Solid papillary carcinoma of the breast with high-grade cytological features: challenging the concept of indolence

Abstract

Solid papillary carcinoma (SPC) of the breast is a rare neoplasm typically regarded as a low-grade tumor with indolent behavior. We report two cases of SPC in elderly women presenting with palpable breast masses. Preoperative imaging demonstrated BI-RADS 4 suspicious lesions, and ultrasound-guided core needle biopsy suggested a papillary neoplasm consistent with SPC. Definitive histopathological examination revealed SPC with unusual high-grade cytological features, including marked atypia, increased mitotic activity, and an elevated Ki-67 proliferation index, despite the absence of conventional invasive morphology in one case. These findings highlight a striking discordance between the typically indolent architectural appearance of SPC and cytological indicators of aggressive potential, underscoring the biological heterogeneity of this rare entity. Recognition of these atypical presentations is essential for accurate pathological diagnosis, risk stratification, and appropriate clinical management.

Introduction

Solid papillary carcinoma (SPC) is a rare breast neoplasm, accounting for ~1% of breast carcinomas, with a marked predominance in elderly women [1]. The median age at diagnosis is around 70 years [1]. It is considered a low-grade tumor, showing neuroendocrine differentiation in nearly 50% of cases [2]. SPC typically arises within dilated ducts of the breast, most often in the central retroareolar region, and is generally regarded as a variant of ductal carcinoma in situ (DCIS).

An invasive component may be associated with SPC in two distinct forms: either as SPC associated with a conventional invasive carcinoma, or as SPC with stromal invasion. In the absence of invasive features, SPC behaves as an indolent tumor with a favorable prognosis [1].

Case report

Case 1

A 86-year-old woman presented with a palpable mass in the upper outer quadrant of the left breast. Clinical examination revealed a firm, well-circumscribed nodule measuring ~2 cm. Preoperative breast imaging, including mammography and ultrasonography, revealed a well-defined hypoechoic lesion measuring 20 × 18 mm, with partially lobulated margins and mild posterior acoustic enhancement. No suspicious microcalcifications or architectural distortion were identified, and there was no evidence of suspicious axillary lymphadenopathy. Based on these imaging findings, the lesion was classified as BI-RADS 4B, warranting tissue sampling. An ultrasound-guided core needle biopsy was subsequently performed and was consistent with SPC.

The patient underwent breast-conserving surgery with sentinel lymph node biopsy. Macroscopic examination revealed a well-circumscribed tumor measuring 21 mm in greatest dimension.

Histopathological examination revealed a well-circumscribed solid papillary neoplasm, composed of expansile nodules with a solid growth pattern and delicate fibrovascular cores. The lesion was sharply demarcated from the surrounding breast parenchyma, with no evidence of stromal invasion. Tumor cells were relatively uniform, with round to oval nuclei, finely granular chromatin, and moderate eosinophilic cytoplasm. Notably, there was marked mitotic activity, estimated at 22 mitoses per 10 high-power fields, which is unusual for this entity. Mild to moderate nuclear atypia was present (Fig. 1). Immunohistochemical analysis showed diffuse ER and PR positivity, HER2 score 1+ (negative), high proliferative index with Ki-67 estimated at 60%, and negative staining for neuroendocrine markers, including chromogranin and synaptophysin (Fig. 2). The sentinel lymph node was free of metastatic involvement.

Overall, the findings are consistent with a SPC with unusually high proliferative activity.

Despite its well-circumscribed architecture and lack of invasion, the high mitotic index and elevated Ki-67 (60%) represent atypical features for this tumor type and may suggest a potential for more aggressive biological behavior, warranting careful clinical follow-up.

Case 2

A 70-year-old woman presented with a palpable right breast mass. Breast ultrasound and mammography revealed multiple irregular hypoechoic nodules in the affected breast, the largest measuring 15 mm. The dominant lesion demonstrated irregular margins and was associated with architectural distortion on mammography, without suspicious microcalcifications. No suspicious axillary lymphadenopathy was identified on imaging. The lesion was classified as BI-RADS 4C, and an ultrasound-guided core needle biopsy was subsequently performed and revealed a papillary lesion with atypical epithelial proliferation. Complete surgical excision was recommended for definitive diagnosis. The patient underwent a right mastectomy with axillary lymph node dissection. Gross examination showed multiple nodular lesions, variably well circumscribed, with focal necrosis (Fig. 3).

Histology demonstrated a multifocal invasive SPC, composed of papillary and solid structures, with moderate atypia and a high mitotic index (20/10 HPF), corresponding to grade II (3 + 2 + 2). An extensive intraductal papillary component was present, with no lymphovascular invasion (Fig. 4).

In both patients, metastatic staging with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed preoperatively and demonstrated no evidence of regional or distant metastatic disease.

Discussion

SPC of the breast is an uncommon neoplasm, representing <1% of all breast carcinomas, and predominantly affects elderly women [2]. This entity is characterized by distinctive clinicopathological features that set it apart from other papillary breast lesions [2]. Initially described by Maluf et al. in 1995, SPC has since gained increasing recognition [3]. Owing to advances in its morphological and biological characterization, it has been formally acknowledged as a distinct pathological entity and was incorporated into the 2019 World Health Organization classification of breast tumors.

Clinical presentation of this tumor typically involves postmenopausal women, with a reported median age of 70 years. Patients usually present with a palpable breast mass, most often located in the retroareolar region [2], or with hemorrhagic nipple discharge. Reported tumor sizes range from 10 to 150 mm [4]. Grossly, these lesions appear as well-circumscribed, solitary, rounded masses with a pink-gray cut surface, occasionally showing cystic degeneration and hemorrhagic changes [5].

Imaging often represents a diagnostic challenge, as mammography establishes the correct diagnosis in only about 50% of cases. Ultrasonography alone is similarly limited, allowing accurate diagnosis in approximately half of patients. When contributory, ultrasound typically demonstrates a solid mass with a characteristic frond-like architecture, occasionally associated with cystic changes and ductal dilatation. [6] Consequently, definitive diagnosis relies on histopathological examination.

According to the Wolrd Health Organization classification, SPC is a low-grade breast neoplasm arising within dilated ducts and characterized by well-demarcated nodular proliferations supported by delicate fibrovascular cores. This entity frequently exhibits neuroendocrine differentiation [7]. Notably, in one of our cases, immunohistochemical staining for neuroendocrine markers was entirely negative, representing an unusual finding within this tumor subtype.

Histologically, the tumor is composed of a relatively monotonous population of small, round neoplastic cells, occasionally exhibiting a spindle-shaped morphology [7]. In contrast to conventional papillary carcinoma, SPC often demonstrates little to no true papillary architecture: the neoplastic cells typically occupy markedly dilated ducts in a predominantly solid growth pattern, while well-formed papillary fronds are absent or only focally present [8].

Nuclear atypia is usually mild to moderate, and mitotic activity is generally low [7]. In this context, both our cases are distinctive, as it shows marked cytologic atypia associated with numerous and atypical mitotic figures, representing an unusual and diagnostically significant deviation from the classic histopathological features of this entity.

SPC typically exhibits a pushing growth pattern, forming well-circumscribed nodules. In the majority of cases, myoepithelial cells are absent, both within the lesion and at its periphery. This feature has led some authors to propose that SPC may represent a form of invasive carcinoma, rather than a purely in situ process, given the lack of a myoepithelial cell layer surrounding the tumor nodules [9–11].

Nevertheless, according to the most recent WHO classification, SPC is currently regarded as a form of carcinoma in situ. This designation is based primarily on its characteristic architectural features, including the presence of well-defined, rounded nodules with smooth, sharply circumscribed borders, regardless of the presence or absence of an identifiable myoepithelial cell layer.

Invasion may be identified in two ways. Most commonly, it is established by the presence of a distinct invasive component, classically represented by mucinous carcinoma, which is the most frequently reported invasive counterpart [3]. Other associated invasive patterns include neuroendocrine carcinoma and conventional invasive carcinoma of no special type. Unlike the commonly described cases, no unequivocal invasive component was identified in our series. However, the presence of significant cytonuclear atypia and frequent mitotic figures supports a more aggressive phenotype. These findings highlight that, even in the absence of overt invasion, certain SPCs may exhibit features suggestive of invasive potential.

Less commonly, invasion may occur as true stromal infiltration by the SPC itself. In such cases, invasion is characterized by the loss of myoepithelial cells, accompanied by irregular, angulated tumor nodules displaying a ‘geographical jigsaw’ configuration, embedded within a desmoplastic stromal reaction [7].

One of the main diagnostic challenges in SPC lies in the assessment of invasion. Immunohistochemical markers commonly used to evaluate the myoepithelial cell layer, such as p63, calponin, smooth muscle myosin heavy chain (SMMHC), and CK5/6, frequently demonstrate absence of myoepithelial cells surrounding SPC nodules [7]. However, this finding alone does not establish invasiveness. When the lesion retains a nodular, well-circumscribed architecture with smooth contours, it is still classified as in situ. In contrast, the presence of irregular, infiltrative borders supports a diagnosis of invasive carcinoma.

Most SPCs display a luminal profile, characterized by strong estrogen and progesterone receptor expression, reflecting their typically low-grade behavior. HER2 overexpression is uncommon, and the Ki-67 proliferation index is generally low, most often remaining below 10%–20% of tumor cells [8]. Our case is notable for the paradoxical association of a well-circumscribed tumor architecture with pronounced cytological atypia, numerous mitotic figures, and a markedly elevated Ki-67 proliferation index. The prognostic significance of Ki-67 in SPC remains poorly established, and current classifications do not integrate proliferative indices into grading or staging of in situ SPC.

Neuroendocrine differentiation is observed in a substantial proportion of SPCs. Immunohistochemical expression of synaptophysin is reported in ~50%–75% of cases, whereas chromogranin A shows positivity in about 30%–50%, often with variable intensity and distribution [12]. Our case did not show any neuroendocrine differentiation, and the absence of neuroendocrine marker expression further highlights the biological heterogeneity of SPC and suggests that reliance on this feature for diagnosis may be limited in atypical cases.

The neoplastic cells characteristically lack expression of high–molecular-weight cytokeratins [7].

In the absence of an invasive component, SPC is classified as in situ regardless of myoepithelial cell status, and grading is based on nuclear features. When invasion is present, staging, Nottingham grading, and receptor status assessment are determined exclusively by the invasive component, following the criteria applied to conventional invasive breast carcinomas [7].

The coexistence of a non-invasive but highly proliferative lesion (Case 1) and an overtly invasive SPC (Case 2) within our series further supports the concept of a morphological and biological spectrum.

SPC poses a significant diagnostic challenge and must be distinguished from several benign and malignant breast lesions with papillary or solid growth patterns. While it may mimic usual ductal hyperplasia, SPC is characterized by a monomorphic epithelial cell population forming solid nodules with fibrovascular cores and lacking CK5/6-positive myoepithelial or basal cells [8]. Encapsulated papillary carcinoma, although closely related, typically presents as a cystic, well-circumscribed lesion with true papillary fronds rather than a predominantly solid architecture [1]. Low-grade DCIS may show cytologic similarities but usually exhibits cribriform or micropapillary patterns and retains a peripheral myoepithelial layer [1]. Invasive ductal carcinoma with neuroendocrine differentiation shares neuroendocrine marker expression but demonstrates infiltrative growth with an associated desmoplastic stroma, while lobular neoplasia is excluded by preserved E-cadherin expression [8]. Ultimately, the combination of solid papillary architecture and absence of myoepithelial cells is central to the diagnosis of SPC.

Overall, SPC is associated with an excellent prognosis. Owing to its typically low-grade morphology and the frequent absence or limited extent of invasion, axillary lymph node metastases are uncommon, even in cases with an invasive component. Consistent with this favorable behavior, Hashmi et al. reported axillary nodal involvement in only 15.4% of cases (6 of 39 patients) [13]. Similarly, Papathomas et al. reported lymph node positivity in ~11% of cases in which sentinel lymph node biopsy was performed [14].

Management of SPC is guided by the presence or absence of invasion. In cases of pure in situ SPC, treatment is surgical and consists of breast-conserving excision or mastectomy depending on lesion extent, with emphasis on achieving clear margins [2]. When an invasive component is identified, management follows standard protocols for invasive breast carcinoma, including appropriate surgical treatment of the breast and axilla and consideration of adjuvant therapy. However, as invasive SPCs are typically low grade, hormone receptor positive, and node negative, most patients experience excellent outcomes with endocrine therapy alone, and chemotherapy is rarely indicated [1].

Conclusion

SPC, although traditionally viewed as an indolent tumor, may display high-grade cytological and proliferative features that challenge this perception. Our findings highlight a potential discordance between morphology and biological behavior, suggesting the existence of an aggressive subset within this entity. Careful integration of architectural and cytological features is essential to avoid both over and underestimation of tumor aggressiveness and to guide appropriate patient management.

Funding

None declared.

Conflicts of interest

None declared.

References