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CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort

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Abstract

Objective

To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort.

Methods

Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) (n = 15), atypical adenoma (AA) (n = 14) and typical adenoma (TA) (n = 17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive.

Results

Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors. Median follow up times were 88 months for CA, 76 months for AA, and 104 months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma.

Conclusions

Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210 months.

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Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by grants from Ministero della Salute of Italy, Ricerca Oncologica “RF-OGR-2006_416850” (to A.Sc), from Ministero della Salute of Italy, Progetti di Ricerca di Interesse Nazionale—cofinanziamento 2007 (PRIN 2007) (to S.M.), from Istituto Superiore di Sanità “ITALIA-USA Program 2007—Malattie Rare” grant no. 8900000 (to A.Sp.) and grants from Ministero della Salute of Italy (Ricerca Corrente 2003 to A.Sc. and 2007 to M.C.) and a fellowship by FIRC 2006 (VG).

Author information

Author notes

  1. Lucia Anna Muscarella

    Present address: Laboratory of Oncology, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013 San Giovanni Rotondo, Foggia, Italy

Authors and Affiliations

  1. Genetics Unit, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013, San Giovanni Rotondo, Foggia, Italy

    Vito Guarnieri, Lucia Anna Muscarella, Filomena Baorda, Leonardo D’Agruma & Massimo Carella

  2. Endocrinology Unit, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013, San Giovanni Rotondo, Foggia, Italy

    Claudia Battista, Raffaella Viti & Alfredo Scillitani

  3. Pathology Unit, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013, San Giovanni Rotondo, Foggia, Italy

    Michele Bisceglia & Celeste Clemente

  4. Surgery Unit, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013, San Giovanni Rotondo, Foggia, Italy

    Danilo de Martino

  5. Oncology Unit, Ospedale “Casa Sollievo della Sofferenza”, Istituto di Ricovero e Cura a Carattere Scientifico, 71013, San Giovanni Rotondo, Foggia, Italy

    Evaristo Maiello

  6. Endocrinology and Diabetology Unit, Department of Medical Sciences, Fondazione Policlinico, Istituto di Ricovero e Cura a Carattere Scientifico, University of Milan, Milan, Italy

    Iacopo Chiodini, Sabrina Corbetta, Cristina Eller-Vainicher & Anna Spada

  7. Department of Clinical Sciences, University of Rome “Sapienza”, Rome, Italy

    Salvatore Minisola & Elisabetta Romagnoli

  8. Departments of Medicine, Physiology, and Human Genetics, McGill University, Montreal, Canada

    Lucie Canaff & Geoffrey N. Hendy

  9. Calcium Research Laboratory, and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec, Canada, H3A 1A1

    Lucie Canaff & Geoffrey N. Hendy

  10. Pathology Unit, Ospedale “Miulli”, 70021, Acquaviva delle Fonti, Bari, Italy

    Michela Iacobellis

  11. Department of Internal Medicine, Policlinico S.Orsola Malpighi, Bologna, Italy

    Nazzarena Malavolta

  12. Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics, University of Toronto, Toronto, Ontario, Canada, M5G 1L5

    David E. C. Cole

Authors
  1. Vito Guarnieri
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  2. Claudia Battista
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  3. Lucia Anna Muscarella
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  4. Michele Bisceglia
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  21. Geoffrey N. Hendy
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  22. David E. C. Cole
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Corresponding author

Correspondence to Alfredo Scillitani.

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Guarnieri, V., Battista, C., Muscarella, L.A. et al. CDC73 mutations and parafibromin immunohistochemistry in parathyroid tumors: clinical correlations in a single-centre patient cohort. Cell Oncol. 35, 411–422 (2012). https://doi.org/10.1007/s13402-012-0100-x

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