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(American Journal of Pathology. 2003;162:1053-1060.)
© 2003 American Society for Investigative Pathology

Short Communication

Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer

Christopher A. French*, Erik K. Alexander{dagger}, Edmund S. Cibas*, Vania Nose{ddagger}, Julia Laguette*, William Faquin§, Jeff Garber, Francis Moore, Jr||, Jonathan A. Fletcher*, P. Reed Larsen{dagger} and Todd G. Kroll**

From the Division of Endocrinology, Departments of Medicine,{dagger} Surgery,|| and Pathology,* Brigham and Women’s Hospital, Boston, Massachusetts; the Department of Pathology,{ddagger} Children’s Hospital, Boston, Massachusetts; the Department of Pathology,§ Massachusetts General Hospital, Boston, Massachusetts; and Harvard Vanguard Medical Associates, Harvard Medical School, Boston, Massachusetts; and the Departments of Pathology and Laboratory Medicine and Hematology and Oncology,** Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. All 11 follicular carcinomas with 3p25 rearrangement exhibited strong, diffuse nuclear immunoreactivity for PPAR{gamma}, consistent with expression of PPAR{gamma} fusion protein. Twelve of 42 (29%) low-stage follicular carcinomas had 3p25 aneusomy without PPAR{gamma} rearrangement (P = 0.01), suggesting that PPAR{gamma} rearrangement and aneuploidy are independent early events in follicular cancer. Eleven of 12 follicular carcinomas with 3p25 aneusomy exhibited no PPAR{gamma} immunoreactivity, supporting the existence of two independent pathways. Follicular carcinoma patients with PPAR{gamma} rearrangement more frequently had vascular invasion (P = 0.01), areas of solid/nested tumor histology (P < 0.001), and previous nonthyroid cancers (P < 0.01) compared with follicular carcinoma patients without PPAR{gamma} rearrangement. Our experiments identify genetic subgroups of low-stage follicular thyroid cancer and provide evidence that follicular carcinomas with PPAR{gamma} rearrangement are a distinct biological entity. The findings support a model in which separate genetic alterations initiate distinct pathways of oncogenesis in thyroid carcinoma subtypes.

Chromosomal rearrangements that create abnormal gene fusions are some of the most early and specific genetic alterations identified in cancer.1,2 Such rearrangements in leukemias play a primary role in establishment and maintenance of malignancy3-7 and in induction of clinical remission by drugs that target activities of the encoded fusion oncoproteins.5,7,8 Gene rearrangements are now used commonly in the molecular diagnosis of cancer.

Aneuploidy is another frequent genetic abnormality in cancer. It results from full or partial aneusomies in which the copy number of entire chromosomes or chromosomal subregions is altered. Aneuploidy per se has been proposed to be an early and genetically destabilizing force in cancer development.9-13 Increasing aneuploidy is associated with cancer progression, but the molecular mechanisms related to aneuploidy in cancer are poorly understood.

Chromosomal rearrangements at 3p25 have been reported in human tumors arising from thyroid follicular epithelial cells.14-22 One such rearrangement, t(2;3)(q13;p25), results in a PAX8-PPAR{gamma} gene fusion,21 and is the predominant member of a family of PPAR{gamma} rearrangements in follicular thyroid carcinoma.20,21 Even so, there is a striking disparity in the overall number of rearrangements that have been discovered in carcinomas compared to leukemias and sarcomas.2 Two adult carcinomas, both arising within the thyroid gland, have been shown to harbor specific gene rearrangement families.20,21,23,24 Thus, the thyroid provides a tractable carcinoma model with which to investigate gene rearrangement mechanisms.

Here, we have used interphase fluorescence in situ hybridization (FISH) and immunohistochemistry to define the prevalence, specificity, and clinicopathological correlates of 3p25 genetic alterations in human follicular thyroid tumors. Our findings suggest that distinct genetic pathways exist in early follicular thyroid cancer and that PPAR{gamma} rearrangements characterize a specific follicular carcinoma entity. The results highlight the thyroid as a natural cancer model with which to investigate both gene rearrangement and aneuploidy mechanisms in epithelial malignancy.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Pathological Diagnoses

We retrieved pathology materials from all thyroidectomy specimens diagnosed with follicular thyroid carcinoma at Brigham and Women’s Hospital (BWH), Boston, MA, in the 13-year period 1988 to 2000. Original pathological diagnoses were rendered by individual staff pathologists at BWH. More than 40% of cases had been reviewed by multiple BWH pathologists and ~15% had been reviewed by outside pathologists in expert consultations. All cases were re-examined independently and blindly with respect to molecular and clinical features by three pathologists (TGK, CAF, and VN) using current morphological criteria.25-27 Four follicular carcinomas were reclassified as papillary carcinomas because well-developed nuclear clearing, grooves, and/or focal papillary architecture were seen. Seven follicular carcinomas were reclassified as follicular adenomas because unequivocal capsular penetration or vascular invasion was not present. The remaining 42 follicular carcinomas and additional study specimens, including 90 papillary carcinomas, 40 follicular adenomas, 15 Hurthle cell carcinomas, and 10 multinodular goiters from BWH, and 15 Hurthle cell carcinomas from the Massachusetts General Hospital (MGH), were included in our final series. Some features of the 6 follicular carcinomas, 20 follicular adenomas, 10 papillary carcinomas, and 10 multinodular goiters have been reported previously.21 The work was approved by the joint BWH/MGH institutional review board.

Cytogenetics and FISH

Karyotyping was performed on Giemsa-banded metaphase spreads as described.28 Formalin-fixed, paraffin-embedded sections were prepared for FISH according to a procedure modified from Bull and Harnden.29 Briefly, 3- to 4-µm sections were deparaffinized in xylene and microwaved for 30 to 60 minutes at 98°C in 100 mmol/L of Tris and 50 mmol/L of disodium ethylenediaminetetraacetic acid, pH 8. The tissue was digested with Digest-All III pepsin (Zymed, South San Francisco, CA) two times at 37°C (15 to 30 minutes each), washed, and postfixed in 10% phosphate-buffered formalin for 1 minute. Slides were denatured at 94°C for 3 to 5 minutes with biotin- and digoxigenin-labeled 3p25 YAC probes (753f7 and 932f3),21 incubated for 18 to 48 hours at 37°C, washed at 72°C in 0.5x standard saline citrate for 5 minutes, and incubated with fluorescein isothiocyanate-anti-digoxigenin (Roche, Indianapolis, IN) and 594 rhodamine streptavidin (Molecular Probes, Eugene, OR) detection reagents in CAS block (Zymed).

Immunohistochemistry

Immunohistochemistry was performed using the monoclonal antibody E8 raised against a human PPAR{gamma} synthetic peptide antigen (Santa Cruz Biotechnology, Santa Cruz, CA). E8 (1:300) was incubated overnight at 4°C on paraffin-embedded tissue sections after microwave antigen retrieval (10 mmol/L citrate buffer, pH 6, at 98°C for 30 minutes). Immune complexes were detected with the ENVISION nonbiotin system (DAKO, Carpinteria, CA) to circumvent known endogenous thyroid biotin-like activities. Controls for antibody specificity included preincubation of E8 with blocking synthetic peptide (Santa Cruz Biotechnology) and exclusion of E8 on tumor and normal thyroid sections. Positive and negative control tissue sections (containing or lacking PPAR{gamma} rearrangement by molecular analyses) were included in each run. Consistent, diffuse PPAR{gamma} nuclear immunoreactivity in tumor relative to normal thyroid tissues in the same sections was scored into three categories for comparative purposes: category 1, immunoreactivity in tumor nuclei comparable or less than that in normal thyroid nuclei; category 2, immunoreactivity in tumor nuclei elevated mildly over normal thyroid nuclei; category 3, immunoreactivity in tumor nuclei elevated highly over normal thyroid nuclei. Only category 3 tumors had PPAR{gamma} rearrangement. Focal PPAR{gamma} nuclear immunoreactivity, seen rarely in small cell clusters and microfollicles within tumors or reactive thyrocytes, and cytoplasmic PPAR{gamma} immunoreactivity, which was generally low, focal, and variable, were disregarded in our analyses.

Clinical and Pathological Features and Statistical Analyses

Tumor pathology data and clinical preoperative and follow-up data were obtained by report and chart reviews and by contact with the patient’s primary endocrinologist and/or primary care physician. Values for continuous variables were calculated as the mean ± SD, and values for categorical variables were calculated as percentages. Statistical differences were assessed using the Student’s t-test for continuous data and the chi-square or Fisher’s exact test for categorical data. All tests were two-tailed. Tumor capsular thickness was scored subjectively as mild, moderate, or thick and objectively using a stage micrometer. Neither method yielded a statistical difference between tumors with or without PPAR{gamma} alterations.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Detection of 3p25/PPAR{gamma} Rearrangement and 3p25 Aneusomy

The single follicular thyroid carcinoma karyotyped in our series contained t(2;3)(q13;p25) (Figure 1A , black arrowheads), a chromosomal rearrangement identified previously in follicular thyroid tumors.15,17-19,21,22 Recent studies have shown that t(2;3)(q13;p25) forms a PAX8-PPAR{gamma} gene fusion21 that is present in a subset of follicular carcinomas.21,30,31 Here, we used interphase FISH with probes flanking the PPAR{gamma} gene to investigate these 3p25 rearrangements.



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  		Figure 1. 3p25 genetic abnormalities in follicular thyroid carcinoma. A: Chromosomal rearrangements such as t(2;3)(q13;p25) (black arrowheads) are present in a subset of follicular thyroid carcinomas. B: A 3p25 FISH assay with DNA probes flanking the PPAR{gamma} gene demonstrates 3p25 rearrangement (white arrowheads) in a paraffin-embedded follicular thyroid carcinoma. C: The FISH assay also detects 3p25 aneusomy (tetrasomy in this tumor) in the presence or absence of 3p25 rearrangement.

 
3p25 rearrangements were observed by FISH in 11 of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 multinodular goiters (Figure 1B , Table 1 ). The FISH assay also detected 3p25 genetic imbalances (3p25 aneusomy) in 12 of 42 (29%) follicular thyroid carcinomas (Figure 1C , Table 1 ). 3p25 aneusomy consisted of trisomy (five cases), trisomy with focal monosomy (one case), and tetrasomy (six cases). No follicular carcinoma had both 3p25 aneusomy and 3p25 rearrangement (P = 0.01). In total, 23 of 42 (55%) follicular thyroid carcinomas had 3p25 genetic alterations.


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  		Table 1. Clinical and Pathologic Features of Follicular Carcinoma Patients with 3p25/PPAR{gamma} Rearrangement and 3p25 Aneusomy

 
Detection of PPAR{gamma} Fusion Protein by Immunohistochemistry

Strong, diffuse nuclear immunoreactivity for PPAR{gamma} was observed in all 11 follicular thyroid carcinomas with 3p25 rearrangement but not in normal thyroid tissues or thyroid tumors such as follicular adenomas without PPAR{gamma} rearrangement (Figure 2A) . On the other hand, 11 of 12 follicular carcinomas with 3p25 aneusomy exhibited no nuclear PPAR{gamma} immunoreactivity (Figure 2A) . Mildly elevated nuclear PPAR{gamma} immunoreactivity relative to normal thyroid tissue was seen in a small subset (6 of 42) of follicular carcinomas without PPAR{gamma} rearrangement (one with 3p25 aneusomy). Cytoplasmic PPAR{gamma} immunoreactivity was infrequent, low, and focal in both tumor and normal thyroid tissues and was disregarded in our analyses. In summary, 18 of 42 (43%) follicular thyroid carcinomas had elevated nuclear PPAR{gamma} expression. Strong, diffuse nuclear PPAR{gamma} expression was observed in all 11 cases with 3p25 rearrangement.



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  		Figure 2. Follicular thyroid carcinomas with 3p25 genetic alterations. A: Follicular thyroid carcinomas (FC) with PPAR{gamma} gene rearrangement exhibit strong, diffuse PPAR{gamma} nuclear immunoreactivity as the result of PPAR{gamma} fusion protein expression. In contrast, normal thyroid tissues and most thyroid tumors without PPAR{gamma} rearrangement exhibit little or no nuclear PPAR{gamma} immunoreactivity. B: Follicular thyroid carcinomas with PPAR{gamma} rearrangement (FC) tend to have vascular invasion (data not shown) and well-defined regions of solid/nested tumor histology shown here adjacent to microfollicular and trabecular areas of the tumor. All histologies in early follicular carcinomas with PPAR{gamma} rearrangement exhibit strong PPAR{gamma} nuclear immunoreactivity.

 
Clinical and Pathological Correlations in Follicular Carcinoma Patients

We compared the clinical and pathological features of patients with follicular thyroid carcinomas containing or lacking 3p25/PPAR{gamma} rearrangement and 3p25 aneusomy. Clinical features that did not differ statistically (P > 0.05) in these groups included patient sex, age at diagnosis, mean tumor size, TMN stage at diagnosis (98% stage I or II), and frequency of regional lymph node spread (Table 1) . Follicular carcinoma patients with PPAR{gamma} rearrangement had previous nonthyroid cancers more frequently than follicular carcinoma patients without PPAR{gamma} rearrangement (P < 0.01, Table 1 ). One patient (36 years of age) had Hodgkin’s disease and a carcinoid tumor metastatic to lung. A second patient (25 years of age) had a testicular germ cell cancer. A third patient (36 years of age) had Hodgkin’s disease and a lung adenocarcinoma. Most follicular carcinoma patients received postsurgical radio-iodine ablation and suppressive thyroxine therapy. Follow-up intervals were statistically similar for patients with (mean, 5.7 years; 9 of 11 patients) or without (mean, 5.3 years; 20 of 31 patients) PPAR{gamma} rearrangement and patients with (mean, 3.9 years; 8 of 12 patients) or without (mean, 5.7 years; 20 of 30 patients) 3p25 aneusomy. No differences in thyroid cancer recurrence, progression, or mortality were noted in these groups.

Pathological features of follicular carcinomas in patients with PPAR{gamma} rearrangement differed significantly from those without PPAR{gamma} rearrangement. Most follicular carcinomas with PPAR{gamma} rearrangement were unilateral, encapsulated tumors that exhibited vascular invasion (P = 0.01) and well-defined areas of solid/nested tumor histology (P < 0.001; Figure 2B ) compared with follicular carcinomas without PPAR{gamma} rearrangement (Table 1) . Follicular carcinomas with PPAR{gamma} rearrangement lacked 3p25 aneusomy (P = 0.01) but were similar to follicular carcinomas without PPAR{gamma} rearrangement in capsular invasion (P = 0.21), capsular penetration (P = 0.51), and capsular thickness (P = 0.27; Table 1 ). Follicular carcinomas with 3p25 aneusomy less frequently exhibited solid/nested tumor histology than follicular carcinomas with PPAR{gamma} rearrangement (P = 0.04; Table 1 ).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Our experiments provide evidence that PPAR{gamma} gene rearrangement and 3p25 aneusomy arise independently in early follicular thyroid carcinoma subgroups. Twenty-three of 42 (55%) follicular carcinomas had either PPAR{gamma} rearrangement or 3p25 aneusomy but none had both. Gene rearrangements are pathogenic aberrations in many blood cell cancers,2,32 in which they are early and perhaps even initiating events. PPAR{gamma} rearrangements seem to provide this type of oncogenic stimulus in follicular carcinomas.21 Aneuploidy is another early genetic alteration in cancer and it may promote genetic instability.9,33 Our findings suggest that PPAR{gamma} rearrangement and aneuploidy have an either/or relationship in early follicular carcinomas and that they are independent genetic events in separate pathways of thyroid tumorigenesis. RAS mutations, other early genetic alterations in follicular carcinoma,34-36 also appear to arise independently of PPAR{gamma} rearrangement (M. Nikiforova, R. Lynch, P. Biddinger, E. Alexander, G. Dorn, G. Tallini, T. Kroll, and Y. Nikiforov, unpublished data). Moreover, papillary carcinomas (thought to arise from the same follicular cells as follicular carcinomas) frequently have rearrangements of the RET37-39 or NTRK140,41 genes. Thus, various early genetic aberrations appear to identify alternative oncogenic pathways within the thyroid. This pattern appears different from the single pathway of step-wise genetic progression envisioned for colorectal and pancreatic carcinomas, which nearly all contain APC10,42,43 or KRAS44 mutations, respectively.

Although PPAR{gamma} rearrangement and aneuploidy appear to arise independently in early follicular carcinomas, they can co-exist16,18 (TG Kroll and JA Fletcher, unpublished data). In two such published cases, PPAR{gamma} rearrangement and aneuploidy appeared together in recurrent16 and metastatic18 follicular cancers. Hence, it is possible that PPAR{gamma} rearrangement, aneuploidy, and other genetic alterations are rarely associated in low-stage tumors but can be acquired sequentially to create follicular cancers with more aggressive clinical behavior.

Considering the overall data, it seems most appropriate to consider follicular carcinomas with PPAR{gamma} rearrangement a distinct thyroid cancer entity. Characteristic pathological features of this entity appear to be vascular invasion (P = 0.01), areas of solid/nested tumor histology (P < 0.001), and the absence of 3p25 aneusomy (P = 0.01). Vascular invasion and capsular penetration are long used morphological criteria for pathological diagnosis of follicular carcinoma,27,45-49 and metastatic follicular carcinomas with PPAR{gamma} rearrangement have been observed18 (T. Dwight and C. Larsson, unpublished data). The solid/nested tumor histology is similar to that seen in poorly differentiated insular carcinomas50,51 except that appreciable necrosis or mitoses are not present. Analysis of higher stage cancers with longer clinical follow-up will be important to define the genetic and biological pathways of progression in follicular carcinomas with PPAR{gamma} rearrangement and aneuploidy.

Strong, diffuse nuclear immunoreactivity for PPAR{gamma} was observed in all 11 follicular carcinomas with 3p25 rearrangement, whereas 6 additional follicular carcinomas without 3p25 rearrangement (one with 3p25 aneusomy) exhibited mildly elevated PPAR{gamma} nuclear immunoreactivity. All remaining follicular carcinomas without PPAR{gamma} rearrangement exhibited no PPAR{gamma} nuclear expression. These observations suggest that multiple mechanisms of PPAR{gamma} deregulation exist in thyroid cancer and this may explain, at least in part, the various growth effects of PPAR{gamma} ligands on thyroid cancer cell lines in vitro52 and in vivo.53 Alternate mechanisms of PPAR{gamma} deregulation could include cryptic rearrangements, point mutations, or deletions that do not disrupt the physical relationship of our FISH probes or epigenetic/regulatory factors that affect PPAR{gamma} transcription, translation, or degradation.

An interesting clinical feature of follicular carcinoma patients with PPAR{gamma} rearrangement was an apparent increase in previous nonthyroid cancers (P < 0.001). The robustness of this correlation is uncertain because of low patient numbers but it raises the possibilities that PPAR{gamma} rearrangement might be associated with cancer predisposition and/or previous cancer therapy. All three patients had previous cancers treated commonly with irradiation, but we could document a definite history of irradiation only in one.

We detected PPAR{gamma} rearrangements in a significant fraction of follicular carcinomas but not other thyroid tumors, supporting their high specificity. PPAR{gamma} rearrangements were absent from most Hurthle cell carcinomas, supporting the idea that follicular and Hurthle cell carcinomas should be considered separate thyroid cancer classes. Although not observed in our series, some follicular adenomas with t(2,3)(q13;p25)/PAX8-PPAR{gamma} have been reported.14,15,17,19,31 We suggest that these morphological follicular adenomas are best considered early in situ follicular carcinomas with malignant potential. Several observations are compatible with the possibility. First, gene rearrangements involving transcription factors are early alterations in many blood cell and connective tissue malignancies and their detection (even by polymerase chain reaction) often defines malignancy. Secondly, the majority of thyroid tumors so far shown to have PPAR{gamma} rearrangements are bonafide follicular carcinomas with vascular invasion, our best pathological indicator of malignancy in absence of local-regional spread or metastases. Advanced stage follicular carcinomas with PPAR{gamma} rearrangement have been observed16,18 (T. Dwight and C. Larsson, unpublished data). Thirdly, a clonal alteration such as PPAR{gamma} rearrangement is expected in some morphological follicular adenomas in which vascular invasion and capsular penetration are not yet developed or are missed by standard histological sectioning. Fourth, the high percentage of follicular carcinoma cells containing PPAR{gamma} rearrangements and the gross pathology patterns argue against follicular carcinomas arising often from benign thyroid (adenomatous) nodules. Finally, cytogenetic.14-16,18-20,54,55 comparative genomic hybridization,56,57 and loss of heterozygosity58-61 studies suggest that follicular adenomas and carcinomas are overall genetically distinct thyroid tumor groups.

We have also observed at low frequency papillary thyroid carcinomas with PPAR{gamma} rearrangement and expect more to be identified.22 It is therefore noteworthy that a minority (3 of 11) of our follicular carcinomas with PPAR{gamma} rearrangement exhibited identifiable but incompletely developed papillary carcinoma-like nuclear changes (clearing and focal grooves). However, all three tumors with such features were encapsulated follicular-patterned lesions with vascular invasion—classic follicular carcinoma characteristics. None were felt to be suspicious for papillary carcinoma on preoperative cytology in which such nuclear changes are most sensitive and specific for papillary carcinoma. Even so, these observations suggest that follicular carcinomas with PPAR{gamma} rearrangements do exhibit some morphological variation.

Well-differentiated follicular thyroid tumors with mixtures of papillary, follicular, and/or Hurthle cell morphologies are not uncommon62-64 and they highlight an overlapping morphological spectra that confounds attempts to diagnose follicular-patterned thyroid lesions in a precise and accurate way.62,65,66 This histological overlap among thyroid carcinoma subtypes poses challenges in evaluating molecular genetic correlates. RET rearrangements were originally thought specific for papillary thyroid carcinoma,67,68 but have recently been identified in up to 50% of benign and malignant Hurthle cell tumors.69-71 Apparently identical RET rearrangements have also been demonstrated in follicular thyroid tumors with very different morphological and biological patterns.72-77 These observations suggest that multiple genetic and/or epigenetic events collaborate to determine overall thyroid cancer phenotype.78 It seems likely that such alterations will ultimately prove useful in classifying thyroid tumors into more definitive biological and clinical subgroups.


   Acknowledgements
 
We thank Ally Allard, Dave Bowman, and Tatiana Zolotarev for technical assistance; and Dr. David Jaye, Dr. Paul Wade, Dr. Charles Parkos, Ally Allard, and Christopher Caulfield for helpful discussion.


   Footnotes
 
Address reprint requests to Todd G. Kroll, M.D., Ph.D., Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 146 Whitehead Building, 615 Michael St., Atlanta, GA 30322. E-mail: tkroll{at}emory.edu

Supported by grant CA75425 from the National Cancer Institute and a Georgia Cancer Coalition Distinguished Clinical Scientist Award (to T. G. K.).

C. A. F. and E. K. A. contributed equally to this work.

Accepted for publication January 3, 2003.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Rowley JD: The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998, 32:495-519[Medline]
  2. Mitelman F: Recurrent chromosome aberrations in cancer. Mutat Res 2000, 462:247-253[Medline]
  3. Pollock JL, Westervelt P, Kurichety AK, Pelicci PG, Grisolano JL, Ley TJ: A bcr-3 isoform of RARalpha-PML potentiates the development of PML-RARalpha-driven acute promyelocytic leukemia. Proc Natl Acad Sci USA 1999, 96:15103-15108[Abstract/Free Full Text]
  4. Huettner CSS, Zhang P, Van Etten RA, Tenen DG: Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000, 24:57-60[Medline]
  5. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001, 293:876-880[Abstract/Free Full Text]
  6. Pandolfi PP: In vivo analysis of the molecular genetics of acute promyelocytic leukemia. Oncogene 2001, 20:5726-5735[Medline]
  7. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001, 344:1038-1042[Abstract/Free Full Text]
  8. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001, 344:1031-1037[Abstract/Free Full Text]
  9. Li R, Sonik A, Stindl R, Rasnick D, Duesberg P: Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc Natl Acad Sci USA 2000, 97:3236-3241[Abstract/Free Full Text]
  10. Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B: Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res 2001, 61:818-822[Abstract/Free Full Text]
  11. Fabarius A, Willer A, Yerganian G, Hehlmann R, Duesberg P: Specific aneusomies in Chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea. Proc Natl Acad Sci USA 2002, 99:6778-6783[Abstract/Free Full Text]
  12. Wang TL, Rago C, Silliman N, Ptak J, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE: Prevalence of somatic alterations in the colorectal cancer cell genome. Proc Natl Acad Sci USA 2002, 99:3076-3080[Abstract/Free Full Text]
  13. Marx J: Debate surges over the origins of genomic defects in cancer. Science 2002, 297:544-546[Free Full Text]
  14. Bondeson L, Bengtsson A, Bondeson AG, Dahlenfors R, Grimelius L, Wedell B, Mark J: Chromosome studies in thyroid neoplasia. Cancer 1989, 64:680-685[Medline]
  15. Teyssier JR, Liautaud-Roger F, Ferre D, Patey M, Dufer J: Chromosomal changes in thyroid tumors. Relation with DNA content, karyotypic features, and clinical data. Cancer Genet Cytogenet 1990, 50:249-263[Medline]
  16. Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW: Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 1990, 66:1213-1220[Medline]
  17. Sozzi G, Miozzo M, Cariani TC, Bongarzone I, Pilotti S, Pierotti MA, Della Porta G: A t(2;3)(q12-13;p24-25) in follicular thyroid adenomas. Cancer Genet Cytogenet 1992, 64:38-41[Medline]
  18. Roque L, Castedo S, Clode A, Soares J: Deletion of 3p25–>pter in a primary follicular thyroid carcinoma and its metastasis. Genes Chromosom Cancer 1993, 8:199-203[Medline]
  19. Roque L, Castedo S, Gomes P, Soares P, Clode A, Soares J: Cytogenetic findings in 18 follicular thyroid adenomas. Cancer Genet Cytogenet 1993, 67:1-6[Medline]
  20. Lui WO, Kyt]ol]a S, Anfalk L, Larsson C, Farnebo LO: Balanced translocation (3;7)(p25;q34): another mechanism of tumorigenesis in follicular thyroid carcinoma? Cancer Genet Cytogenet 2000, 119:109-112[Medline]
  21. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA: PAX8-PPAR{gamma}1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000, 289:1357-1360[Abstract/Free Full Text]
  22. Roque L, Nunes VM, Ribeiro C, Martins C, Soares J: Karyotypic characterization of papillary thyroid carcinomas. Cancer 2001, 92:2529-2538[Medline]
  23. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G: PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990, 60:557-563[Medline]
  24. Tallini G, Asa SL: RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 2001, 8:345-354[Medline]
  25. Hedinger C: Histologic Typing of Thyroid Tumours. 1988 Springer-Verlag, Berlin
  26. Livolsi V: Surgical Pathology of the Thyroid. 1990 W. B. Saunders, Philadelphia
  27. Rosai J, Carcangiu M, DeLellis R: Tumors of the Thyroid Gland. 1992 Armed Forces Institute of Pathology, Washington DC
  28. Fletcher JA, Kozakewich HP, Hoffer FA, Lage JM, Weidner N, Tepper R, Pinkus GS, Morton CC, Corson JM: Diagnostic relevance of clonal cytogenetic aberrations in malignant soft-tissue tumors. N Engl J Med 1991, 324:436-442[Abstract]
  29. Bull JH, Harnden P: Efficient nuclear FISH on paraffin-embedded tissue sections using microwave pretreatment. Biotechniques 1999, 26:416-422[Medline]
  30. Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE: PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 2002, 26:1016-1023[Medline]
  31. Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, Leite V: Expression of PAX8-PPARgamma1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 2002, 87:3947-3952[Abstract/Free Full Text]
  32. Rowley JD: Molecular genetics in acute leukemia. Leukemia 2000, 14:513-517[Medline]
  33. Thiagalingam S, Laken S, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B, Lengauer C: Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc Natl Acad Sci USA 2001, 98:2698-2702[Abstract/Free Full Text]
  34. Lemoine NR, Mayall ES, Wyllie FS, Williams ED, Goyns M, Stringer B, Wynford-Thomas D: High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 1989, 4:159-164[Medline]
  35. Suarez HG, du Villard JA, Severino M, Caillou B, Schlumberger M, Tubiana M, Parmentier C, Monier R: Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 1990, 5:565-570[Medline]
  36. Manenti G, Pilotti S, Re FC, Della Porta G, Pierotti MA: Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer 1994, 7:987-993
  37. Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D, Visconti R, Mastro A, Santoro M, Fusco A: RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 1995, 11:1207-1210[Medline]
  38. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, Carcangiu ML, Fusco A: RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998, 4:287-294[Abstract/Free Full Text]
  39. Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL: Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998, 83:4116-4122[Abstract/Free Full Text]
  40. Bongarzone I, Pierotti MA, Monzini N, Mondellini P, Manenti G, Donghi R, Pilotti S, Grieco M, Santoro M, Fusco A, Vecchio G, Della Porta G: High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 1989, 4:1457-1462[Medline]
  41. Pierotti MA: Chromosomal rearrangements in thyroid carcinomas: a recombination or death dilemma. Cancer Lett 2001, 166:1-7[Medline]
  42. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990, 61:759-767[Medline]
  43. Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ, Wyllie AH, Zheng S, Willson JK, Markowitz SD, Morin P, Kinzler KW, Vogelstein B, Dunlop MG: APC mutations in colorectal tumors with mismatch repair deficiency. Proc Natl Acad Sci USA 1996, 93:9049-9054[Abstract/Free Full Text]
  44. Hruban RH, Wilentz RE, Kern SE: Genetic progression in the pancreatic ducts. Am J Pathol 2000, 156:1821-1825[Abstract/Free Full Text]
  45. Graham A: Malignant epithelial tumors of the thyroid with special reference to invasion of blood vessels. Surg Gynecol Obstet 1924, 39:781-790
  46. Warren S: The significance of blood vessels in adenomas of the thyroid gland. Arch Pathol 1931, 11:255-257
  47. Woolner B, Beahrs O, Black B, McConahey W, Keating R: Classification and prognosis of thyroid carcinoma. Am J Surgery 1961, 102:354-387[Medline]
  48. Brennan MD, Bergstralh EJ, van Heerden JA, McConahey WM: Follicular thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1991, 66:11-22[Medline]
  49. van Heerden JA, Hay ID, Goellner JR, Salomao D, Ebersold JR, Bergstralh EJ, Grant CS: Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery 1992, 112:1130-1138[Medline]
  50. Carcangiu ML, Zampi G, Rosai J: Poorly differentiated ("insular") thyroid carcinoma. A reinterpretation of Langhans’ "wuchernde Struma." Am J Surg Pathol 1984, 8:655-668[Medline]
  51. Pilotti S, Collini P, Mariani L, Placucci M, Bongarzone I, Vigneri P, Cipriani S, Falcetta F, Miceli R, Pierotti MA, Rilke F: Insular carcinoma: a distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Pathol 1997, 21:1466-1473[Medline]
  52. Martelli ML, Iuliano R, Le Pera I, Sama I, Monaco C, Cammarota S, Kroll T, Chiariotti L, Santoro M, Fusco A: Inhibitory effects of peroxisome proliferator-activated receptor gamma on thyroid carcinoma cell growth. J Clin Endocrinol Metab 2002, 87:4728-4735[Abstract/Free Full Text]
  53. Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T: Ligands for peroxisome proliferator-activated receptor gamma inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells. J Clin Endocrinol Metab 2001, 86:2170-2177[Abstract/Free Full Text]
  54. Belge G, Roque L, Soares J, Bruckmann S, Thode B, Fonseca E, Clode A, Bartnitzke S, Castedo S, Bullerdiek J: Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology. Cancer Genet Cytogenet 1998, 101:42-48[Medline]
  55. Roque L, Clode A, Belge G, Pinto A, Bartnitzke S, Santos JR, Thode B, Bullerdiek J, Castedo S, Soares J: Follicular thyroid carcinoma: chromosome analysis of 19 cases. Genes Chromosom Cancer 1998, 21:250-255[Medline]
  56. Frisk T, Kytola S, Wallin G, Zedenius J, Larsson C: Low frequency of numerical chromosomal aberrations in follicular thyroid tumors detected by comparative genomic hybridization. Genes Chromosom Cancer 1999, 25:349-353[Medline]
  57. Hemmer S, Wasenius VM, Knuutila S, Joensuu H, Franssila K: Comparison of benign and malignant follicular thyroid tumours by comparative genomic hybridization. Br J Cancer 1998, 78:1012-1017[Medline]
  58. Zedenius J, Wallin G, Svensson A, Grimelius L, Hoog A, Lundell G, Backdahl M, Larsson C: Allelotyping of follicular thyroid tumors. Hum Genet 1995, 96:27-32[Medline]
  59. Segev DL, Saji M, Phillips GS, Westra WH, Takiyama Y, Piantadosi S, Smallridge RC, Nishiyama RH, Udelsman R, Zeiger MA: Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hurthle cell neoplasms of the thyroid. J Clin Endocrinol Metab 1998, 83:2036-2042[Abstract/Free Full Text]
  60. Grebe SK, McIver B, Hay ID, Wu PS, Maciel LM, Drabkin HA, Goellner JR, Grant CS, Jenkins RB, Eberhardt NL: Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma. J Clin Endocrinol Metab 1997, 82:3684-3691[Abstract/Free Full Text]
  61. Yeh JJ, Marsh DJ, Zedenius J, Dwight T, Delbridge L, Robinson BG, Eng C: Fine-structure deletion mapping of 10q22-24 identifies regions of loss of heterozygosity and suggests that sporadic follicular thyroid adenomas and follicular thyroid carcinomas develop along distinct neoplastic pathways. Genes Chromosom Cancer 1999, 26:322-328[Medline]
  62. Baloch ZW, Livolsi VA: Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol 2002, 117:143-150[Medline]
  63. Renshaw AA, Gould EW: Why there is the tendency to "overdiagnose" the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002, 117:19-21[Medline]
  64. Chan JK: Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002, 117:16-18[Medline]
  65. Saxen E, Franssila K, Bjarnason O, Normann T, Ringertz N: Observer variation in histologic classification of thyroid cancer. Acta Pathol Microbiol Scand [A] 1978, 86A:483-486
  66. Hirokawa M, Carney JA, Goellner JR, DeLellis RA, Heffess CS, Katoh R, Tsujimoto M, Kakudo K: Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 2002, 26:1508-1514[Medline]
  67. Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio G: A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987, 328:170-172[Medline]
  68. Santoro M, Carlomagno F, Hay ID, Herrmann MA, Grieco M, Melillo R, Pierotti MA, Bongarzone I, Della Porta G, Berger N, Peix JL, Paulin C, Fabian N, Vecchio G, Jenkins RB, Fusco A: Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992, 89:1517-1522
  69. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL: Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab 2000, 85:878-882[Abstract/Free Full Text]
  70. Chiappetta G, Toti P, Cetta F, Giuliano A, Pentimalli F, Amendola I, Lazzi S, Monaco M, Mazzuchelli L, Tosi P, Santoro M, Fusco A: The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab 2002, 87:364-369[Abstract/Free Full Text]
  71. Belchetz G, Cheung CC, Freeman J, Rosen IB, Witterick IJ, Asa SL: Hurthle cell tumors: using molecular techniques to define a novel classification system. Arch Otolaryngol Head Neck Surg 2002, 128:237-240[Abstract/Free Full Text]
  72. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA: Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997, 57:1690-1694[Abstract/Free Full Text]
  73. Thomas GA, Bunnell H, Cook HA, Williams ED, Nerovnya A, Cherstvoy ED, Tronko ND, Bogdanova TI, Chiappetta G, Viglietto G, Pentimalli F, Salvatore G, Fusco A, Santoro M, Vecchio G: High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 1999, 84:4232-4238[Abstract/Free Full Text]
  74. Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M, Salvatore G, Chiappetta G, Pacini F, Elisei R, Miccoli P, Pinchera A, Fusco A, Santoro M: Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 2002, 160:247-254[Abstract/Free Full Text]
  75. Fusco A, Chiappetta G, Hui P, Garcia-Rostan G, Golden L, Kinder BK, Dillon DA, Giuliano A, Cirafici AM, Santoro M, Rosai J, Tallini G: Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. Am J Pathol 2002, 160:2157-2167[Abstract/Free Full Text]
  76. Cheung CC, Boerner SL, MacMillan CM, Ramyar L, Asa SL: Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 2000, 24:1622-1626[Medline]
  77. Papotti M, Volante M, Giuliano A, Fassina A, Fusco A, Bussolati G, Santoro M, Chiappetta G: RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 2000, 24:1615-1621[Medline]
  78. Kroll TG: Molecular rearrangements and morphology in thyroid cancer. Am J Pathol 2002, 160:1941-1944[Free Full Text]

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