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Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Soft Tissue Tumors

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Vickie Y Jo at Brigham and Women's Hospital
Vickie Y Jo
Elizabeth G. Demicco
Elizabeth G. Demicco
Elizabeth G. Demicco
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The fifth (5th) edition of the World Health Organization (WHO) Classification of Head and Neck Tumors introduces a new chapter dedicated to soft tissue neoplasms commonly affecting the head and neck. While the diversity, rarity, and wide anatomic range of soft tissue tumors precludes a discussion of all entities that may be found in the head and neck, the addition of this new chapter to the head and neck "blue book" aims to provide a more comprehensive and uniform reference text, including updated diagnostic criteria, of mesenchymal tumor types frequently (or exclusively) arising at head and neck sites. Since publication of the previous edition in 2017, there have been numerous advances in our understanding of the pathogenesis of many soft tissue tumors which have facilitated refinements in tumor classification, identification of novel entities, development of diagnostic markers, and improved prognostication. This review will provide a focused discussion of the soft tissue tumors included in the 5th edition WHO Head and Neck classification, with an emphasis on updates.
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Head and Neck Pathology (2022) 16:87–100
https://doi.org/10.1007/s12105-022-01425-w
UPDATE FROMTHE5TH EDITION OFTHEWORLD HEALTH ORGANIZATION
CLASSIFICATION OFHEAD ANDNECK TUMORS
Update fromthe5th Edition oftheWorld Health Organization
Classification ofHead andNeck Tumors: Soft Tissue Tumors
VickieY.Jo1· ElizabethG.Demicco2,3
Received: 10 December 2021 / Accepted: 3 February 2022 / Published online: 21 March 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
The fifth (5th) edition of the World Health Organization (WHO) Classification of Head and Neck Tumors introduces a new
chapter dedicated to soft tissue neoplasms commonlyaffecting the head and neck. While the diversity, rarity, and wide ana-
tomic range of soft tissue tumors precludes a discussion of all entities that may be found in the head and neck, the addition
of this new chapter to the head and neck "blue book" aims to provide a more comprehensive and uniform reference text,
including updated diagnostic criteria, of mesenchymal tumor types frequently (or exclusively) arising at head and neck sites.
Since publication of the previous edition in 2017, there have been numerous advances in our understanding of the patho-
genesis of many soft tissue tumors which have facilitated refinements in tumor classification, identification of novel entities,
development of diagnostic markers, and improved prognostication. This review will provide a focused discussion of the soft
tissue tumors included in the 5th edition WHO Head and Neck classification, with an emphasis on updates.
Keywords Soft tissue· Sarcoma· Immunohistochemistry· Molecular genetics· Head and neck pathology
Introduction
Soft tissue neoplasms often pose diagnostic challenges in
head and neck pathology, due to their diversity and overlap-
ping histologic spectra. A vast number of soft tissue tumors
may arise throughout the upper aerodigestive tract and sali-
vary glands, and some entities arise preferentially or nearly
exclusively in specific anatomic sites. The fourth (4th) edi-
tion World Health Organization (WHO) Classification of
Head and Neck Tumors (2017) [1] included a small num-
ber of relevant soft tissue tumors within each site-specific
chapter. The fifth (5th) edition of the WHO Classification
of Head and Neck Tumors [2] now includes a dedicated
chapter for soft tissue tumors, providing a centralized and
more practical reference to aid pathologists in the diagnosis
of these challenging tumors. This chapter is organized by
line of differentiation, mirroring the 5th edition of WHO
Classification of Soft Tissue and Bone Tumors (published
in 2020) [3]: adipocytic, fibroblastic and myofibroblastic,
vascular, pericytic (perivascular), smooth muscle, skeletal
muscle, chondro-osseous, peripheral nerve sheath, tumors of
uncertain differentiation, and undifferentiated small round
cell sarcomas. A small number of anatomic site-specific
mesenchymal tumors remain in their respective chapters,
including biphenotypic sinonasal sarcoma in "Soft Tissue
Tumors of the Nasal Cavity, Paranasal Sinuses, and Skull
Base" and ectomesenchymal chondromyxoid tumor in "Oral
Cavity and Mobile Tongue." This review is a focused dis-
cussion of the soft tissue tumors included in the 5th edi-
tion WHO Classification of Head and Neck Tumors, with
an emphasis on recent advances in our understanding of
tumor pathogenesis, diagnostic and prognostic criteria, and
novel immunohistochemical markers. Table1 summarizes
the molecular genetic alterations and surrogate immunohis-
tochemical markers of included entities.
* Vickie Y. Jo
vjo@bwh.harvard.edu
1 Department ofPathology, Brigham andWomen’s Hospital
andHarvard Medical School, 75 Francis Street, Boston,
MA02115, USA
2 Department ofPathology andLaboratory Medicine, Mount
Sinai Hospital, Toronto, ON, Canada
3 Department ofLaboratory Medicine andPathobiology,
University ofToronto, Toronto, ON, Canada
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... SFTs are traditionally assimilated to soft tissue sarcomas and are often positive to CD34 staining. They are broadly classified as mesenchymal tumors based on their histological patterns, albeit their cell of origin remains uncertain (42,43). To unbiasedly determine which tumor transcriptomes are the closest to SFTs, we performed single sample gene set enrichment analysis (ssGSEA) probing the SFT gene signature across the entire Cancer Genome Atlas database (22,687 samples from 223 different tumors). ...
... SFTs were classified as mesenchymal on the basis of their histological patterns and are believed to originate from soft tissue cell types, such as fibroblasts (42,43). When comparing SFT signatures to human tissue RNAseq datasets, we identified greater similarities to CNS tissues but not mesenchymal tissues types. ...
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... In cases of interobserver disagreement, the final diagnosis was reached by consensus. Only tumors that met the diagnostic criteria used by the 5th Edition of the WHO Classification of Head and Neck Tumors [24] were included in the present study. ...
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Article
  • Dec 2020
Background Granular cell tumors (GCTs) are rare neuroectodermal soft tissue neoplasms that mainly affect the skin of the upper limbs and trunks and the oral cavity. GCTs are derived from Schwann cells and, ultrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation. Methods In this study, a convenience set of 22 formalin‐fixed, paraffin‐embedded samples of oral GCTs, all but one sample located at the tongue, was screened for mutations by whole‐exome sequencing. Results Two novel variants in genes of the vacuolar ATPase (V‐ATPase) complex: ATP6AP1 frameshift c.746_749del, leading to p.P249Hfs*4, and ATP6V1A nonsynonymous c.G868A, leading to p.D290N. Each of these mutations occurred in one case. With regard to the samples that were wild‐type for these V‐ATPase variants, at least two samples presented variants in genes that are part of endosomal/lysosomal/autophagosomal networks including ABCA8, ABCC6, AGAP3, ATG9A, CTSB, DNAJC13, GALC, NPC1, SLC15A3, SLC31A2 and TMEM104. Conclusion Although the mechanisms involved in oral GCT initiation and progression remains unclear, our results suggest that oral GCTs have V‐ATPase variants similarly to GCTs from other tissues/organs, and additionally show variants in lysosomes/endosomes/autophagosomal genes.
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DDIT3 Immunohistochemistry Is a Useful Tool for the Diagnosis of Myxoid Liposarcoma
Article
  • Aug 2020
  • AM J SURG PATHOL
Myxoid liposarcoma is a malignant adipogenic neoplasm characterized by prominent arborizing capillaries, occasional lipoblasts, and primitive-appearing spindle cells in a myxoid background. A recurrent translocation in myxoid liposarcoma results in an oncoprotein consisting of full-length DDIT3 (CHOP) fused to an N-terminal segment of either FUS (TLS) or, less often, EWSR1. Here, we explore the diagnostic significance of DDIT3 expression in myxoid liposarcoma using a mouse monoclonal antibody recognizing an epitope in the N-terminal region. Studying a total of 300 tumors, we find diffuse, moderate-to-strong nuclear-localized anti-DDIT3 immunoreactivity in all 46 cases of myxoid liposarcoma representing 36 unique tumors, including 6 cases with high-grade (round cell) morphology. DDIT3 immunohistochemistry also highlighted a distinctive vasculocentric growth pattern in 7 myxoid liposarcomas treated with neoadjuvant radiation. In contrast, the vast majority of other examined lipomatous and myxoid neoplasms exhibited no DDIT3 expression; limited, weak immunoreactivity in <10% of cells was infrequently observed in dedifferentiated liposarcoma (6/39, 15%), solitary fibrous tumor (3/12, 25%), pleomorphic liposarcoma (1/15, 7%), and high-grade myxofibrosarcoma (2/17, 12%). Although this minimal DDIT3 expression did not correlate with DDIT3 amplification or myxoid liposarcoma-like morphology in dedifferentiated liposarcoma, there was evidence among sarcomas (excluding myxoid liposarcoma) of a relationship between expression and exposure to neoadjuvant radiation or cytotoxic chemotherapy. The constellation of findings indicates that DDIT3 immunohistochemistry may have utility in the evaluation of myxoid and lipomatous neoplasms to support the diagnosis of myxoid liposarcoma.
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Radiation‐Associated Sarcomas other than Malignant Peripheral Nerve Sheath Tumors Demonstrate Loss of Histone H3K27 Trimethylation
Article
  • Jul 2020
Background and aims Complete loss of histone H3 lysine 27 trimethylation (H3K27me3) has recently emerged as a biomarker for malignant peripheral nerve sheath tumors (MPNST). Loss of H3K27me3 staining has also been reported in post‐radiation MPNST; however, it has not been evaluated in a large series of radiation‐associated sarcomas of different histologic subtypes. The aim of this study was to assess H3K27me3 labeling by immunohistochemistry in radiation‐associated sarcomas and to determine the prevalence of H3K27me3 loss in these tumors. Methods and results Radiation‐associated sarcomas (n=119) from two tertiary care referral centers were evaluated for loss of H3K27me3, defined as complete loss of staining within tumor cells in the presence of a positive internal control. Twenty‐three cases (19%) showed H3K27me3 loss, including 9/10 (90%) MPNST, 7/77 (9%) undifferentiated spindle cell / pleomorphic sarcomas, 5/25 (20%) angiosarcomas, 1/5 (20%) leiomyosarcomas and 1/2 (50%) osteosarcomas. Conclusions Complete H3K27me3 loss was present in 19% of radiation‐associated sarcomas in our series. Our findings demonstrate that loss of H3K27me3 is not specific for radiation‐associated MPNST and may also occur in other histologic subtypes of RAS, including radiation‐associated undifferentiated spindle cell / pleomorphic sarcoma, angiosarcoma, leiomyosarcoma and osteosarcoma.
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