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Diagnostic and prognostic utility of flow cytometric DNA measurements in follicular thyroid tumors

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Abstract

Distinguishing cellular follicular adenomas (FA) from minimally invasive follicular carcinomas (FC) continues to plague even experienced thyroid pathologists. DNA ploidy analysis has been promoted as a means of making this differentiation; however, the finding of DNA aneuploidy in FA has caused concern that they may demonstrate potential for malignant behavior or should even be reclassified as low-grade noninvasive cancers. In histologically-proven FC, nuclear DNA content has been claimed to have predictive power equivalent to that of all other prognostic factors combined. The aims of the present study, therefore, were to define the DNA ploidy characteristics of FA and FC, to assess the diagnostic potential of cell-cycle parameters, and, in FC, to investigate the prognostic role of such measurements.

We measured DNA content of 124 tumors (60 FA, 64 FC). DNA pattern was normal (diploid) in 75% of FA and 45% of FC, tetraploid/polyploid (T/P) in 13% of FA and 25% of FC, and aneuploid in 12% of FA and 30% of FC. FC was histologically verified in 39% of DNA normal, 67% of T/P, and 73% of aneuploid tumors. DNA index, S-phase, G2M, and S-phase plus G2M were analyzed and were not helpful in differentiating between FA and FC. No patient with FA developed tumor recurrence. In FC (excluding the Hürthle cell variant), no significant differences were found among the 3 DNA ploidy groups with respect to either cancer death or tumor recurrence; however, combining the Hürthle cell variant of follicular carcinomas with pure follicular carcinomas, the presence of distant metastases, DNA aneuploidy, and patient age were the only independently significant prognostic variables. Based on these data, while not valuable for determining the presence of malignancy, DNA ploidy determination is of major prognostic value in follicular carcinomas (including the Hürthle cell variant).

Résumé

Différencier les adénomes folliculaires (AF) et les cancers folliculaires peu invasifs (CF) pose toujours un problème même aux meilleurs anatomopathologistes. On a proposé l'analyse de la ploïde comme moyen de différenciation. Cependent la découverte de la possibilité d'aneuploïdie dans l'AF évoque l'hypothèse d'un potentiel malin de ces adénomes, voire même la nécessité de les reclasser comme des cancers non invasifs à faible malignité. Dans un CF prouvé histologiquement, on pense que le contenu nucléaire en ADN est un facteur pronostique essentiel, équivalant à tous les autres facteurs pronostiques combinés. Les objectifs de cette étude étaient donc d'évaleur les caractéristiques de ploïdie des AF et des CF, d'évaleur le potentiel diagnostique de ces paramètres cellulaires, et examiner le rôle pronostique de ces paramètres dans le CF.

Nous avons mesuré le contenu en ADN de 124 tumeurs (60 AF, 64 CF). La distribution d'ADN était normale (diploïde) dans 75% des AF et 45% des CF, tétraploïde/polyploïde (T/P) dans 13% des AF et 25% des CF, et aneuploïde dans 12% des AF et 30% des CF. Le CF a été vérifié histologiquement chez 39% des tumeurs à ADN normal, 67% des tumeurs T/P, et 73% des tumeurs aneuploïdes. L'analyse de l'index ADN, de la phase S, G2M, et de la phase S combinée avec G2M ne permettait pas de distinguer entre AF et CF. Aucun patient ayant un AF n'a eu de récidive. Dans le CF (excepté la variante cellulaire de Hürthle), on n'a pas trouvé de différence significative parmi les 3 groupes de ploïdie en ce qui concerne les morts dues au cancer ou la récidive tumorale. Cependant, lorsqu'on prenait en compte la variante cellulaire de Hürthle combinée avec les carcinomes folliculaires purs, la présence de métastases à distance, l'aneuploïdie, et l'âge du patient étaient les seules variables indépendantes ayant une valeur pronostique significative. Ces données, bien que sans valeur pour détecter la possibilité de malignité, permettent d'attribuer, à la détermination de la ploïdie une valeur pronostique majeure dans les CF (y compris la variante cellulaire de Hürthle).

Resumen

La distinción entre adenomas celulares foliculares (AF) y carcinomas foliculares mínimamente invasivos (CF) sigue siendo difícil aún para patólogos expertos en patología tiroidea. El análisis de la ploidia del DNA ha sido planteado como una manera de establecer tal diferenciación. Sin embargo, el hallazgo de aneuploidia del DNA en AF ha sido motivo de preocupación en cuanto a que puede ser demostrativo de un potencial de malignidad o aún motivo de su reclasificación como cánceres de bajo grado no invasivos. En CF histológicamente comprobados, el contenido nuclear de DNA ha sido considerado como de una capcidad de predicción de pronóstico igual al de todos los otros factores de pronóstico combinados. Los objetivos del presente estudio fueron definir las características de la ploidia de DNA en AF y CF, determinar el potencial diagnóstico de los parámetros de ciclaje celular, e investigar la capacidad de pronóstico de tales determinaciones en CF.

Se realizaron mediciones del contenido de DNA en 124 tumores, 60 AF y 64 CF. El patrón de DNA resultó normal (diploide) en 75% de los AF y 45% de los CF, tetraploide/ poliploide (T/P) en 13% de los AF y 25% de los CF, y aneuploide en 12% de los AF y 30% de los CF. El CF fue histológicamente verificado en 39% de los tumores con DNA normal, en 67% de aquellos con T/P y en 73% de los tumores aneuploides. El índice de DNA, la fase S, la G2M, y la fase S más G2M fueron analizados y se encontró que no eran de utilidad en la diferenciación entre AF y CF. Ningún paciente con AF desarrolló recurrencia tumoral. En los CF (excluyendo la variedad de células de Hurthle) no se hallaron diferencias entre los 3 grupos de ploidia de DNA y su relación con mortalidad por cancer o recurrencia tumoral. Sin embargo, al combinar la variedad de células de Hurthle de los carcinomas foliculares con los carcinomas foliculares puros, apareció que las metástasis distales, la aneuploidia de DNA, y la edad del paciente son las únicas variables de significación individual en cuanto a pronóstico. Con base en estos datos, se plantea que, aunque no útil para establecer la presencia de malignidad, la determinación de la ploidia del DNA es de valor pronóstico mayor en los carcinomas foliculares (incluyendo la variedad de células de Hurthle).

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Authors and Affiliations

  1. Department of Surgery, Division of Endocrinology and Internal Medicine, Section of Biostatistics, Rochester, Minnesota, USA

    Clive S. Grant M.D., Ian D. Hay M.B., Ph.D., John J. Ryan M.B., Erik J. Bergstralh M.S., Leslie M. Rainwater M.D. & John R. Goellner M.D.

  2. Division of Pathology, Mayo Clinic and Medical Center, Rochester, Minnesota, USA

    Clive S. Grant M.D., Ian D. Hay M.B., Ph.D., John J. Ryan M.B., Erik J. Bergstralh M.S., Leslie M. Rainwater M.D. & John R. Goellner M.D.

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  1. Clive S. Grant M.D.
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Grant, C.S., Hay, I.D., Ryan, J.J. et al. Diagnostic and prognostic utility of flow cytometric DNA measurements in follicular thyroid tumors. World J. Surg. 14, 283–289 (1990). https://doi.org/10.1007/BF01658504

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