Hormone Receptor–Positive Encapsulated Papillary Carcinoma of the Breast With High-Grade Cytological Features: A Case Report With Invasive Heterogeneity

Introduction

Encapsulated papillary carcinoma (EPC) of the breast is an uncommon malignancy, accounting for approximately 0.5% to 2% of all breast cancers [1]. It occurs across a wide age spectrum but is most frequently observed in postmenopausal women and is rarely reported in men [1]. Biologically, EPC is characterized by a well-circumscribed papillary neoplasm enclosed within a thick fibrous capsule and lacking a peripheral myoepithelial layer, features that generally indicate an indolent course unless stromal invasion occurs. EPC with high-grade cytological features is rare, and descriptions in the literature are not detailed. Compared with classic EPC, high-grade EPC often presents with high nuclear grade (ie, enlarged, hyperchromatic, pleomorphic nuclei), solid architectural areas (sheets of tumor cells replacing typical papillae), marked cellular atypia, and high proliferative activity, features that may denote more aggressive biological behavior. These tumors also tend to exhibit more frequent invasive potential and are often hormone receptor negative [2]. In addition, some cases of EPC, including those with high-grade cytological features, may show unusual histologic findings such as focal micropapillary areas or extracellular mucin reminiscent of mucinous carcinoma within the EPC [3]. Despite these observations, existing publications lack detailed analyses of intratumoral heterogeneity, especially cases demonstrating simultaneous high-grade and low-grade invasive components, representing a key gap that this report directly addresses. We herein report a case of hormone receptor–positive EPC with high-grade cytological features and pathological heterogeneity of the breast, in which areas of stromal invasion were identified outside the fibrous capsule, consistent with invasive carcinoma arising in association with EPC. It is important to note that high-grade cytological atypia alone does not indicate invasion; definitive evidence of stromal infiltration beyond the capsule remains necessary for diagnosing invasive disease. In addition, by presenting this case and summarizing the relevant literature, we aim to clarify the pathological spectrum, diagnostic pitfalls, and clinical management implications of this rare tumor subtype, rather than the previous vague statement of “enhancing the medical community’s understanding”. In view of the 5th edition of the World Health Organization (WHO) classification of breast tumors and related literature reports, pathologists generally believe that EPCs with high-grade cytological features or invasive components should be evaluated and managed as invasive breast carcinoma (IBC), as per WHO 2019 guidelines [1,4].

Case Report

A 40-year-old woman first noticed a lump in her right breast in May 2022 and presented to our hospital in November 2022. Ultrasonography at that time revealed a 23-mm circumscribed mass with homogeneous internal echogenicity, which was initially considered benign, and short-term follow-up was recommended. At the follow-up visit in February 2023, the mass had enlarged to 30 mm and showed structural distortion. The lesion additionally exhibited increased internal vascularity on color Doppler, and a disruption of the anterior and posterior mammary fascial planes was observed. These findings were highly suspicious for malignancy (consistent with BI-RADS Category 4C) and prompted an immediate core needle biopsy (CNB). Histopathological examination of the CNB specimen confirmed IBC of no special type (IBC-NST). To strengthen the diagnostic narrative, we further detail that the differential diagnosis at the time of CNB included solid papillary carcinoma, papillary ductal carcinoma in situ, and invasive papillary carcinoma – entities that can mimic EPC both radiologically and histologically. These possibilities were subsequently ruled out based on the absence of a myoepithelial layer, the presence of a thick fibrous capsule, and the identification of discrete extracapsular invasive nests, features characteristic of EPC rather than intraductal papillary proliferations. Mammography and magnetic resonance imaging revealed a centrally located cystic-solid mass with clear boundaries and possible peripheral calcification (Figure 1A, 1B). The patient had no significant personal or family history of malignancy, and laboratory test results showed no remarkable abnormalities. On March 15, 2023, two sentinel lymph nodes were negative on frozen and permanent sections. Given the tumor’s central location and cosmetic considerations, a skin-sparing mastectomy with immediate latissimus dorsi musculocutaneous flap reconstruction was performed. Postoperative adjuvant therapy, consisting of oral fluoropyrimidine (S-1), tamoxifen, and luteinizing hormone-releasing hormone agonists (LHRHa), was selected based on a nuanced risk assessment. Although the tumor exhibited high nuclear grade, suggesting aggressive biological potential, the absence of lymphovascular invasion and lymph node metastasis led us to treat the case more conservatively, analogous to a T1- or carcinoma in situ–equivalent lesion. Given the high cytological grade, however, omitting systemic therapy entirely was considered inappropriate. Therefore, we chose adjuvant S-1, which is indicated for T1, Grade 3 hormone receptor–positive invasive carcinoma, and intensified the endocrine therapy by adding LHRHa (ovarian function suppression) to tamoxifen. The treatment regimen included S-1 for 1 year, and endocrine therapy with tamoxifen and LHRHa for 5 years. The follow-up plan involves clinical examinations, breast ultrasound, and mammography every 6 months. She has remained disease-free and in good health under regular follow-up to date.

Grossly, the specimen measured 42×37×25 mm and contained a well-circumscribed grayish-yellow lesion with cystic and solid areas (Figure 2A). On low-power examination, the tumor was enclosed by a thick fibrous capsule with clear borders (Figure 2B), and a desmoplastic reaction with inflammatory infiltration was seen at the periphery (Figure 2C). Microscopically, papillary, solid, and cribriform structures composed of atypical epithelial cells were observed (Figure 2D, 2E). At higher magnification, tumor cells showed enlarged hyperchromatic nuclei and frequent mitoses (24/10 high-power field [HPF]) (Figure 2F). Beyond the capsule, 3 high-grade invasive foci (1.5–2.5 mm) near the areola exhibited irregular nests with marked atypia and desmoplastic stroma (Figure 2G). In particular, the invasive clusters demonstrated irregular, angulated infiltrative patterns extending beyond the fibrous capsule, accompanied by a prominent desmoplastic reaction, which supports true stromal invasion rather than mere expansile growth. Another 2.8-mm focus showed mild atypia and lower proliferative activity, consistent with a low-grade invasive component (Figure 2H). A peripheral ductal carcinoma in situ component with microcalcification was also identified (Figure 2I).

Immunohistochemically, both the EPC and invasive components were strongly positive for estrogen receptor (ER; Figure 3A–3C) and progesterone receptor (PR; Figure 3D–3F), but negative for human epidermal growth factor receptor 2 (HER2, 1+; Figure 3G–3I), cytokeratin 5/6 (CK5/6), tumor protein p63 (p63), synaptophysin, and chromogranin A. The Ki-67 proliferation index was 46.5% in the EPC area, 36.5% in the high-grade invasive component, and 5% in the low-grade component (Figure 3J–3L). The detailed information of immunohistochemistry results and antibodies are summarized in Table 1.

Absence of myoepithelial markers confirmed the diagnosis of EPC rather than an intraductal papillary lesion. These findings established hormone receptor–positive EPC with high-grade cytological features and limited invasion. Unlike conventional IBC-NST, EPC shows a thick capsule, papillary growth, and expansile rather than infiltrative margins.

Discussion

We described a case of hormone receptor–positive EPC with high-grade features of the breast and associated fibrous extracapsular invasive carcinoma. This case is notable in that both components of the tumor (EPC with high-grade features and invasive components) strongly expressed hormone receptors, and the case report is valuable because it demonstrates heterogeneity in the degree of atypia within the invasive component of EPC, showing high-grade and low-grade component areas. We conducted a focused review of published cases of high-grade EPC and did not identify reports clearly documenting concurrent high-grade and low-grade extracapsular invasive components within the same lesion. This case highlights intratumoral heterogeneity in the invasive component of high-grade EPC and contributes additional detail to the evolving understanding of this entity. In the literature, reports of hormone receptor–positive EPC with high-grade features are very rare. In the limited data available, only 4 cases of hormone receptor–positive EPC with high-grade features and mitotic activity over 20/10 HPF have been reported (24/10 HPF in our case) [3].

Most EPCs have a papillary growth pattern with papillae covered by columnar tumor cells. Some areas may have solid papillary or cribriform structures, and the nuclear grade of the tumor cells is low to intermediate [5]. In this study, we found that a type of breast cancer with EPC structural characteristics had high nuclear grade characteristics. In general, this type of tumor was larger than a traditional EPC (the maximum diameter in our case was 4.2 cm). Qureshi et al reported a case of high-grade EPC of the breast in a young woman, and microscopically, the tumor demonstrated papillary, solid, and cribriform architectural patterns, accompanied by marked cytological atypia of the neoplastic cells [6]. Our morphological findings (Figure 2D–2F) similarly showed papillary, solid, and cribriform patterns with marked atypia and abundant mitoses, reinforcing the consistency of our case with previously described high-grade EPC morphology. In many areas, tumor cells displayed prominent nucleoli, and mitotic figures were readily observed, with a mitotic index reaching 24 per 10 HPF in this case. The lesion was encapsulated by a thick fibrous capsule, and myoepithelial cells were absent both within the tumor nests and along the cyst wall, findings consistent with EPC [7]. In this setting, the absence of myoepithelial cells alone does not constitute frank invasion; unequivocal invasion is defined by neoplastic elements permeating beyond the fibrous capsule with an irregular infiltrative appearance, most often taking the form of IBC of no special type (IBC-NST). In EPC, risk assessment and staging are based on the concept that lesions confined within the fibrous capsule are regarded as equivalent to an in situ carcinoma, and the invasive risk is determined by the presence and extent of frank invasion, defined as irregular permeation of tumor cells beyond the fibrous capsule. However, when EPC shows high-grade cytological features, current WHO recommendations suggest that the lesion should be approached as an IBC as a whole, and graded, staged, and treated according to the principles applied to IBC [4]. From a surgical perspective, recognizing high-grade cytological features and extracapsular invasive foci is important because these lesions should not be approached with the same mindset as classic EPC managed as carcinoma in situ in the absence of frank invasion. Instead, high-grade EPC may warrant planning and pathologic assessment using principles applied to IBC, including careful evaluation of margins and thorough sampling for small extracapsular invasive foci that can be easily overlooked.

In our case, this diagnostic criterion is supported by the high-grade invasive nests beyond the capsule (Figure 2G) and the additional low-grade invasive focus (Figure 2H), further emphasizing the heterogeneity across invasive components. Immunohistochemically, both the EPC and its invasive components were positive for ER and PR and negative for HER2. The differential Ki-67 indices across components (Figure 3J–3L) highest in the EPC with high-grade features, intermediate in the high-grade invasive area, and lowest in the low-grade invasive focus also highlight biological heterogeneity that has not been documented in prior reports. Taken together, these findings illustrate that EPC with high-grade cytological features exhibits striking biological heterogeneity.

Liu et al [8] showed that high-grade EPC was more likely to have a solid structure, triple-negative or basal-like immunophenotype, and a higher Ki-67 index, and was more common in young women than low- or intermediate-grade EPC, suggesting its invasive biological potential. Rakha et al [3] reported a group of high-grade breast EPC in 2015, characterized by tumor cells with nuclear pleomorphism and active nuclear division, hormone receptor negativity, larger tumor volume, and higher likelihood to be accompanied by stromal infiltration. Based on the histological characteristics and clinical biological behavior, the study recommended that the treatment of high-grade EPC should refer to that of traditional invasive carcinoma [3]. The WHO (2019) breast tumor classification cited the above study and proposed that EPC with high-grade cytological features and triple-negative or HER2-positive EPC should be graded, staged, and clinically treated according to invasive breast cancer [1,4]. However, recurrence is uncommon in high-grade EPC, but any invasion warrants classification and treatment as invasive carcinoma.

EPC with high-grade cytological features must be distinguished from classic EPC and other intraductal papillary lesions, including intraductal papilloma, papillary ductal carcinoma in situ, solid papillary carcinoma, and invasive papillary carcinoma [9–13]. Like these entities, EPC often displays a papillary growth pattern and can mimic in situ papillary proliferations. The diagnostic distinction can be challenging, particularly when solid or cribriform patterns mimic solid papillary carcinoma. However, the absence of myoepithelial cells demonstrated by negative p63 and CK5/6 staining in both the cyst wall and within the papillary structures helps differentiate EPC from intraductal papillary lesions. Similarly, the presence of a thick fibrous capsule and the identification of extracapsular invasive foci assist in distinguishing high-grade EPC with invasion from invasive papillary carcinoma. However, EPC typically lacks a myoepithelial cell layer along the cyst wall and within papillae, is surrounded by a thick fibrous capsule, and may show areas of stromal invasion beyond the capsule. In our case, the absence of myoepithelial markers (Figure 3), with ER and PR positivity and p63 and CK5/6 negativity, supports the diagnosis of EPC rather than intraductal papillary lesions, while the extracapsular invasive nests confirm the presence of true invasion. In contrast, intraductal papillomas and papillary ductal carcinoma in situ retain a myoepithelial layer, while solid and invasive papillary carcinomas are not encapsulated. Thus, the recognition of these morphological and immunohistochemical distinctions is essential for accurate diagnosis.

Collectively, published case reports and small series describe high-grade EPC as a distinct subset characterized by high nuclear grade, frequent solid/cribriform architecture, and high proliferative activity [3,6,8]. These tumors show stromal invasion more often than classic EPC, and when invasion is present it most commonly resembles invasive carcinoma of no special type. Prior literature has also noted that some EPCs with high-grade cytology can display additional mixed histologic features, such as focal micropapillary areas or extracellular mucin reminiscent of mucinous carcinoma [3]. Within this reported spectrum, our case adds incremental value by demonstrating heterogeneity in the degree of atypia within the invasive component, with concurrent high-grade and low-grade extracapsular invasive foci and distinct Ki-67 indices.

Management of EPC is guided by the extent of frank invasion; however, current WHO recommendations emphasize that EPC with high-grade cytological features should be approached using principles applied to IBC [4]. In our case, the presence of high-grade cytology with a high proliferative index, together with small but definite extracapsular invasive foci, supported the decision to perform sentinel lymph node evaluation and to consider adjuvant systemic therapy rather than treating the lesion as a purely in situ–equivalent EPC. At the same time, the absence of lymphovascular invasion and nodal metastasis allowed a relatively conservative adjuvant approach. At the time of this report, the patient remains disease-free under close follow-up.

Some reported cases of EPC with high-grade features have exhibited a triple-negative immunophenotype, although hormone receptor–positive cases have also been observed, indicating that they are insensitive to endocrine therapy. Currently, there are no standard therapeutic regimens. Adequate local excision is a reasonable and effective treatment option. For patients with larger masses, simple mastectomy may be a more reliable treatment procedure, and there is no relevant evidence-based medical basis for whether conventional radiotherapy and chemotherapy should be performed after surgery [14]. Given that our case demonstrated high ER and PR expression across all components, it raises the possibility that a subset of high-grade EPC may still benefit from endocrine therapy, although the potential differential response between heterogeneous components warrants further investigation. With the increase in sample size and the deepening of research, we will be able to more clearly understand the structural characteristics of EPC with high-grade cytological features and the analysis of related genes, and we believe that it will bring decisive changes to clinical treatment.

This report is limited by its nature as a single case, and the findings should therefore be interpreted with caution. In addition, molecular or genomic profiling was not performed, and further studies incorporating such analyses will be needed to clarify the biological basis of the observed heterogeneity.

Future studies should incorporate molecular and genomic profiling to clarify the biological basis of intratumoral heterogeneity in EPC with high-grade cytological features, including whether distinct invasive foci represent divergent clones or phenotypic evolution. Correlating these pathologic and molecular findings with clinical outcomes in larger, multi-institutional cohorts will be essential to refine risk stratification and management. In addition, a systematic review focused on invasive patterns (including extracapsular invasion, type of invasive component, and margin/sentinel node practices) in high-grade EPC may help standardize reporting and guide clinical decision-making. Importantly, any invasive foci showing differing degrees of atypia should be documented in detail to facilitate meaningful clinicopathologic correlation.

Conclusions

In this case, we report a rare example of hormone receptor–positive EPC with high-grade cytological features and confirmed stromal invasion. The presence of extracapsular invasive foci, together with high mitotic activity (24/10 HPF) and a markedly elevated Ki-67 index (46.5%), supports the interpretation that this lesion behaves similarly to IBC. Our findings suggest that when high-grade EPC is accompanied by definitive evidence of invasion, management strategies aligned with that of IBC may be appropriate. However, as this is a single-case report, these observations should be interpreted cautiously, and broader studies are needed to validate the clinical significance of such heterogeneity. Nonetheless, this case highlights an uncommon pathological pattern and may assist clinicians and pathologists in recognizing and appropriately evaluating high-grade EPC with potential invasive behavior. Future research should focus on the genetic and molecular characteristics of high-grade EPC to clarify its invasive behavior and to explore whether molecular profiling could guide targeted or personalized therapies.