Twenty-nine PTCs (48 per cent) expressed the RET tyrosine kinase domain (RET-TK). Twelve expressed wild-type RET (WT-RET). One tumour expressed RET/PTC3, one a variant of RET/PTC3, and one RET/PTC1 and WT-RET simultaneously. The remaining 14 expressed RET-TK only. WT-RET expression was detected more frequently in poorly differentiated PTCs (P < 0.05) and in PTCs from patients with aggressive disease (P < 0.01). WT-RET expression remained an independently significant risk factor for aggressive disease when analysed together with other recognized risk factors using a stepwise multiple logistic regression model.
CONCLUSION: Almost half of the PTCs showed RET-TK expression; in only three was this explained by expression of a RET/PTC rearrangement. Instead, expression of WT-RET was detected in 45 per cent of the RET-TK-positive tumours and this expression was an independently significant risk factor for aggressive PTC.
VEGF-D
- VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma.
Yasuoka H, Nakamura Y, Zuo H, Tang W, Takamura Y, Miyauchi A, Nakamura M, Mori I, Kakudo K.
1Department of Pathology, Wakayama Medical University, Wakayama, Japan.
Mod Pathol. 2005 Aug;18(8):1127-33. Abstract quote
Papillary thyroid carcinoma frequently metastasizes to regional lymph nodes, and lymph node metastasis increases the risk of local regional relapse. Recent evidence suggests that vascular endothelial growth factor-D (VEGF-D) promotes lymphangiogenesis, which in turn promotes lymphatic metastasis.
Therefore, the role of VEGF-D messenger RNA transcript levels and VEGF-D immunoreactivity in lymph node metastasis in papillary thyroid carcinoma was investigated. In addition, the role of blood vascular vessel, lymph vessel, and Flt-4-positive vessel densities were studied in relation to their suspected association with lymph node metastasis, and with VEGF-D expression. VEGF-D messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction and VEGF-D immunoreactivity by immunohistochemistry in 49 papillary thyroid carcinomas were also studied. This was followed by quantitative immunohistochemical staining for CD34, podoplanin, and Flt-4. Lymph node metastasis was significantly correlated with VEGF-D messenger RNA transcript levels (P=0.027) and VEGF-D immunoreactivity (P=0.019). Increased lymph vessel density was also correlated with VEGF-D expression and lymph node metastasis.
In conclusion, our findings indicate that VEGF-D expression and increased lymph vessel density may have an important role for lymph node metastasis in papillary thyroid carcinoma.TREATMENT RADIATION
Papillary thyroid carcinoma: prognostic factors and the role of radioiodine and external radiotherapy.Chow SM, Law SC, Mendenhall WM, Au SK, Chan PT, Leung TW, Tong CC, Wong IS, Lau WH.
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China.
Int J Radiat Oncol Biol Phys 2002 Mar 1;52(3):784-95 Abstract quote PURPOSE: To evaluate the role of radioiodine and external radiotherapy treatment in papillary thyroid carcinoma (PTC).
METHODS AND MATERIALS: This is a retrospective study of 842 patients with the diagnosis of PTC registered from 1960 to 1997 at the Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong. The mean follow-up was 9.2 years. The stage distribution according to UICC/AJCC TNM staging was as follows: 58.6%, Stage I; 9.6%, Stage II; 26.1%, Stage III; 2.3%, Stage IV; and 3.4%, not stated.
RESULTS: The 10-year cause-specific survival (CSS) rates were as follows: Stage I, 99.8%; Stage II, 91.8%; Stage III, 77.4%; and Stage IV, 37.1%. Multivariate analysis showed that the statistically significant poor prognostic factors for CSS were as follows: age older than 45, postoperative gross locoregional (LR) residual disease, distant metastasis (DM) at presentation, and lack of radioactive iodine (RAI) treatment. In patients with no DM and no postoperative LR disease, adjuvant RAI ablation reduced both LR failure (RR [relative risk] = 0.29) and DM (RR = 0.2), although the CSS was not affected. In the subgroup of T1N0 M0 disease, no patient with RAI treatment had a relapse. External radiotherapy reduced the risk of LR failure to 0.35. Subgroup analysis revealed that external radiotherapy was particularly effective in increasing the probability of LR control of disease in patients with gross postoperative LR disease (RR = 0.36).
CONCLUSIONS: Both RAI and external radiotherapy were effective treatment in PTC. Total or near-total thyroidectomy followed by RAI treatment appears to result in the best outcome. External radiotherapy to improve LR control is indicated in patients with gross postoperative residual disease. Treatment should be individualized for patients with T1N0 M0 disease.
SURGERY
The sentinel node procedure with Patent Blue V dye in the surgical treatment of papillary thyroid carcinoma.Pelizzo MR, Boschin IM, Toniato A, Bernante P, Piotto A, Rinaldo A, Ferlito A.
Department of Medical and Surgical Science, 3rd Clinic of General Surgery, University of Padua, Italy.
Acta Otolaryngol 2001 Apr;121(3):421-4 Abstract quote How far to extend the surgical treatment of papillary thyroid carcinoma (PTC) is still an open question. A contribution may come from intra-operative lymphatic mapping because, in other malignancies, the procedure has become an important aid in defining lymph node status.
To assess the feasibility of using the sentinel lymph node (SLN) technique with the intratumoral injection of Patent Blue V dye to guide nodal dissection in PTC, 29 patients with a preoperative diagnosis of PTC and no clinical or ultrasonographic evidence of nodal involvement underwent cervicotomy and exposure of the thyroid gland, followed by Patent Blue V dye injection into the thyroid nodule. Total thyroidectomy was subsequently performed, resecting the lymph nodes at levels III, IV, VI and VII. The thyroid, SLN and the other lymph nodes were snap-frozen and submitted for both intra-operative and subsequent definitive pathological evaluation. Intra-operative lymphatic mapping located the SLN in 22/29 patients (75.9%) and the SLN revealed neoplastic involvement in 4/22 (18.2%); other lymph nodes were also positive in 2 cases.
In the 18 patients whose SLNs were not metastatic, the other nodes were also disease-free. The SLN technique thus seems helpful in avoiding unnecessary lymph node dissection in PTC without spread to the SLN.
Accuracy of sentinel lymph node in papillary thyroid carcinoma.Arch-Ferrer J, Velazquez D, Fajardo R, Gamboa-Dominguez A, Herrera MF.
Department of Surgery, Instituto Nacional de Ciencias Medicas y Nutricion, Tlalpan, Mexico City, Mexico.
Surgery 2001 Dec;130(6):907-13 Abstract quote BACKGROUND: The sentinel lymph node has been used in several tumors. The aim of this study was to analyze the accuracy of the sentinel node in papillary thyroid carcinoma.
METHODS: A series of 22 patients with papillary thyroid carcinoma were included. Approximately 0.5 cc of isosulfan blue dye was injected at operation to trace the sentinel node. Lymph node dissection of the ipsilateral central compartment and extensive sampling of the jugular compartment were performed in addition to sentinel node resection. Surgical specimens were stained with hematoxylin-eosin, and negative sentinel nodes were subsequently stained with immunohistochemistry for cytokeratin-7.
RESULTS: Mean age was 37 +/- 14 years. Twenty patients were women, and 2 were men. Mean tumor size was 2.5 +/- 1 cm. A sentinel lymph node was found in 20 patients. With use of hematoxylin-eosin, metastases were identified in 12/20 sentinel nodes (60%). Eleven patients with positive sentinel nodes presented additional lymph node metastases: 9 in the central compartment, 1 in the jugular compartment, and 1 in both compartments. Two patients with negative sentinel nodes had lymph node metastases elsewhere. When sentinel nodes were processed by immunohistochemistry, accuracy increased to 100%.
CONCLUSIONS: Sentinel node is highly accurate for diagnosing metastases in papillary thyroid carcinoma.
Sentinel lymph node biopsy in patients with papillary thyroid carcinoma.Fukui Y, Yamakawa T, Taniki T, Numoto S, Miki H, Monden Y.
Department of Surgery, Kochi Municipal Hospital, Kochi, Japan.
Cancer 2001 Dec 1;92(11):2868-74 Abstract quote BACKGROUND: It remains controversial whether modified radical neck dissection (MRND) for patients with papillary thyroid carcinoma improves prognosis. However, it is highly probable that the incidence of local recurrence is reduced by lymph node dissection. Sentinel lymph node (SLN) biopsy (SLNB) for patients with melanoma and breast carcinoma has been validated as an accurate method for assessing lymph node status. The objective of this study was to determine the feasibility of SLNB for the evaluation of cervical lymph node status in patients with papillary thyroid carcinoma.
METHODS: After injection of methylene blue around the tumor in 22 patients with papillary thyroid carcinoma, blue-stained lymph nodes were dissected as SLNs. After the SLNB, all patients also underwent subtotal thyroidectomy and MRND. SLNs and other lymph nodes were investigated with regard to their number, distribution, size, lymph node status, and ratio of metastatic area.
RESULTS: There was concordance between the SLN findings and the regional lymph node status in 19 of 21 patients (90.5%; 7 patients had both positive SLN and regional lymph node results, and 12 patients had both negative SLN and regional lymph node results). Two patients had negative SLN results but, in the end, had positive nonsentinel lymph nodes (NSLNs). The overall reliability rate of SLNB was 86.3% (19 of 22 patients). The authors experienced no complications with the use of methylene blue for the detection of SLNs.
CONCLUSIONS: SLNB using methylene blue is feasible technically and is safe, and the findings correlate with cervical lymph node status. Therefore, SLNB is a good technique for estimating the status of cervical lymph nodes in patients with papillary thyroid carcinoma.
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