Papillary ductal carcinoma in situ
Breast Tumours (WHO Classification, 5th ed.)
Primary Author(s)*
Sresi Singh and Katherine Geiersbach, MD
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Breast Tumours (5th ed.) |
| Category | Epithelial tumours of the breast |
| Family | Papillary neoplasms: Introduction |
| Type | Papillary ductal carcinoma in situ |
| Subtype(s) | N/A |
Related Terminology
| Acceptable | Papillary carcinoma in situ; intraductal papillary ductal carcinoma in situ |
| Not Recommended | Intracystic papillary ductal carcinoma; encapsulated/solid papillary carcinoma |
Gene Rearrangements
No recurrent gene rearrangements have been identified in papillary DCIS, which is primarily characterized by mutations and copy number alterations.
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
Individual Region Genomic Gain/Loss/LOH
Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q. Amplification of 17q12 containing the ERBB2 gene contributes to HER2 overexpression in a subset of lesions and has been associated with malignancy rather than DCIS.[1]
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 1 | Gain | 1q | P | No | Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression. In papillary lesions, 1q gains including 1q21.3-1q23.1 (including PRCC and NTRK1) have been associated with intracystic papillary carcinoma but not concurrent DCIS.[2] | |
| 8 | Gain | 8q22-8q24 | SPAG1, RHPN1, MYC | P | No | Gain of 8q results in MYC activation and increased cell proliferation in breast tumors. In papillary DCIS, gains on 8q including SPAG1 (8q22) RHPN1 (8q24) are associated with increased cell motility and cell adhesion programs.[2] |
| 11 | Gain | 11q13 | CCND1 | P | No | Amplification of CCND1 leads to dysregulated cell cycle progression and has been reported in breast tumors. |
| 13 | Loss | 13q14 | RB1 | P | No | Loss of RB1 contributes to cell cycle dysregulation in breast cancer. |
| 16 | LOH | 16p13 | TSC2, PKD1 | D | No | LOH on chromosome 16p13 was present in 10 of 16 (63%) informative cases of either papillary carcinoma or carcinoma arising in a papilloma as well as in 6 of 10 (60%) informative cases of intraductal papilloma with florid epithelial hyperplasia (IDH) in a 1998 study from the Armed Forces Institute of Pathology (AFIP), suggesting the presence of a tumor suppressor gene mutated early in papillary neoplasia. [3] |
| 16 | Loss / LOH | 16q | CDH1 | P | No | Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ. In papillary lesions, 16q LOH is associated with malignancy.[4][5] |
| 17 | Amp | 17q12 | ERBB2 | D, P, T | Yes (NCCN) | Amplification of ERBB2 results in HER2 overexpression and may guide targeted therapy decisions in breast cancer. In papillary lesions, ERBB2 amplification / overexpression (HER2 positive status) is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features.[1] |
Characteristic Chromosomal or Other Global Mutational Patterns
Breast neoplasms including ductal carcinoma in situ frequently demonstrate chromosomal instability and aneuploidy, which contribute to copy-number alterations and genomic heterogeneity. In some tumors, defects in DNA repair pathways such as homologous recombination also contribute to mutational accumulation.
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| Chromosomal instability (CIN) | Accumulation of chromosomal gains and losses due to defects in mitotic segregation and DNA repair pathways | Common (>20%) | P | No | Chromosomal instability contributes to genomic heterogeneity and tumor evolution in breast tumors. |
| Aneuploidy | Abnormal chromosome numbers caused by chromosomal missegregation during cell division | Common (>20%) | P | No | Aneuploidy is frequently observed in breast tumors and is associated with tumor progression. |
| Homologous recombination deficiency | Homologous recombination deficiency | Rare (<5%) | P, T | Yes | HR deficiency may influence response to PARP inhibitor therapy in breast cancer; however, PARP inhibitor therapy is not applicable to in situ disease. |
Gene Mutations (SNV/INDEL)
Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others[6]. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms. Intraductal papilloma (IDP) is a non-obligate precursor of papillary DCIS with a high frequency of PIK3CA and AKT1 mutations observed; the majority of synchronous DCIS in cases of IDP exhibit non-papillary morphology.[7][8]
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| PIK3CA | Activating mutations | Oncogene | Common | T | Yes (NCCN) | Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease. |
| AKT1 | Activating mutations | Oncogene | Recurrent | T | Yes (NCCN) | Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease. |
| TP53 | Inactivating mutations | TSG | Recurrent | P | Yes | Associated with genomic instability and aggressive tumor behavior. In papillary lesions, TP53 mutation is associated with malignancy.[9] |
| GATA3 | Inactivating mutations | Other | Recurrent | P | No | Transcription factor regulating luminal cell differentiation in breast epithelium.[10] |
| ERBB2 | Activating mutations, amplification | Oncogene | Recurrent | D, P, T | Yes (NCCN) | Drives HER2 signaling and may guide targeted therapy decisions. In papillary lesions, ERBB2 amplification is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features and is a marker of high risk and chemotherapy benefit.[1] |
| MAP3K1 | Inactivating mutations | TSG | Recurrent | P | No | Implicated in MAPK signaling and luminal breast cancer development. |
| CDH1 | Inactivating mutations | TSG | Rare | P | Yes | Loss of E-cadherin disrupts cell adhesion and promotes tumor progression. |
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Epigenetic changes in breast tumor development include alterations in DNA methylation and chromatin remodeling. Hyper-methylation of tumor suppressor gene promoters, such as RASSF1A, CDH1, and BRCA1, in breast tumor samples has been documented and is believed to lead to gene silencing. Abnormalities in histone modification and chromatin remodeling are also known to affect gene expression patterns controlling cell proliferation and differentiation.
Genes and Main Pathways Involved
Overexpression of MET may be a key factor in papillary differentiation.[11][12]
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| PIK3CA, AKT1; activating mutations / PTEN inactivating mutations | PI3K-AKT-mTOR signaling | Increased cell proliferation and survival |
| MET; c-Met overexpression | HGF/c-Met | Cell motility, epithelial-to-mesenchymal transition |
| TP53; inactivating mutations | DNA damage response | Genomic instability and tumor progression |
| ERBB2; amplification or activating mutations | MAPK/PI3K signaling pathways | Enhanced growth signaling and tumorigenesis |
| GATA3; inactivating mutations | Estrogen signaling pathways | Altered luminal epithelial cell differentiation |
| FOXA1; activating mutations | Estrogen signaling pathways | Maintains papillary phenotype |
| VEGFA; VEGF overexpression | VEGF signaling pathway | Angiogenesis, promotes cancer cell survival, proliferation, and migration |
Genetic Diagnostic Testing Methods
Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.
Familial Forms
While the majority of breast tumors are considered to be sporadic, some cases are linked with hereditary cancer syndromes. Germline mutations in BRCA1 and BRCA2, PALB2, and CHEK2 are the most common genes associated with a hereditary predisposition to breast cancer. Additional susceptibility genes include TP53, which causes Li-Fraumeni syndrome, and PTEN, which causes Cowden syndrome.
Additional Information
Breast tumors are a diverse group of neoplastic disorders that vary in their molecular and histopathologic characteristics. Recent advances in genomic profiling have significantly enhanced our current understanding of tumor biology and have paved the way to develop novel therapeutic strategies. Molecular classification and genetic testing are assuming a significant role in diagnosis, prognosis, and treatment of breast cancer.
Links
WHO Classification of Tumours – Breast Tumours: https://publications.iarc.fr/581
cBioPortal for Cancer Genomics: https://www.cbioportal.org/
COSMIC – Catalogue of Somatic Mutations in Cancer: https://cancer.sanger.ac.uk/cosmic
The Cancer Genome Atlas (TCGA) Breast Cancer Dataset: https://www.cancer.gov/tcga
References
- ↑ 1.0 1.1 1.2 Rakha, Emad A.; Tan, Puay Hoon; Raymond, Wendy A. (2026-03). "The spectrum of breast in situ papillary carcinomas with invasion and invasive breast carcinomas with papillary features: an overview of histological subtypes and diagnostic challenges". Histopathology. 88 (4): 747–768. doi:10.1111/his.70072. ISSN 1365-2559. PMC 12891923. PMID 41404713.
{{cite journal}}: Check date values in:|date=(help) - ↑ 2.0 2.1 Khoury, Thaer; Hu, Qiang; Liu, Song; Wang, Jianmin (2014-02). "Intracystic papillary carcinoma of breast: interrelationship with in situ and invasive carcinoma and a proposal of pathogenesis: array comparative genomic hybridization study of 14 cases". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 27 (2): 194–203. doi:10.1038/modpathol.2013.136. ISSN 1530-0285. PMC 4389629. PMID 23907150.
{{cite journal}}: Check date values in:|date=(help) - ↑ Lininger, R. A.; Park, W. S.; Man, Y. G.; Pham, T.; MacGrogan, G.; Zhuang, Z.; Tavassoli, F. A. (1998-10). "LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast". Human Pathology. 29 (10): 1113–1118. doi:10.1016/s0046-8177(98)90422-1. ISSN 0046-8177. PMID 9781650.
{{cite journal}}: Check date values in:|date=(help) - ↑ Di Cristofano, Claudio; Mrad, Karima; Zavaglia, Katia; Bertacca, Gloria; Aretini, Paolo; Cipollini, Giovanna; Bevilacqua, Generoso; Ben Romdhane, Kaled; Cavazzana, Andrea (2005-03). "Papillary lesions of the breast: a molecular progression?". Breast Cancer Research and Treatment. 90 (1): 71–76. doi:10.1007/s10549-004-3003-3. ISSN 0167-6806. PMID 15770529.
{{cite journal}}: Check date values in:|date=(help) - ↑ Yoshida, Miwa; Tsuda, Hitoshi; Yamamoto, Sohei; Kinoshita, Takayuki; Akashi-Tanaka, Sadako; Hojo, Takashi; Fukutomi, Takashi (2012-05). "Loss of heterozygosity on chromosome 16q suggests malignancy in core needle biopsy specimens of intraductal papillary breast lesions". Virchows Archiv: An International Journal of Pathology. 460 (5): 497–504. doi:10.1007/s00428-012-1200-8. ISSN 1432-2307. PMID 22476400.
{{cite journal}}: Check date values in:|date=(help) - ↑ Kader, Tanjina; Elder, Kenneth; Zethoven, Magnus; Semple, Timothy; Hill, Prue; Goode, David L.; Thio, Niko; Cheasley, Dane; Rowley, Simone M. (2020). "The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma". NPJ breast cancer. 6: 9. doi:10.1038/s41523-020-0150-6. ISSN 2374-4677. PMC 7067788. PMID 32195332.
- ↑ Kader, Tanjina; Elder, Kenneth; Zethoven, Magnus; Semple, Timothy; Hill, Prue; Goode, David L.; Thio, Niko; Cheasley, Dane; Rowley, Simone M. (2020). "The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma". NPJ breast cancer. 6: 9. doi:10.1038/s41523-020-0150-6. ISSN 2374-4677. PMC 7067788. PMID 32195332.
- ↑ Troxell, Megan L.; Levine, Judith; Beadling, Carol; Warrick, Andrea; Dunlap, Jennifer; Presnell, Ajia; Patterson, Janice; Shukla, Arielle; Olson, Neal R. (2010-01). "High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 23 (1): 27–37. doi:10.1038/modpathol.2009.142. ISSN 1530-0285. PMID 19898424.
{{cite journal}}: Check date values in:|date=(help) - ↑ Di Cristofano, Claudio; Mrad, Karima; Zavaglia, Katia; Bertacca, Gloria; Aretini, Paolo; Cipollini, Giovanna; Bevilacqua, Generoso; Ben Romdhane, Kaled; Cavazzana, Andrea (2005-03). "Papillary lesions of the breast: a molecular progression?". Breast Cancer Research and Treatment. 90 (1): 71–76. doi:10.1007/s10549-004-3003-3. ISSN 0167-6806. PMID 15770529.
{{cite journal}}: Check date values in:|date=(help) - ↑ Medford, Arielle J.; Velimirovic, Marko; Gefen, Yifat; Niemierko, Andrzej; Gerratana, Lorenzo; Davis, Andrew A.; Clifton, Katherine; Keenan, Jennifer; Podany, Emily (2025-08). "Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes". Breast Cancer Research and Treatment. 212 (3): 437–447. doi:10.1007/s10549-025-07710-w. ISSN 1573-7217. PMC 12209021. PMID 40439821.
{{cite journal}}: Check date values in:|date=(help) - ↑ Ruco, L. P.; Stoppacciaro, A.; Ballarini, F.; Prat, M.; Scarpino, S. (2001-05). "Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis". The Journal of Pathology. 194 (1): 4–8. doi:10.1002/path.847. ISSN 0022-3417. PMID 11329134.
{{cite journal}}: Check date values in:|date=(help) - ↑ Nusrat, A.; Parkos, C. A.; Bacarra, A. E.; Godowski, P. J.; Delp-Archer, C.; Rosen, E. M.; Madara, J. L. (1994-05). "Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium". The Journal of Clinical Investigation. 93 (5): 2056–2065. doi:10.1172/JCI117200. ISSN 0021-9738. PMC 294323. PMID 8182137.
{{cite journal}}: Check date values in:|date=(help)
Notes
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Prior Author(s): *Citation of this Page: “Papillary ductal carcinoma in situ”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 04/12/2026, https://ccga.io/index.php/BRST5:Papillary ductal carcinoma in situ.