HER2 positive primary breast squamous cell carcinoma with good prognosis: a case report

Introduction

Primary breast squamous cell carcinoma (PBSCC) also known as squamous cell carcinoma (SCC) of the breast, is a rarely seen subtype of metaplastic breast carcinoma, making up less than 0.1% of the total breast carcinoma cases (1). The etiology and pathogenesis of PBSCC is still uncertain. In clinical practice, metastatic SCC from other organs, such as esophagus, lung, urinary bladder and cervix, should be excluded to confirm the diagnosis of PBSCC. The average age of PBSCC onset is reported to be 54 years, typically occurring in postmenopausal women (1,2).

PBSCC is often aggressive and has a tendency to grow and spread quickly. It is usually discovered and diagnosed at an advanced stage, compared to other types of breast cancer (3). Different from ductal carcinoma, PBSCC exhibits a heterogeneous clinical course with regard to tumor volume, lymph node involvement, metastatic status and medical decision. Treatment of PBSCC involves a combination of surgery, chemotherapy, radiation therapy and targeted therapy. However, limited literature and information available for the best treatment approaches and prognosis due to its rarity. To date, no unified management is available. The majority of current case reports of PBSCC are triple-negative tumors with poor prognosis. Here, we report a human epidermal growth factor receptor 2 (HER2) positive case with good clinical outcome, which may contribute to the development of appropriate guidelines and imprecise management of PBSCC. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-138/rc).

Case presentation

All the procedures performed in this study were conducted in accordance with the ethical standards of Shijiazhuang Pingan Hospital and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Physical examination

A 45-year-old Chinese female visited the oncology clinic for a palpable mass in the right medial-upper quadrants of breast, which she had noticed inadvertently two months ago. Physical palpation detected a firm lump in the upper inner quadrant of the right breast. The lump was tender, with uneven surface, unclear boundary, poor mobility and no adhesion to the chest wall and skin. The skin over the lump was normal and no retraction or discharge from the nipple was seen. The patient is a nonsmoker, without any systemic diseases or any family history of breast or ovary cancer.

Imaging examinations

Bilateral mammography suggested a solid mass in the right breast at 12 o’clock located 2.5 cm away from the nipple. Further, ultrasonography showed an irregular-shaped hypoechoic lesion measuring 2.4 cm × 2.3 cm × 1.5 cm with an internal heterogeneous anechoic area and sticky blood flow signal on color Doppler, indicating a malignant neoplasm, which was classified as breast imaging reporting and data system (BI-RADS) 4C. A 2.4 cm × 0.7 cm hypoechoic nodule with the hilar structure of lymph node was seen. No abnormal changes were observed in left breast and left axillary lymph nodes (Figure 1A). ​tomography (CT) scans also showed a 2.2 cm × 1.7 cm soft tissue mass with uneven enhancement and the surrounding glands with high enhancement in the medial-upper quadrant of right breast and enlarged lymph node is seen in the right axilla, which was consistent with the ultrasound results of malignant tumor. CT images of the chest and abdomen revealed no other space occupying lesions (Figure 1B). Thus, the patient received modified radical mastectomy and axillary sentinel lymph node dissection of the right breast. The surgical specimen showed a 2.2 cm × 1.8 cm × 1.5 cm, tan-white and solid lesion located in the right breast.

Figure 1 Imaging examinations. (A) Ultrasonography. An irregular-shaped hypoechoic lesion measuring 2.4 cm × 2.3 cm × 1.5 cm with an internal heterogeneous anechoic area was detected in the medial-upper quadrants of the right breast. (B) Computed tomography scan. A 2.2 cm × 1.7 cm soft tissue mass with uneven enhancement was detected in the right breast.

Laboratory examinations

Histopathological examination revealed that the predominant components consist of malignant SCC with hyperchromatic round to oval nuclei, condensed chromatin, prominent intercellular bridges, keratin-pearl formation and squamoid nests. No distinctive component of invasive ductal carcinoma or other features of metaplastic carcinoma, such as spindle cells and mesenchymal differentiation, and no definite involvement of the skin or the nipple was observed under the microscope (Figure 2). Immunohistochemical (IHC) staining showed the positive expression of cytokeratin 5/6 (CK5/6), tumor protein p53 (P53), tumor protein p63 (P63), HER2, and the negative expression of alcian blue-periodic acid-Schiff (AB-PAS), estrogen receptor (ER), progesterone receptor (PR) and programmed cell death ligand 1 (PD-L1) in the tumor cells. The Ki67 labeling index was 40% (Figure 3). Additionally, the tumor cells were continuously point positive in cell membrane with a HER2 score of 2+ according to the IHC scoring criteria of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) (4). Subsequently, fluorescence in situ hybridization (FISH) detection showed a cluster amplification of HER2 gene and the ratio of HER2 to CEP17 was 2.72 (Figure 4). Moreover, no metastatic cancer cells were found in the swollen lymph node in her axilla.

Figure 2 Hematoxylin-eosin staining (10×). The predominant component was consisted of malignant squamous cell characterized by hyperchromatic round to oval nuclei, keratin-pearl and squamoid nests.

Figure 3 Immunohistochemical staining (10×). (A) AB-PAS negative. (B) Cytokeratin 5/6 positive. (C) Tumor protein p53 positive. (D) Tumor protein p63 positive. (E) Ki67 (positive index 40%). (F) Estrogen receptor negative. (G) Progesterone receptor negative. (H) HER2 positive (2+). (I) PD-L1 negative. AB-PAS, Alcian blue-periodic acid-Schiff; PD-L1, programmed cell death ligand 1.

Figure 4 Fluorescence in situ hybridization detection (100×). The ratio of HER2 (red dots) to CEP17 (green dots) ratio was 2.72.

Treatments

The patient was classified as clinical stage IIA breast cancer (T2N0M0). After surgery, she underwent AC-TH chemotherapy regimen that comprises of 4 cycles of doxorubicin (A, 40 mg) and cyclophosphamide (C, 600 mg/m²) was conducted every 21 days and followed by 4 cycles of T-docetaxel (T, 75 mg/m²) and trastuzumab (H, 8→6 mg/kg) every 21 days, and then received maintenance treatment with trastuzumab (H, 6 mg/kg) and pertuzumab (P, 840→420 mg) every three weeks. During treatment, nausea and vomiting were common adverse events and no unanticipated events happened. Clinical follow-up suggests that she has achieved clinical complete remission (CR) and has survived for over 4 years (Figure 5).

Figure 5 Treatment schedule. The patient underwent modified radical mastectomy and axillary sentinel lymph node dissection of the right breast and chemotherapy regimen of AC-TH and trastuzumab-pertuzumab maintenance treatment. AC-TH, doxorubicin, cyclophosphamide, T-docetaxel and trastuzumab; A, doxorubicin; C, cyclophosphamide; T, T-docetaxel; H, trastuzumab; P, pertuzumab; HER2, human epidermal growth factor receptor 2.

Discussion

PBSCC is an exceptionally rare histological subtype and has been classified into metaplastic carcinoma according to the World Health Organization (WHO) Classification 5^th Edition (5). It accounts for less than 0.1% of all breast carcinoma. Etiology and pathogenesis of this subtype is still uncertain (6). Breast implant-associated squamous cell carcinoma (BIA-SCC) cases have been reported successively since early 1990s, indicating that breast implants may be a potential risk factor of PBSCC (7,8). In the present case, she had no history of breast augmentation surgery and SCC in other areas has been ruled out. As reported before, the clinical manifestations and imaging characteristics of PBSCC are similar to other invasive breast cancer, thus its diagnosis relies on tissue histomorphology and IHC staining.

PBSCC is more common in postmenopausal women with a median onset age of 54 years old. Main clinical features reported include breast pain, a swelling or palpable mass, nipple retraction or discharge, and infrequently, skin ulceration or breast abscess. The involvement of axillary lymph node varied from case to case, and also did its clinical outcome (9,10). In the present case, she had normal menstrual cycles and a palpable lump was the only clinical manifestation during presentation. Imaging examination detected an enlarged ipsilateral axillary lymph node.

Currently, the optimum therapeutic regimens of patients with metaplastic breast carcinoma remain unclear. Based on the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, surgery and adjuvant systemic therapies are recommended treatments for metaplastic breast carcinoma, considering its unfavorable prognosis (11). Modified radical mastectomy and axillary sentinel lymph node dissection should be conducted on patients who don’t present with locally advanced disease and are eligible for surgery (12). As for adjuvant systemic therapies, no standard therapeutic schedule has been established. Case reports covered disputable treatment responses of PBSCC patients to chemotherapy regimens such as anthracycline, methotrexate, 5-fluorouracil, cyclophosphamide and taxanes, which are commonly used for ductal carcinoma of the breast (12,13).

The patient underwent modified radical mastectomy and was histopathologically diagnosed as PBSCC without axillary lymph node metastasis. The positive expression of CK5/6, P53 and P63 was detected by IHC, which further proved the histopathological diagnosis of PBSCC. PBSCC is usually a high-grade and triple-negative neoplasm. In our case, the negative expression of hormone receptor ER, PR and immune checkpoint PD-L1 indicates that patients may be unable to benefit from hormone-based therapy and PD-1/PD-L1 immune checkpoint inhibitors. Rarely but fortunately, HER2 over-expressed was detected and confirmed, which means a potential treatment benefit from anti-HER2 therapy.

Clinical management to improve the outcomes of HER2-positive breast cancer patients relies on magnifying adjuvant chemotherapy with the combination of taxanes and dual anti-HER2 drugs. Taxanes, alone or in combination with other anti-tumor drugs, such as anthracyclines and cyclophosphamide, with/without anti-HER2 drugs, are essential components in the majority of chemotherapy recommendation. Their predominance in disease-free survival and overall survival are well-documented in extensive clinical trials (14-16). In high-risk cohort, the sequential administration of anthracycline and taxanes, concurrently with trastuzumab or docetaxel, carboplatin, is suggested (17). Current international guidelines recommend that trastuzumab should be given for 1 year (11,18), which can minimize the risk of recurrence and death, compared with chemotherapy alone (19). Updated data from pivotal trial indicates that 1-year administration of trastuzumab is a standard regimen for HER2-positive breast cancer patients (20).

Survival analysis showed that the disease-free survival of HER2-positive metaplastic squamous cell carcinoma (MSCC) cases was significantly lower than that of triple-negative MSCC cohort (21). Considering the adverse prognosis reported and the enlarged axillary lymph node detected by ultrasound, the patient agreed to accept AC-TH chemotherapy and maintenance treatment of dual anti-HER2 therapy after the operation. Fortunately, the clinical outcome is encouraging.

However, this is the only PBSCC patient we have encountered. Whether the comprehensive treatment is suitable for other HER2-positive PBSCC cases still needs more clinical practice.

Conclusions

PBSCC is a rare breast cancer with no standard clinical strategy. Due to non-specific imaging manifestations, its diagnosis relies on histomorphology. IHC staining helps to clarify the pathological type, hormone receptor status, HER2 amplification and PD-L1 expression, which is essential for clinical decision-making. HER2-positive PBSCC patients may benefit from AC-TH chemotherapy and 1-year anti-HER2 therapy is necessary to good prognosis. If possible, dual anti-HER2 therapy, combined with trastuzumab and pertuzumab, is recommended. Finally, positive clinical prognosis of PBSCC may be attributed to early detection, immediate surgery, precise diagnosis and proper adjuvant treatment strategy.

Acknowledgments

Funding: This study was granted by the Science and Technology Research and Development Plan of Shijiazhuang (No. 211200763, to Y.L.).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-138/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-138/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-138/coif). Y.L. reports that this study was granted by the Science and Technology Research and Development Plan of Shijiazhuang (No. 211200763 to Y.L.). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of Shijiazhuang Pingan Hospital and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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