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“To Be or Not to Be in a Good Shape”: Diagnostic and Clinical Value of Nuclear Shape Irregularities in Thyroid and Breast Cancer

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Cancer Biology and the Nuclear Envelope

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 773))

Abstract

Variation in both nuclear shape and size (“pleomorphism”), coupled with changes in chromatin amount and distribution, remains the basic criteria for microscopy in a cytologic diagnosis of cancer. The biological determinants of nuclear shape irregularities are not clarified, so, rather than on the genesis of nuclear irregularities, we here focus our attention on a descriptive analysis of nuclear pleomorphism. We keep in mind that evaluation of nuclear shape as currently practiced in routine preparations is improper because it is indirectly based on the distribution of DNA as revealed by the affinity for basic dyes. Therefore, over the last years we have been using as criteria morphological features of nuclei of thyroid and breast carcinomas as determined by immunofluorescence, in situ hybridization, and 3D reconstruction. We have translated this approach to routine diagnostic pathology on tissue sections by employing immunoperoxidase staining for emerin. Direct detection of nuclear envelope irregularities by tagging nuclear membrane proteins such as lamin B and emerin has resulted in a more objective definition of the shape of the nucleus. In this review we discuss in detail methodological issues as well as diagnostic and prognostic implications provided by decoration/staining of the nuclear envelope in both thyroid and breast cancer, thus demonstrating how much it matters “to be in the right shape” when dealing with pathological diagnosis of cancer.

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Abbreviations

FISH:

Fluorescence in situ hybridization

H&E:

Hematoxylin and eosin

NE:

Nuclear envelope

PTC:

Papillary thyroid carcinoma

PDC:

Poorly differentiated carcinoma

NEP:

nuclear envelope pleomorphism

References

  1. Bussolati G (2008) Proper detection of the nuclear shape: ways and significance. Rom J Morphol Embryol 49(4):435–439, 490408435439 [pii]

    PubMed  CAS  Google Scholar 

  2. Ghadially F (1988) Ultrastructural pathology of the cell and matrix: a text and atlas of physiological and pathological alterations in the fine structure of cellular and extracellular components, vol 1, 3rd edn. Butterworths, London

    Google Scholar 

  3. Frost J (1986) The cell in health and disease: an evaluation of cellular morphologic expression of biologic behavior. Karger, Basel, 2nd revised edn

    Google Scholar 

  4. Johannessen JV, Gould VE, Jao W (1978) The fine structure of human thyroid cancer. Hum Pathol 9(4):385–400

    Article  PubMed  CAS  Google Scholar 

  5. Batistatou A, Scopa CD (2009) Pathogenesis and diagnostic significance of nuclear grooves in thyroid and other sites. Int J Surg Pathol 17(2):107–110. doi:10.1177/1066896908316071, 1066896908316071 [pii]

    Article  PubMed  Google Scholar 

  6. LiVolsi VA (2011) Papillary thyroid carcinoma: an update. Mod Pathol 24(Suppl 2):S1–S9. doi:10.1038/modpathol.2010.129, modpathol2010129 [pii]

    Article  PubMed  CAS  Google Scholar 

  7. Arora SK, Dey P (2012) Intranuclear pseudoinclusions: morphology, pathogenesis, and significance. Diagn Cytopathol 40(8):741–744. doi:10.1002/dc.21714

    Article  PubMed  Google Scholar 

  8. Cancer TIAfRo (2004) Pathology and genetics of tumours of endocrine organs (IARC WHO classification of tumours), 1st edn. IARC Press, Lyon

    Google Scholar 

  9. Asioli S, Bussolati G (2009) Emerin immunohistochemistry reveals diagnostic features of nuclear membrane arrangement in thyroid lesions. Histopathology 54(5):571–579. doi:10.1111/j.1365-2559.2009.03259.x, HIS3259 [pii]

    Article  PubMed  Google Scholar 

  10. Papotti M, Manazza AD, Chiarle R, Bussolati G (2004) Confocal microscope analysis and tridimensional reconstruction of papillary thyroid carcinoma nuclei. Virchows Arch 444(4):350–355. doi:10.1007/s00428-003-0962-4

    Article  PubMed  Google Scholar 

  11. Holmes TJ (1992) Blind deconvolution of quantum-limited incoherent imagery: maximum-likelihood approach. J Opt Soc Am A 9(7):1052–1061

    Article  PubMed  CAS  Google Scholar 

  12. Holmes TJ, O’Connor NJ (2000) Blind deconvolution of 3D transmitted light brightfield micrographs. J Microsc 200(Pt 2):114–127, jmi751 [pii]

    Article  PubMed  CAS  Google Scholar 

  13. Baloch ZW, LiVolsi VA (2002) Etiology and significance of the optically clear nucleus. Endocr Pathol 13(4):289–299, EP:13:4:289 [pii]

    PubMed  Google Scholar 

  14. Asioli S, Maletta F, Pacchioni D, Lupo R, Bussolati G (2010) Cytological detection of papillary thyroid carcinomas by nuclear membrane decoration with emerin staining. Virchows Arch 457(1):43–51. doi:10.1007/s00428-010-0910-z

    Article  PubMed  CAS  Google Scholar 

  15. Kinsella MD, Hinrichs B, Cohen C, Siddiqui MT (2012) Highlighting nuclear membrane staining in thyroid neoplasms with emerin: review and diagnostic utility. Diagn Cytopathol 41(6):497–504. doi:10.1002/dc.22870

    Article  PubMed  Google Scholar 

  16. Fischer AH, Taysavang P, Weber CJ, Wilson KL (2001) Nuclear envelope organization in papillary thyroid carcinoma. Histol Histopathol 16(1):1–14

    PubMed  CAS  Google Scholar 

  17. Fischer AH, Taysavang P, Jhiang SM (2003) Nuclear envelope irregularity is induced by RET/PTC during interphase. Am J Pathol 163(3):1091–1100

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Bell CD, Coire C, Treger T, Volpe R, Baumal R, Fornasier VL (2001) The ‘dark nucleus’ and disruptions of follicular architecture: possible new histological aids for the diagnosis of the follicular variant of papillary carcinoma of the thyroid. Histopathology 39(1):33–42, his1137 [pii]

    Article  PubMed  CAS  Google Scholar 

  19. Liu J, Singh B, Tallini G, Carlson DL, Katabi N, Shaha A, Tuttle RM, Ghossein RA (2006) Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer 107(6):1255–1264. doi:10.1002/cncr.22138

    Article  PubMed  Google Scholar 

  20. Chan J (2002) Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 117(1):16–18. doi:10.1309/P7QL-16KQ-QLF4-XW0M

    Article  PubMed  Google Scholar 

  21. Lloyd RV, Erickson LA, Casey MB, Lam KY, Lohse CM, Asa SL, Chan JK, DeLellis RA, Harach HR, Kakudo K, LiVolsi VA, Rosai J, Sebo TJ, Sobrinho-Simoes M, Wenig BM, Lae ME (2004) Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 28(10):1336–1340, 00000478-200410000-00009 [pii]

    Article  PubMed  Google Scholar 

  22. Suster S (2006) Thyroid tumors with a follicular growth pattern: problems in differential diagnosis. Arch Pathol Lab Med 130(7):984–988. doi:10.1043/1543-2165(2006) 130[984:TTWAFG]2.0.CO;2, 2006-0069-RAR [pii]

    PubMed  Google Scholar 

  23. Volante M, Collini P, Nikiforov YE, Sakamoto A, Kakudo K, Katoh R, Lloyd RV, LiVolsi VA, Papotti M, Sobrinho-Simoes M, Bussolati G, Rosai J (2007) Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach. Am J Surg Pathol 31(8):1256–1264. doi:10.1097/PAS.0b013e3180309e6a, 00000478-200708000-00017 [pii]

    Article  PubMed  Google Scholar 

  24. Cibas ES, Ali SZ (2009) The Bethesda System For Reporting Thyroid Cytopathology. Am J Clin Pathol 132(5):658–665. doi:10.1309/AJCPPHLWMI3JV4LA, 132/5/658 [pii]

    Article  PubMed  Google Scholar 

  25. Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK (2002) Diagnosis of “follicular neoplasm”: a gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol 26(1):41–44, 10.1002/dc.10043 [pii]

    Article  PubMed  Google Scholar 

  26. Baloch ZW, Sack MJ, Yu GH, Livolsi VA, Gupta PK (1998) Fine-needle aspiration of thyroid: an institutional experience. Thyroid 8(7):565–569

    Article  PubMed  CAS  Google Scholar 

  27. Gharib H (1994) Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect. Mayo Clin Proc 69(1):44–49

    Article  PubMed  CAS  Google Scholar 

  28. Asa SL (2005) The role of immunohistochemical markers in the diagnosis of follicular-patterned lesions of the thyroid. Endocr Pathol 16(4):295–309, EP:16:4:295 [pii]

    PubMed  Google Scholar 

  29. Papotti M, Rodriguez J, De Pompa R, Bartolazzi A, Rosai J (2005) Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential. Mod Pathol 18(4):541–546. doi:10.1038/modpathol.3800321, 3800321 [pii]

    Article  PubMed  CAS  Google Scholar 

  30. Bartolazzi A, Orlandi F, Saggiorato E, Volante M, Arecco F, Rossetto R, Palestini N, Ghigo E, Papotti M, Bussolati G, Martegani MP, Pantellini F, Carpi A, Giovagnoli MR, Monti S, Toscano V, Sciacchitano S, Pennelli GM, Mian C, Pelizzo MR, Rugge M, Troncone G, Palombini L, Chiappetta G, Botti G, Vecchione A, Bellocco R (2008) Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study. Lancet Oncol 9(6):543–549. doi:10.1016/S1470-2045(08)70132-3, S1470-2045(08)70132-3 [pii]

    Article  PubMed  CAS  Google Scholar 

  31. Saggiorato E, De Pompa R, Volante M, Cappia S, Arecco F, Dei Tos AP, Orlandi F, Papotti M (2005) Characterization of thyroid ‘follicular neoplasms’ in fine-needle aspiration cytological specimens using a panel of immunohistochemical markers: a proposal for clinical application. Endocr Relat Cancer 12(2):305–317. doi:10.1677/erc.1.00944, 12/2/305 [pii]

    Article  PubMed  CAS  Google Scholar 

  32. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  33. Marchio C, Reis-Filho JS (2008) Molecular diagnosis in breast cancer. Diagn Histopatho 14:5

    Article  Google Scholar 

  34. Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, Ellis I, Elston C (1995) Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol 26(8):873–879

    Article  PubMed  CAS  Google Scholar 

  35. Meyer JS, Alvarez C, Milikowski C, Olson N, Russo I, Russo J, Glass A, Zehnbauer BA, Lister K, Parwaresch R (2005) Breast carcinoma malignancy grading by Bloom-Richardson system vs proliferation index: reproducibility of grade and advantages of proliferation index. Mod Pathol 18(8):1067–1078. doi:10.1038/modpathol.3800388, 3800388 [pii]

    Article  PubMed  Google Scholar 

  36. Sloane JP, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Boecker W, Bussolati G, Coleman D, Connolly CE, Eusebi V, De Miguel C, Dervan P, Drijkoningen R, Elston CW, Faverly D, Gad A, Jacquemier J, Lacerda M, Martinez-Penuela J, Munt C, Peterse JL, Rank F, Sylvan M, Tsakraklides V, Zafrani B (1999) Consistency achieved by 23 European pathologists from 12 countries in diagnosing breast disease and reporting prognostic features of carcinomas. European Commission Working Group on Breast Screening Pathology. Virchows Arch 434(1):3–10

    Article  PubMed  CAS  Google Scholar 

  37. Bussolati G, Marchio C, Gaetano L, Lupo R, Sapino A (2008) Pleomorphism of the nuclear envelope in breast cancer: a new approach to an old problem. J Cell Mol Med 12(1):209–218. doi:10.1111/j.1582-4934.2007.00176.x, JCMM176 [pii]

    Article  PubMed  Google Scholar 

  38. Kau TR, Way JC, Silver PA (2004) Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer 4(2):106–117. doi:10.1038/nrc1274, nrc1274 [pii]

    Article  PubMed  CAS  Google Scholar 

  39. Sapino A, Goia M, Recupero D, Marchio C (2013) Current challenges for HER2 testing in diagnostic pathology: state of the art and controversial issues. Front Oncol 3:129. doi:10.3389/fonc.2013.00129

    Article  PubMed Central  PubMed  Google Scholar 

  40. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF; American Society of Clinical Oncology; College of American Pathologists (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013. doi: 10.1200/JCO.2013.50.9984. Epub 2013 Oct 7

    Google Scholar 

  41. Zullo JM, Demarco IA, Pique-Regi R, Gaffney DJ, Epstein CB, Spooner CJ, Luperchio TR, Bernstein BE, Pritchard JK, Reddy KL, Singh H (2012) DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149(7):1474–1487. doi:10.1016/j.cell.2012.04.035, S0092-8674(12)00591-0 [pii]

    Article  PubMed  CAS  Google Scholar 

  42. Sutherland H, Bickmore WA (2009) Transcription factories: gene expression in unions? Nat Rev Genet 10(7):457–466. doi:10.1038/nrg2592, nrg2592 [pii]

    Article  PubMed  CAS  Google Scholar 

  43. Lamond AI, Spector DL (2003) Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4(8):605–612. doi:10.1038/nrm1172, nrm1172 [pii]

    Article  PubMed  CAS  Google Scholar 

  44. Misteli T, Soutoglou E (2009) The emerging role of nuclear architecture in DNA repair and genome maintenance. Nat Rev Mol Cell Biol 10(4):243–254. doi:10.1038/nrm2651, nrm2651 [pii]

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Van de Vosse DW, Wan Y, Lapetina DL, Chen WM, Chiang JH, Aitchison JD, Wozniak RW (2013) A role for the nucleoporin Nup170p in chromatin structure and gene silencing. Cell 152(5):969–983. doi:10.1016/j.cell.2013.01.049, S0092-8674(13)00141-4 [pii]

    Article  PubMed Central  PubMed  Google Scholar 

  46. Fischer AH, Zhao C, Li QK, Gustafson KS, Eltoum IE, Tambouret R, Benstein B, Savaloja LC, Kulesza P (2010) The cytologic criteria of malignancy. J Cell Biochem 110(4):795–811. doi:10.1002/jcb.22585

    Article  PubMed  CAS  Google Scholar 

  47. Fischer AH, Bond JA, Taysavang P, Battles OE, Wynford-Thomas D (1998) Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 153(5):1443–1450

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423(6937):293–298. doi:10.1038/nature01629, nature01629 [pii]

    Article  PubMed  CAS  Google Scholar 

  49. Maraldi NM, Lattanzi G, Capanni C, Columbaro M, Merlini L, Mattioli E, Sabatelli P, Squarzoni S, Manzoli FA (2006) Nuclear envelope proteins and chromatin arrangement: a pathogenic mechanism for laminopathies. Eur J Histochem 50(1):1–8

    PubMed  CAS  Google Scholar 

  50. Polychronidou M, Grobhans J (2011) Determining nuclear shape: the role of farnesylated nuclear membrane proteins. Nucleus 2(1):17–23. doi:10.4161/nucl.2.1.13992, 1949-1034-2-1-4 [pii]

    Article  PubMed Central  PubMed  Google Scholar 

  51. Hetzer M, Gruss OJ, Mattaj IW (2002) The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nat Cell Biol 4(7):E177–E184. doi:10.1038/ncb0702-e177, ncb0702-e177 [pii]

    Article  PubMed  CAS  Google Scholar 

  52. Bendris N, Arsic N, Lemmers B, Blanchard JM (2012) Cyclin A2, Rho GTPases and EMT. Small GTPases 3(4):225–228. doi:10.4161/sgtp.20791, 20791 [pii]

    Article  PubMed Central  PubMed  Google Scholar 

  53. Recchi C, Seabra MC (2012) Novel functions for Rab GTPases in multiple aspects of tumour progression. Biochem Soc Trans 40(6):1398–1403. doi:10.1042/BST20120199, BST20120199 [pii]

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Ntantie E, Gonyo P, Lorimer EL, Hauser AD, Schuld N, McAllister D, Kalyanaraman B, Dwinell MB, Auchampach JA, Williams CL (2013) An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci Signal 6(277):ra39. doi:10.1126/scisignal.2003374, 6/277/ra39 [pii]

    Article  PubMed  Google Scholar 

  55. Lee RK, Lui PP, Ngan EK, Lui JC, Suen YK, Chan F, Kong SK (2006) The nuclear tubular invaginations are dynamic structures inside the nucleus of HeLa cells. Can J Physiol Pharmacol 84(3–4):477–486. doi:10.1139/y05-110, y05-110 [pii]

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

GB is funded by Persother (SMIS-CSRN:549/12.024); AS is funded by AIRC (IG10787) and Ricerca Sanitaria Finalizzata (RF-2010-2310674); and CM is funded by AIRC (MFAG 13310).

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Authors and Affiliations

  1. Department of Medical Sciences, University of Turin, via Santena 7, 10126, Turin, Italy

    Gianni Bussolati, Francesca Maletta, Sofia Asioli, Laura Annaratone, Anna Sapino & Caterina Marchiò

  2. Institut Victor Babes, Bucharest, Romania

    Gianni Bussolati

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  1. Gianni Bussolati
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  2. Francesca Maletta
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  3. Sofia Asioli
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  4. Laura Annaratone
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  5. Anna Sapino
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  6. Caterina Marchiò
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Correspondence to Gianni Bussolati .

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Editors and Affiliations

  1. University of Edinburgh Wellcome Trust Centre for Cell Biology, Edinburgh, United Kingdom

    Eric C. Schirmer

  2. University of Edinburgh Wellcome Trust Centre for Cell Biology, Edinburgh, United Kingdom

    Jose I. de las Heras

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Bussolati, G., Maletta, F., Asioli, S., Annaratone, L., Sapino, A., Marchiò, C. (2014). “To Be or Not to Be in a Good Shape”: Diagnostic and Clinical Value of Nuclear Shape Irregularities in Thyroid and Breast Cancer. In: Schirmer, E., de las Heras, J. (eds) Cancer Biology and the Nuclear Envelope. Advances in Experimental Medicine and Biology, vol 773. Springer, New York, NY. https://doi.org/10.1007/978-1-4899-8032-8_5

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