Adenomyoepithelioma of the breast with recurrent misdiagnoses: A case report highlighting diagnostic challenges and the role of immunohistochemistry

INTRODUCTION

Adenomyoepithelioma (AME) is a rare biphasic tumor with epithelial and myoepithelial differentiation that mimics benign and malignant lesions, causing diagnostic uncertainty.^[1] Representing <1% of mammary neoplasms, it features breniphasic proliferation of epithelial and myoepithelial cells. While typically benign, malignant transformation occurs in 10-15% of cases, often resembling common malignancies. Diagnostic confusion with fibroadenomas, phyllodes tumors, and invasive carcinomas is prevalent due to overlapping histological features. Hayes (2011) reported that up to 18% of breast lesions generate varied opinions in uncommon cases like AME, attributed to its biphasic pattern.^[2] However, recent evidence suggests AMEs may arise through luminalto-basal trans differentiation of luminal progenitors.^[3]Beyond identified TSG101 overexpression in experimental models, H-RAS gene mutations have been recently identified as important in AME pathogenesis.^[4]

CASE REPORT

A 28-year-old nulliparous woman presented in January 2023 with a painless left breast lump noticed over several weeks. She had no history of oral contraceptive use, breast disease, hypertension, diabetes, connective tissue disease, malignancy, or prior surgery. There was no family history of breast cancer, hereditary malignancies, or familial cancer syndromes. She had no prior surgical history before this presentation, and there was no previous chest irradiation, smoking or alcohol consumption and recreational drug use. No psychosocial concerns of healthcare access barriers were identified at presentation.

Physical examination showed a well-defined, mobile, non-tender left breast mass with the overlying skin intact without erythema, ulceration, peau d’orange, nipple retraction, or discharge. The right breast was unremarkable. No axillary, supraclavicular, or cervical lymphadenopathy was detected. There were normal cardiovascular, respiratory, and abdominal examinations with no constitutional symptoms.

Excisional biopsy in January 2023 revealed a benign fibroepithelial lesion, and no further treatment was recommended. In April 2023, the patient re-presented with recurrent enlargement on the same left breast side. Clinical examination revealed a firm, mobile, non-tender mass without skin changes, nipple abnormalities, or lymphadenopathy. Systemic examination was unremarkable. Core needle biopsy demonstrated infiltrated cords of epithelioid cells with nuclear pleomorphism, frequent mitoses, and stromal response [Figure 1], leading to provisional invasive ductal carcinoma.

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Figure 1: Core needle biopsy of the left breast mass. (a) Low magnification (H&E, ×40) showing disruption of normal breast architecture by irregular epithelial clusters and cords extending into the surrounding stroma. (b) Medium power (H&E, ×100) demonstrating cohesive groups of atypical epithelioid cells arranged in nests and linear cords within a reactive stromal background. (c) High magnification (H&E, ×200) revealing enlarged, pleomorphic nuclei with hyperchromasia, conspicuous nucleoli, and frequent mitotic figures. (d) Higher power (H&E, ×400) illustrating pronounced cytological atypia and active mitosis, features that, without broader architectural assessment or immunohistochemical staining, were interpreted as consistent

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After the diagnosis, the patient underwent a simple mastectomy in June 2023. Gross examination showed a well-circumcised lesion. Microscopic evaluation demonstrated a biphasic neoplasm composed of gland-form epithelial structures surrounded by spindled to polygonal cells in tubular and lobulated patterns, without stromal invasion [Figure 2].

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Figure 2: Histomorphology of adenomyoepithelioma, hematoxylin & eosin stain. (a) At low magnification (×40), the lesion appears well-demarcated with a lobulated outline and preserved tissue architecture. (b) At medium power (×100), a dual-cell population is evident, consisting of glandular epithelial elements encircled by an outer layer of spindle-shaped to polygonal cells. (c) Higher magnification (×200) shows tubular epithelial formations with clearly defined lumina. (d) At high power (×400), the peripheral myoepithelial cells are better appreciated, exhibiting spindle morphology without evidence of stromal invasion or desmoplastic response.

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Epithelial components were positive for cytokeratin and epithelial membrane antigen as shown by the immunohistochemistry, while surrounding cells were positive for p63, smooth muscle action, and S-100 protein [Figure 3].

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Figure 3: Immunohistochemical profile demonstrating biphasic differentiation (a) Cytokeratin staining (×200) highlights the inner epithelial cell layer. (b) EMA expression (×200) further supports epithelial lineage within the glandular component. (c) p63 positivity (×200) outlines a continuous myoepithelial layer surrounding the epithelial structures. (d) Smooth muscle actin and S-100 staining (×200) confirm myoepithelial differentiation of the outer cell. population. EMA: Epithelial membrane antigen.

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During the same period, a separate lump in a different quadrant of the left breast was identified. Wide local excision in April 2023 revealed marked stromal overgrowth, severe nuclear atypia, necrosis, high mitotic activity and infiltrative margins, consistent with malignant phyllodes tumor [Figure 4].

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Figure 4: Histological features of malignant phyllodes tumor, hematoxylin & eosin stain. (a) Low-power view (×40) reveals a characteristic leaf-like architecture with expanded stromal areas. (b) At ×100 magnification, there is prominent stromal cellularity with areas of overgrowth. (c) High-power examination (×200) demonstrates marked nuclear atypia and increased mitotic activity. (d) Additional fields (×200–400) show necrotic foci and irregular, infiltrative tumor margins. H&E: Hematoxylin & eosin.

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The case was reviewed at a multidisciplinary tumor board in August 2023, where adjuvant radiotherapy was recommended for the malignant phyllodes tumor. The patient was subsequently lost to follow-up without commencing treatment for about five months. Approximately six months later, she re-presented with a rapidly enlarging, fungating mass involving the left breast and chest wall, including ulceration and necrotic discharge. No clinical evidence of distant organomegaly or distant metastases. She underwent debulking surgery and adjuvant radiotherapy with delayed wound closure planned in collaboration with the plastic and reconstructive surgery team.

DISCUSSION

AME of the breast is an uncommon biphasic neoplasm whose diagnosis is frequently complicated by architectural heterogeneity and cytological variability. The present case illustrates how sequential histological representations of the same lesion, as demonstrated across Figures 1–3, can yield differing interpretations that directly influence clinical management decisions.^[5]

The core needle biopsy findings shown in Figure 1 demonstrated infiltrating cords of epithelioid cells with marked nuclear pleomorphism, frequent mitoses, and a stromal response. In isolation, these features were consistent with an invasive epithelial malignancy. At this stage, the absence of a low-power architectural context and lack of immunohistochemical assessment limited recognition of a biphasic growth pattern. Consequently, the histological impression derived from Figure 1 directly informed the clinical decision to proceed with definitive surgical treatment.^[6-10]

In contrast, examination of the mastectomy specimen provided a broader architectural perspective [Figure 2]. The lesion was well circumscribed and composed of glandular epithelial structures encased by a continuous peripheral cellular layer, arranged in tubular and lobulated patterns, without stromal invasion or desmoplasia. These architectural features differed fundamentally from those expected in invasive ductal carcinoma and prompted reconsideration of the initial diagnosis. Thus, the low-power histological organization depicted in Figure 2 served as the critical stimulus for further diagnostic refinement.^[8-10]

Immunohistochemical analysis [Figure 3] provided definitive clarification. The epithelial component showed strong positivity for cytokeratin and epithelial membrane antigen, while the surrounding cells demonstrated consistent expression of p63, smooth muscle action, and S-100 protein. The spatial correlation of these markers confirmed true epithelial–myoepithelial differentiation, establishing the diagnosis of AME. The findings in Figure 3 retrospectively explained the cytological atypia observed in Figure 1 and demonstrated that the apparent infiltrative pattern reflected sampling of a myoepithelial-rich area rather than true stromal invasion. These results reinforce the indispensable role of immunohistochemistry in resolving ambiguity in biphasic breast lesions.^[11,12]

The diagnostic complexity of this case was further heightened by the synchronous presence of a second lesion with distinct histological behavior. Figure 4 illustrates the wide local excision specimen showing marked stromal overgrowth, severe nuclear atypia, high mitotic activity, necrosis, and infiltrative margins, establishing the diagnosis of malignant phyllodes tumor. Unlike the circumscribed architecture seen in Figure 2, the aggressive stromal features demonstrated in Figure 4 justified escalation of local treatment and informed the multidisciplinary recommendation for adjuvant radiotherapy.^[5]

The divergent biological behavior illustrated across Figures 1–4 underscores the importance of lesion-specific evaluation in patients with multiple breast tumors. While AME typically follows an indolent course when completely excised, malignant phyllodes tumors are characterized by aggressive local behavior and a high risk of recurrence. The patient’s subsequent loss to follow-up and re-presentation with a rapidly progressive fungating mass is consistent with the natural history of inadequately treated malignant phyllodes tumors, as reflected by the infiltrative features shown in Figure 4.^[13,14]

Collectively, this case highlights several critical contrasts: limited versus comprehensive tissue sampling, morphology alone versus morphology supported by immunohistochemistry, and indolent versus aggressive biphasic breast neoplasms. Each figure represents a discrete step in the diagnostic pathway, with direct implications for clinical decision-making. Accurate diagnosis of rare breast tumors requires integration of architectural assessment, immunophenotypic confirmation, and clinicopathological correlation to guide appropriate surgical and adjuvant management strategies.^[11-13]

CONCLUSION

This case illustrates the diagnostic challenges and treatment complications associated with atypical breast mesenchymal tumors. Advances in the histopathological classification underscore the need for specialized pathology assessments with concomitant immunohistochemical studies to guarantee proper diagnosis. Complete surgical extirpation with adequate margins still retains a central place in treatment, with the addition of adjuvant radiotherapy in the case of recurrence or aggressive behavior. Further studies targeting the molecular characterization of atypical mesenchymal tumors could provide additional insight into the dynamics of the tumors and be used to design individualized therapies.