厚生連医誌

第１４巻

１号 ５５〜５８ ２００５Case report

One case of so―called thyroid adenoma with bizarre nucleithat was reconfirmed as thyroid carcinoma based on the genetic mutation of the exon ５ of p５
３by Polymerase chain re３―
action ― single strand conformational polymorphism（ p ５SSCP）
of the formalin―fixed paraffin―embedded specimen
Department of Pathology, Pathology Center ; Pathologist １），
Department of Genetic diagnosis（Chu―etsu genetic diagnosis study group）；Clinical technologist ２）

Toshihiko Ikarashi １），Hidehiro Hasegawa ２）（SSCP），p５３―SSCP, formalin―fixed paraffin―embedded
７
specimen, immunohistochemistry, Ki―６

Background : Generally the cytopathological atypism isconsidered to be one of diagnostic criteria of cancer. But
it is thought that even benign tumors often show cellularatypism in endocrine tumors, which cannot be regarded as
the malignant criterion. Among thyroid tumors of endocrine organ, however, the true biological malignancy of
thyroid follicular adenoma with bizarre nuclei, alias atypical follicular adenoma of thyroid, has not been distinctly
settled yet and this pathological diagnosis has been usedwith an uncertain malignant potentiality. We had an opportunity to study a case of follicular adenoma with nuclear atypism genetically and report its biological malignancy. Case：３０―year―old female patient revealed single
expansive mass of ４ cm in diameter with multicystic andcalcified configuration. An aspiration cytology revealed
several aggregates of follicular cells with bizarre nuclei
and multinucleated cells without any necrosis and dispersed single tumor cells. Anaplastic carcinoma of thyroid
gland was cytopathologically suggested. Postoperative pathology indicated follicular adenoma with bizarre nuclei,mainly consisted of usual follicular adenoma without any
atypism. On immunohistochemistry there was a slight in３―positivecrement of Ki―６７―positive cells with no p５
cells. Surrounding usual follicular tumor cells failed to bestained with above two reagents. In a genomic analysis ofp５
３ suppressor gene the mutation of exon ５ was detected in bizarre cells of adenoma, but not in the usual
follicular adenoma and the normal control specimen. Conclusion : The genomic mutation of p５
３ suppressor genehas been often seen in undifferentiated thyroid carcinoma
or in the dedifferentiation progression of thyroid carcinoma. These observation made us speculate that some follicular adenomas with bizarre nuclei were minute de novo
anaplastic carcinomas or borderline lesions between adenoma and anaplastic carcinoma.

Case report
３０―year―old female patient revealed single expansive
mass of ４ cm in diameter with multicystic and calcified
configuration. An aspiration cytology revealed several aggregates of follicular cells with bizarre nuclei and multinucleated cells without any necrosis and dispersed single
tumor cells（Fig．
１）．
Anaplastic carcinoma of thyroid gland
was cytopathologically suggested. A hemilobectomy wasperformed. Postoperative pathology indicated follicularadenoma with bizarre nuclei, mainly consisted of usual
follicular adenoma without any atypism（Fig．
２）．Immunohistochemically only several follicular cells with bizarre
７ antibody regardlessnuclei were stained with anti―Ki―６of their atypism, less than５％，but there was no positive
cells in p５３investigation（Fig．
３）．There was no infiltration nor metastasis. In a genomic analysis of p５
３ suppressor gene deoxyribonucleic acid（DNA）was extracted
from the trimmed focus consisted of cells with bizarre nuclei in routinely processed formalin―fixed paraffin―embedded tissue specimen. p５
３―SSCP was performed according
to our previously reported method（２―４）．The mutationof exon ５ was detected as an additional band in bizarre
cells of adenoma, but not in the usual follicular adenoma
and the normal control specimen（Fig．
４）．There was nomutations in other exons, including exon６，７，and８．
Discussion
p５３ is one of the suppressor genes, which prevent anoncogenesis. So the oncogenesis is promoted by the abortive genomic mutation of suppressors against tumorigenesis. This type of p５３genomic mutation has been reported
in the process of carcinoma of both poorly or anaplastic
differentiation and metastatic potentiality（Fig．
５）（１，５）．The mutation of exon ５ of p５
３ was revealed
within the specified cells with cellular atypism in our follicular adenoma with bizarre nuclei by p５３―SSCP study.

Key words : thyroid adenoma with bizarre nuclei, atypical follicular adenoma of thyroid, polymerase chain reaction ― single strand conformational polymorphism― 55 ―

One case of so−called thyroid adenoma with bizarre nuclei that was reconfirmed as thyroid carcinoma based on the genetic mutation of the exon５of
p５３ by Polymerase chain reaction−single strand conformational polymorphism（p５３−SSCP）of the formalin−fixed paraffin−embedded specimen

This genetic mutation of p５
３ was also reported !．
These p５
３ genomic defects suggested that the cells withatypism in follicular adenoma with bizarre nuclei wereanaplastic carcinoma of early phase, namely, follicularadenoma with bizarre nuclei consisted of both usual adenoma and minute anaplastic carcinoma. It was useful torecognize the aggressive carcinoma at the early stage forpreventing from life―threatening. On immunohistochemistry there was no overproduction of defective p５３―products.
Because there were still variations of cellular atypism
among cases and previous reports consisted of only casereports, the biological malignancy of this tumor remained
to be established. It is necessary to analyze its malignancy
by the genomic study with p５３―SSCP in all cases.
Acknowledgement
Grateful acknowledgement was made to Dr. Emura（Nagaoka Red Cross Hospital）for his offer of pathologicalmaterials.
References
１．Tzen C, Huang Y, Fu Y. Is atypical follicular adenoma of the thyroid a preinvasive malignancy? HumPathol ２００３；３４：６
６６―９．
２．Hasegawa H, Ikarashi T. Detection analysis of the p
５３ genomic mutations by PCR―SSCP method. Niigata―ken Koseiren Med J ２００１；１１：４２―５．
３．Ikarashi T, Hasegawa H. Periodic reevaluation of ourgenetic pathological diagnosis by application of polymerase chain reaction（PCR）to routine formalin―fixedparaffin―embedded tissues. Niigata―ken Koseiren Med J
２００３；１２：９５―８．
４．Manual of genetic pathological diagnosis with fromalin―fixed and paraffin―embedded specimens. Ver．
３．
eds
Genetic examination room in Pathology Center of Niigata Pref. Health Assoication, and Chuetu Genetic Diagnosis Study Group. Nagaoka，
２００４．
（CD―R available
from : URL : http : //www.nkp―center.jp/, E―mail : byori@abeam.ocn.ne.jp）
５．Genopathological diagnosis and immunohistochemistry. In : Ikarashi's medical ABC understandable evenby a cat ―Clinicopathological mechanism and its
medical stratery―．Ikarashi T. et．
４１ed. Nagaoka : Pimento Press；２００４（５１．
５GB of content）（Soft : Windows , Exel , PowerPoint （ Microsoft ）， Photoshop（Adobe），Ichitaroh（Justsystem），and DocuWorks
Desk（Fuji Xerox）．

和 文 抄録

ホルマリン固定―パラフィン包埋材料を使った遺伝
子検査上 p５３―SSCP 変異を同定し、甲状腺癌が示唆された巨大核を伴う甲状腺腺腫の一症例
病理センター、病理科；病理医 １）、遺伝子診断室（中越遺伝子診断研究会）；臨床検査技師 ２）
いか らしとしひこ

はせ がわひでひろ五十嵐俊彦 １）、長谷川秀浩 ２）
背景：通常、細胞病理学的異型性は、がんの病理学的診断基準のうちの １ つであると考えられる。しかし、内分泌臓器の腫瘍に関しては、良性腫瘍でさえしばしば高度な細胞異型を示すとされ、細胞異型性は悪性基準とならない。内分泌臓器としての甲状腺の腫瘍において、奇怪な核異型を伴う甲状腺濾胞性腺腫（別名、異型濾胞性甲状腺腺腫）の真実の生物学的悪性度は未だ明確となっておらず、この病理診断名が不確かな悪性度のまま日常臨床で使用されている。
今回、我々は、奇怪な核異型を伴う甲状腺濾胞性腺腫の遺伝病理学的検査を実施し、その生物学的悪性度を検討する機会を得たので、報告する。症例：症例は３０才の女性で、単発性で、多嚢胞性の直径４cm の圧排限局性腫瘤であった。腫瘍穿刺細胞学的所見上、壊死を欠如した、散在性の奇怪な核と多核細胞を伴う濾胞性腫瘍細胞集簇が認められ、甲状腺の未分化癌が示唆された。
手術後の摘出物の病理組織学的検討上、奇怪な核を伴う濾胞性腺腫と診断されたが、細胞異型性を欠如した通常の濾胞性腺腫が主体であった。免疫組織化学的検査上、細胞異型の高度な腫瘍細胞は p５３陰性で、Ki―６７陽性細胞が散在性に少数認められた。周囲の濾胞性腺腫細胞は両者とも陰性であった。p５３抑制遺伝
子の遺伝子分析において、通常の濾胞性腺腫部分と正常対象組織では遺伝子変異は認められず、奇怪な核異型を伴う甲状腺濾胞性腺腫の細胞異型部分においてのみエクソン ５ の遺伝子変異が認められた。結論：p５３抑制遺伝子の変異は、甲状腺の未分化がんまたは甲状腺がんの退形成に伴ってしばしば認められる。このことは、我々を奇怪な核を伴う濾胞性腺腫は、良性の腺腫と未分化がんの中間群、または、de novo に発生した未分化がんの早期がんであると推定された。
キーワード：巨大核を伴う甲状腺腺腫、異型濾胞性甲状腺腺腫、p５３―SSCP、ホルマリン固定―パラフィン
包埋材料、免疫組織化学、Ki―６７― 56 ―

厚生連医誌

第１４巻

１号 ５５〜５８ ２００５

Fig.１aFig.２aFig.１b

Fig.２b

Fig.１cFig.２cFig.１dFig.２d― 57 ―

One case of so−called thyroid adenoma with bizarre nuclei that was reconfirmed as thyroid carcinoma based on the genetic mutation of the exon５of
p５３ by Polymerase chain reaction−single strand conformational polymorphism（p５３−SSCP）of the formalin−fixed paraffin−embedded specimen

Fig.３c. Immunohistochemical results
cytopathology
follicular adenoma

p５３Ki−６７without any atypism−−

with bizarre nuclei−＋（＜５％）

Fig.３aFig. ４

Fig.３b

Fig.５. Mutation of suppressor gene p５
３was found in various processes of carcinomas *― 58 ―