Cribriform tumor is a rare sweat-gland neoplasm of uncertain malignant potential. Although its histopathologic features are well described, the molecular underpinnings of cribriform tumor remain incompletely characterized. We performed comprehensive molecular profiling of 6 cribriform tumors from 3 institutions using whole-exome sequencing, transcriptome sequencing, and single-nucletide polymorphism array copy number analysis. The cohort included 3 women and 3 men (median age, 54 years; range, 40-66 years), with tumors measuring 0.3 to 2.0 cm. Most arose on the extremities, with one located on the back. The most consistent genomic alteration was arm-level losses of chromosomes 6q and 9q, detected in 5 out of 6 cases. These alterations were validated across independent sequencing and single-nucletide polymorphism array platforms. Whole-exome sequencing identified likely pathogenic variants in 2 tumors (CHEK2 p.R145W and NF1 p.R1830H). No gene fusions were detected. Taken together, these findings provide independent confirmation that 6q/9q loss represents a consistent cytogenomic alteration in cribriform tumor, supporting its use as a molecular hallmark of this tumor.

Bioptická Laboratoř Pilsen Czech Republic; Department of Pathology Faculty of Medicine in Plzen Charles University Plzen Czech Republic

Department of Dermatology Dartmouth Hitchcock Medical Center Lebanon New Hampshire; Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire

Department of Pathology and Laboratory Medicine Dartmouth Hitchcock Medical Center Lebanon New Hampshire

Department of Pathology Cleveland Clinic Pathology and Laboratory Medicine Institute Cleveland Ohio

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Requena L, Kiryu H, Ackerman AB. Cribriform carcinoma. In: Ackerman AB, ed. Neoplasms with Apocrine Differentiation. Philadelphia, PA: Lippincott-Raven; 1998:879

Jiang D, Tian Y, Tian J, Liu H, Guan Y. Primary cutaneous cribriform tumor: A case report and literature review. J Cutan Pathol. 2025;52(1):9–15. doi: 10.1111/cup.14723 PubMed DOI

World Health Organization. WHO Classification of Skin Tumours. 5th ed. International Agency for Research on Cancer; 2023

Cazzato G, Daruish M, Fortarezza F, et al. Gene Fusion-Driven Cutaneous Adnexal Neoplasms: An Updated Review Emphasizing Molecular Characteristics. Am J Dermatopathol. 2025;47(6):453–461. doi: 10.1097/DAD.0000000000002933 PubMed DOI

North JP, McCalmont TH, Fehr A, van Zante A, Stenman G, LeBoit PE. Detection of MYB Alterations and Other Immunohistochemical Markers in Primary Cutaneous Adenoid Cystic Carcinoma. Am J Surg Pathol. 2015;39(10):1347–1356. doi: 10.1097/PAS.0000000000000463 PubMed DOI

Bishop JA, Taube JM, Su A, et al. Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands. Am J Surg Pathol. 2017;41(1):62–66. doi: 10.1097/PAS.0000000000000734 PubMed DOI

Sekine S, Kiyono T, Ryo E, et al. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest. 2019;129(9):3827–3832. doi: 10.1172/JCI126185 PubMed DOI PMC

Russell-Goldman E, Hanna J. MAML2 Gene Rearrangement Occurs in Nearly All Hidradenomas: A Reappraisal in a Series of 20 Cases. Am J Dermatopathol. 2022;44(11):806–811. doi: 10.1097/DAD.0000000000002276 PubMed DOI

Goto K, Kukita Y, Hishima T, et al. Primary Cutaneous NUT Carcinoma: Clinicopathologic and Genetic Study of 4 Cases. Am J Surg Pathol. 2024;48(8):942–952. doi: 10.1097/PAS.0000000000002240 PubMed DOI

Matsuyama A, Hisaoka M, Hashimoto H. PLAG1 expression in cutaneous mixed tumors: an immunohistochemical and molecular genetic study. Virchows Arch. 2011;459(5):539–545. doi: 10.1007/s00428-011-1149-z PubMed DOI

Macagno N, Kervarrec T, Thanguturi S, et al. SOX10-Internal Tandem Duplications and PLAG1 or HMGA2 Fusions Segregate Eccrine-Type and Apocrine-Type Cutaneous Mixed Tumors. Mod Pathol. 2024;37(3):100430. doi: 10.1016/j.modpat.2024.100430 PubMed DOI

Bishop JA, Williams EA, McLean AC, et al. Microsecretory adenocarcinoma of the skin harboring recurrent SS18 fusions: A cutaneous analog to a newly described salivary gland tumor. J Cutan Pathol. 2023;50(2):134–139. doi: 10.1111/cup.14271 PubMed DOI

Shah PS, Hughes EG, Sukhadia SS, et al. Validation and Implementation of a Somatic-Only Tumor Exome for Routine Clinical Application. J Mol Diagn. 2024;26(9):815–824. doi: 10.1016/j.jmoldx.2024.05.013 PubMed DOI PMC

Tam W, Gomez M, Chadburn A, Lee JW, Chan WC, Knowles DM. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood. 2006;107(10):4090–4100. doi: 10.1182/blood-2005-09-3778 PubMed DOI

Pasqualucci L, Compagno M, Houldsworth J, et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med. 2006;203(2):311–317. doi: 10.1084/jem.20052204 PubMed DOI PMC

Donlon TA, Morris BJ, Chen R, et al. FOXO3 longevity interactome on chromosome 6. Aging Cell. 2017;16(5):1016–1025. doi: 10.1111/acel.12625 PubMed DOI PMC

van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277(5327):805–808. doi: 10.1126/science.277.5327.805 PubMed DOI

Mak BC, Yeung RS. The tuberous sclerosis complex genes in tumor development. Cancer Invest. 2004;22(4):588–603. doi: 10.1081/cnv-200027144 PubMed DOI

Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–851. doi: 10.1016/s0092-8674(00)81268-4 PubMed DOI

Bonilla X, Parmentier L, King B, et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet. 2016;48(4):398–406. doi: 10.1038/ng.3525 PubMed DOI

Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–2179. doi: 10.1056/NEJMoa1113713 PubMed DOI PMC

Stolz A, Ertych N, Bastians H. Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability. Clin Cancer Res. 2011;17(3):401–405. doi: 10.1158/1078-0432.CCR-10-1215 PubMed DOI

Bell DW, Varley JM, Szydlo TE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528–2531. doi: 10.1126/science.286.5449.2528 PubMed DOI

Wu X, Webster SR, Chen J. Characterization of tumor-associated Chk2 mutations. J Biol Chem. 2001;276(4):2971–2974. doi: 10.1074/jbc.M009727200 PubMed DOI

Wu X, Dong X, Liu W, Chen J. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006;27(8):742–747. doi: 10.1002/humu.20321 PubMed DOI

Weischer M, Heerfordt IM, Bojesen SE, et al. CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. J Invest Dermatol. 2012;132(2):299–303. doi: 10.1038/jid.2011.303 PubMed DOI

Cybulski C, Górski B, Huzarski T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131–1135. doi: 10.1086/426403 PubMed DOI PMC

Mo J, Moye SL, McKay RM, Le LQ. Neurofibromin and suppression of tumorigenesis: beyond the GAP. Oncogene. 2022;41(9):1235–1251. doi: 10.1038/s41388-021-02156-y PubMed DOI PMC

Chaker-Margot M, Werten S, Dunzendorfer-Matt T, et al. Structural basis of activation of the tumor suppressor protein neurofibromin. Mol Cell. 2022;82(7):1288–1296.e5. doi: 10.1016/j.molcel.2022.03.011 PubMed DOI

Philpott C, Tovell H, Frayling IM, Cooper DN, Upadhyaya M. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics. 2017;11(1):13. doi: 10.1186/s40246-017-0109-3 PubMed DOI PMC

Arps DP, Chan MP, Patel RM, Andea AA. Primary cutaneous cribriform carcinoma: report of six cases with clinicopathologic data and immunohistochemical profile. J Cutan Pathol. 2015;42(6):379–387. doi: 10.1111/cup.12469 PubMed DOI

Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534(7605):47–54. doi: 10.1038/nature17676 PubMed DOI PMC

Skálová A, Hyrcza MD, Vaneček T, Baněčková M, Leivo I. Fusion-positive salivary gland carcinomas. Genes Chromosomes Cancer. 2022;61(5):228–243. doi: 10.1002/gcc.23020 PubMed DOI

Rütten A, Kutzner H, Mentzel T, et al. Primary cutaneous cribriform apocrine carcinoma: a clinicopathologic and immunohistochemical study of 26 cases of an under-recognized cutaneous adnexal neoplasm. J Am Acad Dermatol. 2009;61(4):644–651. doi: 10.1016/j.jaad.2009.03.032 PubMed DOI

Moore RF, Cuda JD. Secretory carcinoma of the skin: Case report and review of the literature. JAAD Case Rep. 2017;3(6):559–562. doi: 10.1016/j.jdcr.2017.07.003 PubMed DOI PMC

Liau JY, Tsai JH, Huang WC, Lan J, Hong JB, Yuan CT. BRAF and KRAS mutations in tubular apocrine adenoma and papillary eccrine adenoma of the skin. Hum Pathol. 2018;73:59–65. doi: 10.1016/j.humpath.2017.12.002 PubMed DOI

Bogiatzi S, Estenaga A, Louveau B, et al. Microsecretory adenocarcinoma of the skin, a novel type of sweat gland carcinoma: Report of three additional cases. J Cutan Pathol. 2023;50(10):897–902. doi: 10.1111/cup.14408 PubMed DOI

Adamski H, Le Lan J, Chevrier S, Cribier B, Watier E, Chevrant-Breton J. Primary cutaneous cribriform carcinoma: a rare apocrine tumour. J Cutan Pathol. 2005;32(8):577–580. doi: 10.1111/j.0303-6987.2005.00375.x PubMed DOI

Prieto-Granada CN, Zhang L, Antonescu CR, Henneberry JM, Messina JL. Primary cutaneous adenoid cystic carcinoma with MYB aberrations: report of three cases and comprehensive review of the literature. J Cutan Pathol. 2017;44(2):201–209. doi: 10.1111/cup.12856 PubMed DOI PMC

Sohier P, Battistella M, Mouthon M, et al. Comprehensive Molecular Profiling of Cribriform Tumors: Identification of Recurrent 6q/9q Codeletion and CD38 Expression. Mod Pathol. Published online September 12, 2025. doi: 10.1016/j.modpat.2025.100889 DOI