PSCCB is a subtype of breast carcinoma as defined by the 2019 WHO classification of breast tumors. It is characterized as pure squamous cell carcinoma when the squamous cell component exceeds 90%. When the squamous component ranges from 10 to 90% in conjunction with non-special type invasive breast carcinoma, it is classified as mixed breast carcinoma. Additionally, this classification mandates that the tumor does not have direct contact with the skin epidermis and excludes the possibility of metastatic squamous cell carcinoma from other sites. As a result, many reported cases may not be recognized as PSCCB by the World Health Organization, complicating the accurate assessment of its true incidence. The pathogenesis of PSCCB remains unclear, although most scholars postulate that it originates from the complete squamous metaplasia of the breast ductal epithelium, which subsequently undergoes malignant transformation [16]. Some studies have identified cases of PSCCB among individuals who have undergone breast augmentation surgery, suggesting a potential link between such procedures and an increased risk of developing PSCCB [17].

PSCCB typically manifests in postmenopausal, middle-aged women, with a median age of 50 years. The tumors are generally large and can exhibit rapid growth; most masses exceed 5 cm, and some cases present initially with nipple discharge [18]. Ultrasonography can provide diagnostic clues for PSCCB, with tumors often displaying a cystic-solid echo pattern, including hypoechoic areas associated with liquefactive necrosis. The imaging characteristics are nonspecific, typically revealing large masses at a laterstage, classified as T3 to T4 at presentation [19]. Histologically, PSCCB exhibits diverse features, showcasing keratinized and non-keratinized patterns, spindle cell and acantholytic squamous cell, with varying degrees of differentiation. In typical cases, keratin pearls and intercellular bridges can be observed, with tumor cells displaying round, vacuolated nuclei, prominent nucleoli, marked atypia, and abundant eosinophilic cytoplasm, some regions may also exhibit components of ductal carcinoma in situ.

A thorough literature search in the PubMed database yielded only eleven reports concerning treatment outcomes for HER2-positive PSCCB (Table 1). Previous studies indicated a lower lymph node metastasis rate of 10–30% compared to non-special type invasive carcinoma, but is prone to distant metastasis compared with non-specific types of invasive carcinoma [20]. although PSCCB is known for a propensity for distant metastasis. In our analysis, we noted that the rate of lymph node metastasis among HER2-positive PSCCB patients reached 72.7% (8 /11), reinforcing the notion that HER2-positive PSCCB is often diagnosed at more advanced stages and carries a poor prognosis. Additionally, existing research has indicated that PSCCB patients may experience distant metastases, particularly to the lungs and brain, even in the absence of lymph node involvement [21]. The patient in this case exhibited metastases to the lungs and brain, but no lymph node metastasis was observed.

When diagnosing PSCCB, it is crucial to emphasize that the tumor bears no relationship to the epidermis, while also ruling out the possibility of metastasis from primary squamous cell carcinoma (SCC) located in other sites such as the lungs, cervix, bladder, or head and neck. Literature reports indicate that TRPS1 and SOX-10 are positively expressed in PSCCB, whereas they are negatively expressed in metastatic squamous cell carcinoma [22, 23]. PSCCB should be differentiated from non-special type invasive breast cancer, which exhibits diverse histological patterns, lacks keratin pearls and intercellular bridges, and shows focal expression of P63, while PSCCB demonstrates diffuse expression. Research has shown that P63 protein is associated with the migration and invasion of breast cancer cells, highlighting its significant role in maintaining the stem cell properties of breast cancer, involving signaling pathways such as WNT/β-catenin and Hedgehog [24]. Acantholytic squamous cell carcinoma can form pseudoglandular cavities that may resemble vascular luminal structures, necessitating differentiation from angiosarcoma. Additionally, primary squamous cell carcinoma of the breast should be distinguished from benign squamous cell lesions, such as squamous metaplasia in Zuska disease involving the lactiferous ducts and major ducts, skin ulcerations due to ductal ectasia, and squamous metaplasia following the formation of sinus tracts.

Currently, there are no standardized treatment guidelines for PSCCB, clinical management typically emphasizes surgical resection, often supplemented by chemotherapy and radiotherapy. The molecular subtype of PSCCB is predominantly triple-negative, showing no significant response to conventional endocrine therapy; thus, endocrine treatment is not recommended [5]. There are only a few case reports in the literature regarding HER2-positive PSCCB. In some studies, HER2-positive PSCCB patients achieved pathological complete response following neoadjuvant chemotherapy combined with targeted therapy [8, 13, 25]. Yuki Usui and Wang Gui each reported one case of HER2-positive PSCCB treated with neoadjuvant chemotherapy combined with targeted therapy, resulting in significant reduction of the breast mass and achieving partial response [11, 14]. Tateishi K reported a case of HER2-positive PSCCB that received neoadjuvant chemotherapy combined with targeted therapy, but the patient developed resistance to treatment [16]. Lei Ruixue documented two cases of HER2-positive PSCCB, noting that due to its rarity and lack of targeted treatment guidelines, clinicians selected surgical resection followed by chemotherapy based on individual patient circumstances, without employing targeted therapy. Notably, one patient experienced lung metastasis 14 months post-surgery [10].

The immunophenotype of the biopsy tissue from this patient was HER2-positive, with negative ER and PR status. Consequently, the patient was treated with the TCb-HP regimen (docetaxel + carboplatin + trastuzumab + pertuzumab), but the patient showed no significant response to treatment and developed distant metastasis within eight months after therapy. Although the chemotherapy and targeted therapy regimen was subsequently intensified, unfortunately, the disease continued to progress. Among our cases, HER2-positive PSCCB patients exhibited variable treatment responses, regardless of whether they received neoadjuvant chemotherapy or chemotherapy combined with targeted therapy, indicating that this tumor type has a high malignancy degree, significant metastatic potential, and resistance to combined chemotherapy and targeted therapies. Resistance may be associated with alterations in HER2 receptors, changes in signaling pathways, immune evasion, tumor microenvironment influences, and epigenetic modifications, warranting further investigation in the future.

Currently, research on the treatment of HER2-positive PSCCB is limited. Although reports indicate that neoadjuvant chemotherapy combined with HER2-targeted therapy has achieved pathological complete response and partial response in select cases, there are instances of disease progression post-treatment, underscoring the variability in treatment responses. Therefore, while neoadjuvant chemotherapy combined with HER2-targeted agents may be effective for certain HER2-positive PSCCB patients, its applicability to all patients remains uncertain. Given the currently limited number of cases, further extensive studies are needed to determine the applicability of these treatments and how to enhance treatment efficacy through personalized approaches.