Title:A Case of Squamous Cell Carcinoma Arising from an Intraductal Papilloma of the BreastAuthors:Kanako Nishiyama, Department of Breast Surgery, Matsuyama Red Cross Hospital, Bunkyo-cho, Matsuyama-city, Ehime, JapanKumiko Okujima, Department of Breast Surgery, Matsuyama Red Cross Hospital, Bunkyo-cho, Matsuyama-city, Ehime, JapanCorresponding Author:Kanako Nishiyama, Department of Breast Surgery, Matsuyama Red Cross Hospital, Bunkyo-cho, Matsuyama-city, Ehime, JapanEmail: ryosukemama130@gmail.comPhone:81-89-924-1111Key Clinical MessageThis rare case highlights invasive squamous cell carcinoma arising from an intraductal papilloma, emphasizing early detection and aggressive re-biopsy for accurate diagnosis and effective treatment.Abstract:We present a rare case of squamous cell carcinoma arising from an intraductal papilloma in a 60-year-old female. Histopathology revealed an invasive squamous carcinoma with p63 positivity, coexisting with a benign papilloma. Following partial mastectomy and adjuvant therapy, the patient remained disease-free for 4 years and 8 months, highlighting the importance of early detection.Keywords:Breast cancer, squamous cell carcinoma, intraductal papilloma, squamous differentiationFigures and Tables:Figures: 3, Tables: 0IntroductionIntraductal papilloma (IDP) is a benign breast tumor arising from the mammary duct epithelium, with an incidence of 2-3%.1Diagnosis typically involves imaging followed by histological confirmation to rule out malignancy. IDPs are known to undergo metaplastic changes (apocrine, squamous, and sebaceous) as a reactive process.2 Squamous metaplasia in papilloma is rare, usually benign, and typically presents as a small focus in all cases. In extreme cases, papillomas can undergo complete squamous metaplasia and transform into squamous cell carcinoma (SqCC) in situ.3,4 Here, we report a rare case of a patient with an IDP who underwent complete squamous metaplasia and malignant transformation.Case History / ExaminationA 60-year-old female with a medical history of chronic hepatitis C and no significant family history was referred to our department four years earlier following an abnormal breast cancer screening result. Imaging revealed benign findings in the right breast, which remained stable without notable changes during follow-up. However, routine follow-up revealed a newly developed mass in the left breast. Mammography identified a focal asymmetrical density (FAD) in the upper outer quadrant of the left breast. Breast ultrasonography further showed a well-defined, smooth, hypoechoic mass measuring 9.2 × 8.8 × 6.0 mm (Figure 1A). A core needle biopsy was performed, and the lesion was diagnosed as benign IDP.Six months later, follow-up ultrasonography revealed an increase in tumor size to approximately 11.2 mm (Figure 1B). Another six months later, the lesion further enlarged to 13 mm (Figure 1C), prompting a repeat vacuum-assisted biopsy. Histopathological examination revealed the coexistence of benign IDP and invasive carcinoma with squamous differentiation. Immunohistochemical analysis showed that the tumor was negative for the estrogen receptor (ER), progesterone receptor (PgR), and HER2, confirming the diagnosis of triple-negative breast cancer (TNBC).Differential DiagnosisContrast-enhanced MRI demonstrated a 1.1-cm mass in the upper outer quadrant of the left breast, showing heterogeneous internal fast-washout enhancement and surrounding regional non-mass enhancement. Based on these findings, we considered primary breast cancer, particularly invasive ductal carcinoma arising from ductal carcinoma in situ (DCIS), or IDP with squamous metaplasia for the differential diagnosis. Re-biopsy and histopathology confirmed invasive SqCC arising from pre-existing IDP.Conclusion and ResultsBased on these findings, the patient was diagnosed with left breast cancer, cT1N0M0, Stage I. Surgical management involved a partial mastectomy with sentinel lymph node biopsy. No lymph node metastasis was detected, and axillary dissection was omitted. Histopathological examination after surgery confirmed invasive SqCC with a maximum invasion diameter of 10 mm coexisting with areas of benign IDP (Figure 2). Immunohistochemical analysis demonstrated p63 positivity in the tumor cells (Figure 3), consistent with squamous differentiation. Notably, the lesion exhibited biphasic characteristics comprising areas of benign IDP and atypical squamous epithelial cells infiltrating the stroma, with no evidence of glandular carcinoma components. Based on these findings, the tumor was diagnosed as SqCC arising from pre-existing IDP.The patient underwent adjuvant chemotherapy and radiotherapy. At 4 years and 8 months postoperatively, there was no evidence of recurrence and the patient remained disease-free.DiscussionPrimary SqCC of the breast is a rare malignancy, accounting for less than 0.1% of all invasive breast cancers.5,6 It is thought to arise from the squamous metaplasia of ductal carcinoma cells or the mammary ductal epithelium. Breast SqCC tumors are generally larger than conventional breast cancer histological subtypes, with an average size exceeding 5 cm. Breast SqCC typically occurs in elderly patients and is associated with a low incidence of lymph node metastases but carries a risk of distant metastases.5,6 These tumors lack estrogen and progesterone receptors and are known to exhibit resistance to conventional breast cancer chemotherapy regimens.7 Importantly, the diagnosis of breast SqCC requires the exclusion of other primary sites of SqCC within the body. Although treatment often follows standard breast cancer protocols, including mastectomy and lymph node dissection, the prognosis remains unclear and no definitive treatment guidelines for breast SqCC have been established.7Although SqCC is typically identified as an advanced invasive carcinoma, non-invasive SqCC of the breast is an extremely rare entity characterized by the presence of pure squamous cells without glandular differentiation.4 In contrast, DCIS is defined by the presence of malignant epithelial cells confined within the ducts, without invasion beyond the basement membrane. DCIS exhibits various structural patterns, including solid, cribriform, micropapillary, and mixed types.8 In situ squamous cell carcinoma is exceptionally rare, with only a few reported cases in the literature.4,9,10 Histologically, these cases exhibit distinctive features such as keratinized squamous cells, intercellular bridges, and keratin pearl formation. Immunohistochemical analyses typically demonstrate positivity for markers associated with squamous differentiation, including p63, p40, and cytokeratin. Reports of in situ SqCC, including the present case, suggest that squamous differentiation may occur during the early stages of breast cancer development.Squamous metaplasia of the breast is an exceptionally rare pathology that can closely resemble malignant lesions on imaging and fine needle aspiration biopsy.11 Chronic inflammation, particularly in response to foreign materials such as silicone implants, has been identified as a potential causative factor and may play a pivotal role in the development of squamous metaplasia.12 This phenomenon has been observed in various breast lesions, including IDP and fibroadenoma, and often raises a strong suspicion of malignancy. To minimize unnecessary surgical intervention, intraoperative frozen section analysis has been demonstrated as a critical tool for distinguishing benign from malignant lesions.11 However, in cases where a biopsy confirms the presence of a benign IDP but findings such as tumor growth or irregular margins raise concerns for malignancy, prompt re-biopsy should be performed to achieve an accurate diagnosis. This approach ensured appropriate management and reduced the risk of overtreatment.In the present case, SqCC in situ was identified during the follow-up of IDP, suggesting that squamous differentiation may represent an early event in the development of breast cancer. However, similar cases are exceedingly rare, highlighting the need for further case collection and analyses to elucidate the underlying mechanisms and clinical significance of this phenomenon.References1. Tarallo V, Canepari E, Bortolotto C. Intraductal papilloma of the breast: A case report. 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Squamous metaplasia on the breast implant capsule. Int J Surg Pathol . 2010;18(6):570-574. doi: 10.1177/1066896908329587.ImagesFigure1. Serial ultrasound images of the left breast mass.(A) Initial presentation: The lesion was identified and diagnosed as an IDP via needle biopsy. (B) Six months later: A slight increase in size was observed. (C) One year later: The lesion demonstrated further enlargement with irregular margins, raising suspicion of malignancy.Figure2. Low-power view of the left breast tumor.Hematoxylin and eosin staining revealed SqCC components (outlined in red) intermingled with areas of benign IDP. In some regions, SqCC infiltrated beyond the ductal structures.Figure3. High-power view (×100) of the left breast tumor.(A) Hematoxylin and eosin staining highlights the juxtaposition of IDP (left) and SqCC components (right). (B) Immunohistochemical staining for p63 demonstrates positivity in the SqCC component.Patient Consent StatementWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images.AcknowledgementsThe authors thank Dr. Yosuke Mizuno, a pathologist, for her contributions to this paper.Author ContributionsKanako Nishiyama: Conceptualization; data curation; investigation; writing –originaldraft; writing –review and editing.Kumiko Okujima: Writing –review and editing.Conflict of Interest statementThe authors declare that there are no conflicts of interest regarding the publication of this article.