Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics

Ono, Sawako; Fukawa, Yuki; Hirose, Katsutoshi; Hori, Yumiko; Motooka, Daisuke; Harada, Hiroyuki; Morii, Eiichi; Toyosawa, Satoru; Ishimaru, Naozumi; Yamamoto, Hidetaka

doi:https://doi.org/10.1007/s12105-026-01921-3

Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics

Ono, Sawako; Fukawa, Yuki; Hirose, Katsutoshi et al.

Head and Neck Pathology, 2026, 20, 48

アクセス数:35件（2026-07-27 00:37 集計）

固定URL: https://hdl.handle.net/11094/105121

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タイトル	Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics
著者	NRID 1000040836673 1000040836673 著者名 Ono, Sawako
	NRID 1000070981760 1000070981760 著者名 Fukawa, Yuki
	NRID 1000000824898 1000000824898 ORCID 0000-0003-4148-1106 0000-0003-4148-1106 researchmap permalink -hirose -hirose Scopus Author ID 57190276392 57190276392 著者名 Hirose, Katsutoshi
	NRID 1000060528785 1000060528785 ORCID 0009-0007-2306-345X 0009-0007-2306-345X researchmap permalink yhhori yhhori Scopus Author ID 36089890600 36089890600 著者名 Hori, Yumiko
	NRID 1000010636830 1000010636830 researchmap permalink daisukem daisukem Scopus Author ID 35315737900 35315737900 ORCID 0000-0002-4616-9608 0000-0002-4616-9608 著者名 Motooka, Daisuke
	NRID 1000040343149 1000040343149 著者名 Harada, Hiroyuki
	NRID 1000010283772 1000010283772 ORCID 0000-0001-8490-3650 0000-0001-8490-3650 researchmap permalink read0046454 read0046454 Scopus Author ID 7003914326 7003914326 著者名 Morii, Eiichi
	NRID 1000030243249 1000030243249 ORCID 0000-0002-0338-0251 0000-0002-0338-0251 researchmap permalink osteobone0729 osteobone0729 Scopus Author ID 7003411866 7003411866 著者名 Toyosawa, Satoru
	NRID 1000060314879 1000060314879 著者名 Ishimaru, Naozumi
	NRID 1000030404073 1000030404073 著者名 Yamamoto, Hidetaka
キーワード等	Squamous cell carcinoma
	Oral squamous cell carcinoma
	Carcinoma cuniculatum
	TP53
	CDKN2A
内容	Ono Sawako, Fukawa Yuki, Hirose Katsutoshi, et al. Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics. Head and Neck Pathology 20, 48 (2026); https://doi.org/10.1007/s12105-026-01921-3.
抄録	Purpose: Oral carcinoma cuniculatum (CC) is a rare variant of oral squamous cell carcinoma (OSCC), characterized by a well-differentiated, burrowing invasive pattern and minimal cellular atypia. Its diagnosis is challenging owing to its bland morphology, which makes differentiation from non-neoplastic lesions difficult on biopsy. Despite this, CC often requires distinction from conventional OSCC, even in surgical specimens. Histological overlap with conventional OSCC suggests a continuous spectrum of diseases. To clarify the genetic identity of pure CC, we analyzed 23 cases of OSCC with burrowing invasive patterns and classified them into three groups: CC, conventional OSCC (SCC), and uncertain CC (UCC). Methods: We retrospectively reviewed 2002 OSCC cases from multicenter archives. From this cohort, 23 cases exhibiting a burrowing invasive pattern characteristic of CC were selected. The cases were classified into the three study groups based on the WHO diagnostic criteria, and clinicopathological features were reviewed. Targeted next-generation sequencing was performed to identify clinically significant genetic alterations, and immunohistochemical staining was also conducted. Results: The 23 cases were histologically classified into CC (n = 8), UCC (n = 7), and SCC (n = 8) groups. Clinically, the CC group predominantly affected the gingiva with no recurrence or metastasis. Conversely, the SCC group primarily involved the tongue and showed recurrence and metastasis. Genetic alterations were detected in 87.5% (7/8) of CC cases, with low frequencies of TP53 (12.5%) and CDKN2A (25.0%) alterations and higher frequencies of FAT1 (50.0%), NOTCH1 (37.5%), PIK3CA (37.5%), and CASP8 (50.0%) alterations. In contrast, the SCC group showed frequent TP53 (75.0%) and CDKN2A (75.0%) alterations, whereas FAT1 and NOTCH1 alterations were absent. Consistent with these findings, p53 staining revealed wild-type patterns in the CC group along with a lower Ki-67 labeling index. The UCC group exhibited intermediate clinicopathological and genetic characteristics. Conclusion: This study provides the first genetic characterization of oral CC, distinct from that of conventional OSCC. This genetic signature may contribute to the biological behavior of CC and offer a potential tool for its differential diagnosis. Further studies with larger cohorts are required to confirm the relationship between CC and conventional OSCC, and to fully elucidate the genetic landscape of CC.
出版者	Springer Science and Business Media LLC
収録物名	Head and Neck Pathology
巻(号)	20
ページ	48
刊行年月	2026-05-25
言語	英語
ハンドルURL	https://hdl.handle.net/11094/105121
eISSN	19360568
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1007/s12105-026-01921-3
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Head and Neck Pathology. 2026, 20, p. 48
DC.title	Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics
DC.creator	Ono, Sawako
	Fukawa, Yuki
	Hirose, Katsutoshi
	Hori, Yumiko
	Motooka, Daisuke
	Harada, Hiroyuki
	Morii, Eiichi
	Toyosawa, Satoru
	Ishimaru, Naozumi
	Yamamoto, Hidetaka
DC.publisher	Springer Science and Business Media LLC
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2026-05-25
DC.identifier	https://doi.org/10.1007/s12105-026-01921-3
DC.subject	Squamous cell carcinoma
	Oral squamous cell carcinoma
	Carcinoma cuniculatum
	TP53
	CDKN2A
DC.description	Ono Sawako, Fukawa Yuki, Hirose Katsutoshi, et al. Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics. Head and Neck Pathology 20, 48 (2026); https://doi.org/10.1007/s12105-026-01921-3.
DCTERMS.abstract	Purpose: Oral carcinoma cuniculatum (CC) is a rare variant of oral squamous cell carcinoma (OSCC), characterized by a well-differentiated, burrowing invasive pattern and minimal cellular atypia. Its diagnosis is challenging owing to its bland morphology, which makes differentiation from non-neoplastic lesions difficult on biopsy. Despite this, CC often requires distinction from conventional OSCC, even in surgical specimens. Histological overlap with conventional OSCC suggests a continuous spectrum of diseases. To clarify the genetic identity of pure CC, we analyzed 23 cases of OSCC with burrowing invasive patterns and classified them into three groups: CC, conventional OSCC (SCC), and uncertain CC (UCC). Methods: We retrospectively reviewed 2002 OSCC cases from multicenter archives. From this cohort, 23 cases exhibiting a burrowing invasive pattern characteristic of CC were selected. The cases were classified into the three study groups based on the WHO diagnostic criteria, and clinicopathological features were reviewed. Targeted next-generation sequencing was performed to identify clinically significant genetic alterations, and immunohistochemical staining was also conducted. Results: The 23 cases were histologically classified into CC (n = 8), UCC (n = 7), and SCC (n = 8) groups. Clinically, the CC group predominantly affected the gingiva with no recurrence or metastasis. Conversely, the SCC group primarily involved the tongue and showed recurrence and metastasis. Genetic alterations were detected in 87.5% (7/8) of CC cases, with low frequencies of TP53 (12.5%) and CDKN2A (25.0%) alterations and higher frequencies of FAT1 (50.0%), NOTCH1 (37.5%), PIK3CA (37.5%), and CASP8 (50.0%) alterations. In contrast, the SCC group showed frequent TP53 (75.0%) and CDKN2A (75.0%) alterations, whereas FAT1 and NOTCH1 alterations were absent. Consistent with these findings, p53 staining revealed wild-type patterns in the CC group along with a lower Ki-67 labeling index. The UCC group exhibited intermediate clinicopathological and genetic characteristics. Conclusion: This study provides the first genetic characterization of oral CC, distinct from that of conventional OSCC. This genetic signature may contribute to the biological behavior of CC and offer a potential tool for its differential diagnosis. Further studies with larger cohorts are required to confirm the relationship between CC and conventional OSCC, and to fully elucidate the genetic landscape of CC.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	105121
citation_title	Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics
citation_author	Ono, Sawako
	Fukawa, Yuki
	Hirose, Katsutoshi
	Hori, Yumiko
	Motooka, Daisuke
	Harada, Hiroyuki
	Morii, Eiichi
	Toyosawa, Satoru
	Ishimaru, Naozumi
	Yamamoto, Hidetaka
citation_publisher	Springer Science and Business Media LLC
citation_language	英語
citation_date	2026-05-25
citation_journal_title	Head and Neck Pathology
citation_volume	20
citation_firstpage	48
citation_doi	https://doi.org/10.1007/s12105-026-01921-3
citation_public_url	https://hdl.handle.net/11094/105121

Genetic Landscape of Oral Carcinoma Cuniculatum and its Histological Mimics

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