Is atypical follicular adenoma of the thyroid a preinvasive malignancy?

doi:10.1016/S0046-8177(03)00241-7

Human Pathology

Volume 34, Issue 7, July 2003, Pages 666-669

https://doi.org/10.1016/S0046-8177(03)00241-7 Get rights and content

Abstract

Among the follicular neoplasms of the thyroid, the definition and nature of atypical adenoma have been confusing. Despite the original speculation about the biologic behavior of preinvasive malignancies, this term is currently used as an expression of uncertainty. To examine the molecular features of a typical adenoma, we analyzed the p53 genes in 2 atypical adenomas and 12 control lesions (6 typical follicular adenomas and 6 follicular carcinomas). Mutations of p53 were detected in the bizarre cells of the atypical adenomas, but not in the bland-looking follicular cells or in the control specimens. Both atypical adenomas showed an identical point mutation in codon 273 (CGT→CAT), a common mutation in various human cancers, including anaplastic carcinoma of the thyroid. This finding supports the view that atypical follicular adenoma is a precursor of thyroid anaplastic carcinoma and suggests that “atypical adenoma” should not be used to express diagnostic uncertainty about the nature of a lesion.

Section snippets

Specimen selection and microscopic examination

Review of the pathology archives of Mackay Memorial Hospital showed 2 cases coded as atypical adenoma during the period 1997-2001. For comparison, 6 cases of follicular adenoma and 6 cases of follicular carcinoma diagnosed in the same period were selected using the hospital computer. The diagnostic criteria for these disease entities were based on previously described definitions.4

Hematoxylin and eosin-stained sections and paraffin-embedded blocks were available in all 14 cases. Histological

Results

On pathologic examination, the first atypical adenoma was characterized by hypercellularity with complete encapsulation. The tumor cells grew in trabecular to solid fashion. Most tumor cells were polygonal with moderately abundant cytoplasm and well-defined borders. The nuclei were normochromatic and round to oval. However, there was focal atypia characterized by nuclear hyperchromasia and pleomorphism (Fig 1A). Mitoses were not identified. The second case was characterized by trabecular,

Discussion

During the past decade, advances in molecular biology have enhanced understanding of the mechanisms of development in thyroid follicular cell neoplasms. For example, evidence indicates that the PTEN gene plays a role in the development of follicular adenoma, that a ras mutation is frequently found in follicular carcinomas, and that RET/TRK genetic rearrangements are found exclusively in papillary carcinomas.5 Mutation of the p53 gene is observed predominantly in anaplastic carcinoma3, 6, 7, 8

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Cited by (35)

Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study
2010, Human Pathology
Citation Excerpt :
Their morphological criteria for poorly differentiated carcinoma are therefore very close to ours. Finally, Tzen et al [25] found P53 mutations in the pleomorphic cells of 2 atypical follicular adenomas. However, their cases did not have significant mitotic activity and tumor necrosis.
Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.
Prediction of KIT Mutation in Gastrointestinal Stromal Tumors by the Immunoprofile of the Tumor Cells
2010, Journal of the Formosan Medical Association
Human KIT protooncogene is the cellular homolog of v-kit from the Hardy– Zuckerman 4 feline sarcoma virus, and encodes a 145-kDa type III tyrosine kinase growth factor receptor that is often mutated in gastrointestinal stromal tumors (GIST). Standardized mutation analysis is not available in many countries; therefore, we aimed to determine if the presence of KIT mutation in GIST can be predicted by the immunoprofile of the tumor cells.
One hundred and forty-nine GIST were subjected to mutation analysis for KIT and immunohistochemical analysis for the expression of CD117, CD34, α-smooth muscle actin (SMA), and S100 protein. Mutation and immunohistochemistry data were correlated.
KIT mutation rates were higher in certain immunoprofile subsets of GIST than in GIST in general. Compared with the overall mutation rate of KIT (70%), all GIST with CD117⁺ and S100⁺ had > 80% probability of harboring mutated KIT, and the subset with additional CD34⁺ and SMA⁻ had a mutation rate of 88%. The overall KIT mutation rate in CD117⁻ GIST was 31%. However, the probability of KIT mutation in CD117⁻ GIST with CD34⁺ SMA⁺S100⁻CD34⁻SMA⁻S100⁺ and CD34⁺SMA⁻S100⁺ was 100%, 100%, and 67%, respectively. Compared with the overall mutation rate (8.7%) of exon 9, GISTs with CD34⁺SMA⁺ had ≥ 20% probability of harboring an exon 9 mutation, and all GISTs in the small intestine had a probability of 19%.
When mutation analysis is not available, immunoprofiles based on CD117, CD34, SMA, and S100 can be used to predict the presence of KIT mutation, but it is less useful for the prediction of exon 9 mutation in GISTs.
Follicular Carcinoma
2009, Clinical Management of Thyroid Disease
Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors
2008, European Journal of Surgical Oncology
Citation Excerpt :
This study was approved by the Institutional Review Board of Mackay Memorial Hospital. DNA was isolated from formalin-fixed paraffin-embedded tumors according to previously described procedures.15 In brief, representative paraffin blocks of formalin-fixed tumor were cut at 8-μm using a clean disposable microtome blade for each block.
Recent studies reported various mutation rates in gastrointestinal stromal tumors (GISTs) and inconsistent prognostic value of mutation in GIST patients. Our purpose was to analyze the frequency and spectrum of KIT and PDFGRA in a large series study and to determine if the presence of mutation and mutation type serve as prognostic factors in GIST patients.
A total of 134 GISTs were subjected to mutation analysis of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 10, 12, 14, and 18). Clinicopathologic characteristics and survivals were correlated to KIT mutation.
Approximately 69% of GISTs had KIT/PDGFRA mutation in Taiwanese GIST patients, with 99% of mutations occurred in KIT and 1% occurred in PDGFRA. Mutation rate was significantly increased in GISTs with mitotic counts >5 per 50 high power fields (χ² test, p = 0.045). However, KIT mutations, regardless of the location (exons 9 versus 11) and type (missense, insertion, and deletion, including deletion specifically involving codons 557 and 558) of mutation, were not significantly associated with poor progression-free survivals. Comparing the overall survival in imatinib-treated patients, there was no significant difference between patients with exon 11 mutation and those with exon 9 mutation (p = 0.473).
GISTs were commonly associated with KIT mutation, but rarely associated with PDGFRA mutation in Taiwan. The presence of KIT mutation and mutation type was not significant prognostic factors in GIST patients without imatinib treatment, suggesting that there is no need to stratify GIST patients by mutation status in clinical trials of targeted therapy.
Thyroid adenomatous nodule with bizarre nuclei: A case report and mutation analysis of the p53 gene
2008, Pathology Research and Practice
We present a rare case of adenomatous nodule with bizarre nuclei. The patient was incidentally found to have a nodule in the left lobe of the thyroid gland by ultrasonographic examination. Papillary thyroid carcinoma was suspected by fine needle aspiration cytology, and hemithyroidectomy was performed. The demarcated 1.5-cm nodule had a multinodular appearance with various features, including micro- and macrofollicular components, cystic degeneration, a hyalinized area, and a papillary structure. Hyperchromatic bizarre nuclei with cytoplasmic inclusions were restrictively observed in the microfollicular area. The bizarre nuclei demonstrated diffuse p53 protein immmunoreactivity, but no mutation in exons 5–9 of the p53 gene was detected. The bizarre nuclei were reactive for anti-5-methyl-2′-deoxycytidine antibody, indicating the enclosure of presumably inactive methylated DNA. The intranuclear cytoplasmic inclusions (ICIs) were proven to contain vimentin and β-catenin by immunohistochemistry. In this case, a degenerative process is involved in the formation of bizarre nuclei because of the compression by surrounding micronodules, unidentifiable mitotic figures, and a quite low proliferative activity. This case suggests that bizarre nuclei and ICIs, which might be identical to those of papillary carcinomas, can be seen in benign thyroid lesions, and overdiagnosis should be avoided regardless of immunohistochemical overexpression of p53.
ND4 mutation in transitional cell carcinoma: Does mitochondrial mutation occur before tumorigenesis?
2007, Mitochondrion
To investigate how mitochondrial mutation occurs in cancers, we analyzed ND4 mutation in 53 transitional cell carcinomas (TCCs) of the upper urinary tract and the normal counterpart (perirenal soft tissue). Three methods, i.e., DNA sequencing, restriction fragment length polymorphism (RFLP), and denaturing high-performance liquid chromatography (DHPLC), were employed because of their different sensitive of detecting mutation. The results of sequencing and RFLP showed that ND4 mutations were only found in 24.5% (13/53) of tumor. However, 11 of these mutations could also be identified in the normal tissue by DHPLC, indicating that most mitochondrial mutations identified in tumors preexist as minor components, which are too low in quantity to be detected by less sensitive methods such as DNA sequencing. The result suggests that mtDNA mutation occurs before tumorigenesis and become apparent in cancer cells.

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^☆: Supported in part by a grant from the National Science Council (NSC 89-2320-B-195-006).

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Human Pathology

Abstract

Section snippets

Specimen selection and microscopic examination

Results

Discussion

References (17)

Thyroid cancer

Cancer Lett

Thyroid carcinoma is characterized by genomic instabilityEvidence from p53 mutations

Mol Genet Metab

Mechanisms and pathogenesis of thyroid cancer in animals and man

Mutat Res

Atypical adenoma of the thyroid

Arch Pathol

Benign and malignant epithelial tumors of the thyroid gland

Arch Surg

Follicular adenoma

Oncogenes and thyroid cancer

Clin Chem Lab Med

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas

J Clin Invest

Cited by (35)

Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study

Prediction of KIT Mutation in Gastrointestinal Stromal Tumors by the Immunoprofile of the Tumor Cells

Follicular Carcinoma

Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors

Thyroid adenomatous nodule with bizarre nuclei: A case report and mutation analysis of the p53 gene

ND4 mutation in transitional cell carcinoma: Does mitochondrial mutation occur before tumorigenesis?

Original contributionIs atypical follicular adenoma of the thyroid a preinvasive malignancy?☆

Abstract

Section snippets

Specimen selection and microscopic examination

Results

Discussion

Cancer Lett

Mol Genet Metab

Mutat Res

Atypical adenoma of the thyroid

Arch Pathol

Benign and malignant epithelial tumors of the thyroid gland

Arch Surg

Follicular adenoma

Oncogenes and thyroid cancer

Clin Chem Lab Med

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas

J Clin Invest

Original contribution
Is atypical follicular adenoma of the thyroid a preinvasive malignancy?☆