Virchows Archiv

, Volume 471, Issue 1, pp 31–47 | Cite as

Thymus neuroendocrine tumors with CTNNB1 gene mutations, disarrayed ß-catenin expression, and dual intra-tumor Ki-67 labeling index compartmentalization challenge the concept of secondary high-grade neuroendocrine tumor: a paradigm shift

  • Alessandra Fabbri
  • Mara Cossa
  • Angelica Sonzogni
  • Paolo Bidoli
  • Stefania Canova
  • Diego Cortinovis
  • Maria Ida Abbate
  • Fiorella Calabrese
  • Nazarena Nannini
  • Francesca Lunardi
  • Giulio Rossi
  • Stefano La Rosa
  • Carlo Capella
  • Elena Tamborini
  • Federica Perrone
  • Adele Busico
  • Iolanda Capone
  • Barbara Valeri
  • Ugo Pastorino
  • Adriana Albini
  • Giuseppe Pelosi
Original Article


We herein report an uncommon association of intimately admixed atypical carcinoid (AC) and large cell neuroendocrine (NE) carcinoma (LCNEC) of the thymus, occurring in two 20- and 39-year-old Caucasian males. Both tumors were treated by maximal thymectomy. The younger patient presented with a synchronous lesion and died of disease after 9 months, while the other patient was associated with a recurrent ectopic adrenocorticotropic hormone Cushing’s syndrome and is alive with disease at the 2-year follow-up. MEN1 syndrome was excluded in either case. Immunohistochemically, disarrayed cytoplasmic and nuclear ß-catenin expression was seen alongside an intra-tumor Ki-67 antigen labeling index (LI) ranging from 2 to 80% in the younger patient’s tumor and from 3 to 45% in the other. Both exhibited upregulated cyclin D1 and retinoblastoma, while vimentin was overexpressed in the recurrent LCNEC only. Next-generation sequencing revealed CTNNB1, TP53, and JAK3 mutations in the synchronous tumor and CTNNB1 mutation alone in the metachronous tumor (the latter with the same mutation as the first tumor of 17 years prior). None of the 23 T-NET controls exhibited this hallmarking triple alteration (p = 0.003). These findings suggested that LCNEC components developed from pre-existing CTNNB1-mutated AC upon loss-of-function TP53 and gain-of-function JAK3 mutations in one case and an epithelial-mesenchymal transition upon vimentin overexpression in the other case. Both tumors maintained intact cyclin D1–retinoblastoma machinery. Our report challenges the concept of secondary LCNEC as an entity that develops from pre-existing AC as a result of tumor progression, suggesting a paradigm shift to the current pathogenesis of NET.


Thymus ß-catenin Large cell neuroendocrine carcinoma Atypical carcinoid Next-generation sequencing Immunohistochemistry 



The paper has been professionally proofread by PRS ( Ltd., Devonshire Business Centre, Works Road, Letchworth Garden City, Herts SG6 1GJ, United Kingdom).

This work is dedicated to the memory of Carlotta, an extraordinarily lively girl who untimely died of cancer in the prime of her life.

Compliance with ethical standards

The study was approved by the independent ethics committee of the National Tumor Institute IRCCS Foundation, Milan, Italy (accession number INT-17/16). All patients gave their written consent for diagnosis and research activities when they were admitted to the hospital.


This work was supported by an unrestricted grant from Novartis Farma Italia, Origgio (VA), Italy (no accession number). The Funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, which are responsibilities of the authors only.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

428_2017_2130_MOESM1_ESM.docx (93 kb)
ESM 1 Antibody panel used in the study divided by markers (DOCX 92 kb)
428_2017_2130_Fig4_ESM.jpg (53 kb)

Representative p53 immunohistochemistry images of the no. 2 patient’s tumors. The 1997 tumor featuring atypical carcinoid exhibited only focal and faint nuclear decoration for p53 (A), whilst the large cell neuroendocrine carcinoma component showed by far higher p53 nuclear accumulation in keeping with the presence of the relevant gene mutation (B). (JPEG 53 kb)

428_2017_2130_MOESM2_ESM.tif (10.1 mb)
High-resolution image (TIFF 10356 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Alessandra Fabbri
    • 1
  • Mara Cossa
    • 1
  • Angelica Sonzogni
    • 1
  • Paolo Bidoli
    • 2
  • Stefania Canova
    • 2
  • Diego Cortinovis
    • 2
  • Maria Ida Abbate
    • 2
  • Fiorella Calabrese
    • 3
  • Nazarena Nannini
    • 3
  • Francesca Lunardi
    • 3
  • Giulio Rossi
    • 4
  • Stefano La Rosa
    • 5
  • Carlo Capella
    • 6
  • Elena Tamborini
    • 1
  • Federica Perrone
    • 1
  • Adele Busico
    • 1
  • Iolanda Capone
    • 1
  • Barbara Valeri
    • 1
  • Ugo Pastorino
    • 7
  • Adriana Albini
    • 8
  • Giuseppe Pelosi
    • 9
    • 10
    • 11
  1. 1.Department of Pathology and Laboratory MedicineFondazione IRCCS Istituto Nazionale TumoriMilanItaly
  2. 2.Division of Medical Oncology, San Gerardo HospitalMonzaItaly
  3. 3.Department of Cardiothoracic and Vascular Sciences, Pathological Anatomy SectionUniversity of Padua Medical SchoolPaduaItaly
  4. 4.Division of Anatomic Pathology, Regional Hospital “Umberto Parini”AostaItaly
  5. 5.Institute of PathologyUniversity Hospital–CHUVLausanneSwitzerland
  6. 6.Department of Surgical and Morphological SciencesUniversity of InsubriaVareseItaly
  7. 7.Division of Thoracic SurgeryFondazione IRCCS Istituto Nazionale TumoriMilanItaly
  8. 8.Laboratory of Vascular Biology and Angiogenesis, Science & Technology ParkIRCCS MultiMedica GroupMilanItaly
  9. 9.Department of Oncology and Hemato-OncologyUniversità degli Studi di MilanoMilanItaly
  10. 10.Inter-hospital Pathology Division, Science & Technology ParkIRCCS MultiMedica GroupMilanItaly
  11. 11.Servizio Interaziendale di Anatomia Patologica, Polo Scientifico e TecnologicoMilanItaly

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