PMID- 33086236
OWN - NLM
STAT- MEDLINE
DCOM- 20210510
LR  - 20231213
IS  - 1532-0979 (Electronic)
IS  - 0147-5185 (Linking)
VI  - 45
IP  - 4
DP  - 2021 Apr 1
TI  - The Myoepithelial Cells of Salivary Intercalated Duct-type Intraductal Carcinoma 
      Are Neoplastic: A Study Using Combined Whole-slide Imaging, Immunofluorescence, 
      and RET Fluorescence In Situ Hybridization.
PG  - 507-515
LID - 10.1097/PAS.0000000000001605 [doi]
AB  - Intraductal carcinoma (IDC) is a salivary gland tumor currently believed to be 
      analogous to breast ductal carcinoma in situ, consisting of a complex neoplastic 
      epithelial proliferation surrounded by a continuous layer of myoepithelial cells 
      presumed to be native and non-neoplastic. Recent molecular insights have shown 
      that there are at least 3 different types of IDC: (1) intercalated duct-like, 
      with frequent NCOA4-RET fusions; (2) apocrine, with multiple mutations similar to 
      salivary duct carcinoma; and (3) mixed intercalated duct-like and apocrine with 
      frequent RET fusions, especially TRIM27-RET. Recent observations (eg, IDC 
      occurring in lymph nodes) have challenged the notion that the myoepithelial cells 
      of IDC are non-neoplastic. Five IDCs with known RET fusions by RNA sequencing 
      were retrieved from the authors' archives, including 4 intercalated duct-like 
      IDCs with NCOA4-RET, and 1 mixed intercalated duct-like/apocrine IDC with 
      TRIM27-RET. A panel of immunohistochemistry antibodies (S100 protein, p63 or p40, 
      mammaglobin, smooth muscle actin, calponin, androgen receptor) was tested. To 
      precisely localize RET split-positive cells, each case was subjected to 
      sequential retrieval of whole-slide imaging data of hematoxylin and eosin (HE) 
      staining, immunofluorescence staining for calponin, and fluorescence in situ 
      hybridization (FISH) for RET. Because NCOA4-RET is an inversion difficult to 
      visualize on conventional RET FISH, a novel 3-color FISH technique was utilized 
      to demonstrate it clearly. In all 5 cases, the proliferative ducts were 
      completely surrounded by a layer of myoepithelial cells that were positive for 
      p63 or p40, smooth muscle actin, and calponin. Using combined HE, calponin 
      immunofluorescence, and RET FISH imaging, the positive signals were unmistakably 
      identified in both calponin-negative ductal cells and peripheral, 
      calponin-positive myoepithelial cells in all 5 cases. Utilizing combined HE, 
      calponin immunofluorescence, and RET FISH imaging, we demonstrated that IDCs with 
      RET fusions harbored this alteration in both the ductal and myoepithelial cells. 
      This is compelling evidence that the myoepithelial cells of IDC are not mere 
      bystanders, but are rather a component of the neoplasm itself, similar to other 
      biphasic salivary gland neoplasms like pleomorphic adenoma and 
      epithelial-myoepithelial carcinoma. This finding raises questions about the 
      appropriate terminology, classification, and staging of IDC.
CI  - Copyright (c) 2020 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Bishop, Justin A
AU  - Bishop JA
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX.
FAU - Rooper, Lisa M
AU  - Rooper LM
AD  - Departments of Pathology.
AD  - Oncology, The Johns Hopkins Hospital, Baltimore, MD.
FAU - Sangoi, Ankur R
AU  - Sangoi AR
AD  - Department of Pathology, El Camino Hospital, Mountain View.
FAU - Gagan, Jeffrey
AU  - Gagan J
AD  - Department of Pathology, UT Southwestern Medical Center, Dallas, TX.
FAU - Thompson, Lester D R
AU  - Thompson LDR
AD  - Southern California Permanente Medical Group, Woodland Hills Medical Center, 
      Woodland Hills, CA.
FAU - Inagaki, Hiroshi
AU  - Inagaki H
AD  - Department of Pathology and Molecular Diagnostics, Graduate School of Medical 
      Sciences, Nagoya City University, Nagoya, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Surg Pathol
JT  - The American journal of surgical pathology
JID - 7707904
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Microfilament Proteins)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret)
RN  - EC 2.7.10.1 (RET protein, human)
SB  - IM
MH  - Aged
MH  - Automation, Laboratory
MH  - *Biomarkers, Tumor/analysis/genetics
MH  - Calcium-Binding Proteins/*analysis
MH  - *Carcinoma, Ductal/chemistry/genetics/pathology
MH  - Female
MH  - *Fluorescent Antibody Technique
MH  - Gene Fusion
MH  - Humans
MH  - Image Interpretation, Computer-Assisted
MH  - *In Situ Hybridization, Fluorescence
MH  - Male
MH  - Microfilament Proteins/*analysis
MH  - Middle Aged
MH  - Predictive Value of Tests
MH  - Proto-Oncogene Proteins c-ret/*genetics
MH  - *Salivary Gland Neoplasms/chemistry/genetics/pathology
MH  - Calponins
COIS- Conflicts of Interest and Source of Funding: This study was supported in part by 
      the Jane B. and Edwin P. Jenevein, MD Endowment for Pathology at UT Southwestern 
      Medical Center. Supported in part by grants-in-aid for scientific research, MEXT, 
      Japan to H.I. (No. 16H04713). The remaining authors have disclosed that they have 
      no significant relationships with, or financial interest in, any commercial 
      companies pertaining to this article.
EDAT- 2020/10/22 06:00
MHDA- 2021/05/11 06:00
CRDT- 2020/10/21 20:08
PHST- 2020/10/22 06:00 [pubmed]
PHST- 2021/05/11 06:00 [medline]
PHST- 2020/10/21 20:08 [entrez]
AID - 00000478-202104000-00007 [pii]
AID - 10.1097/PAS.0000000000001605 [doi]
PST - ppublish
SO  - Am J Surg Pathol. 2021 Apr 1;45(4):507-515. doi: 10.1097/PAS.0000000000001605.