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BACKGROUND: Although tumor cells undergoing epithelial-mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. METHODS: We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. RESULTS: Our primary culture revealed carcinoma cells expressing diverse epithelial-mesenchymal traits, consistent with epithelial-mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal-epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. CONCLUSIONS: Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma.

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We present a unique case of metastatic metaplastic breast carcinoma responding dramatically to immunochemotherapy. A 46-year-old Japanese woman with primary metaplastic carcinoma of the breast, which was immunohistochemically confirmed to be triple-negative breast cancer, underwent radical surgery, followed by adjuvant chemotherapy with an anthracycline and a taxane. Since multiple lung metastases were detected two months post-chemotherapy and the primary site was shown to be PD-L1-positive, the immune checkpoint inhibitor (ICI) pembrolizumab plus gemcitabine/carboplatin was initiated. While the treatment was discontinued after 15 days due to suspected drug-induced pneumonitis, the lung metastases significantly shrank with no development of new lesions for three months. The patient remained alive as of approximately 15 months after the recurrence date. This case highlights the potential of immunochemotherapy in treating metaplastic breast carcinomas.

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Metaplastic breast cancer represents a very rare and histopathologically diverse subtype of breast cancer. It shows neoplastic epithelial differentiation into squamous cells and/or mesenchymal-like components, resulting in its aggressive behavior and poor prognosis compared to other types of breast cancer. Here, we describe the case of a 43-year-old woman diagnosed with metaplastic carcinoma of the breast who presented like any other case of breast lump in the right breast for six months. The tumor had a large size with an ulcerative lesion of the breast. Ultrasound showed heterogeneous echogenicity and lymph node involvement. Surgical resection with axillary lymph node dissection was done. The microscopic examination after tissue processing showed highly pleomorphic tumor cells along with chondromyxoid stroma and osseous differentiation, suggestive of metaplastic breast cancer which was triple-negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 on immunohistochemistry. The axillary lymph nodes identified were negative for tumor cells. The rarity and aggressive nature of this cancer pose diagnostic challenges and highlight the importance of multidisciplinary approaches for effective management.

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Malignant phyllodes tumors (MPTs) represent the most pernicious type of intralobular stromal proliferation known as a "fibroepithelial lesion" (FEL). They comprise a small fraction of breast malignancies and can present as either a pure MPT or sometimes include a heterologous component (liposarcoma, chondrosarcoma, osteosarcoma, or rhabdomyosarcoma). Of the fraction of MPTs that include heterologous components, very little about those with chondroblastic osteosarcomatous differentiation has been described in the literature. As such, a characteristic staining profile has yet to be established, even though morphological analysis is the cornerstone of diagnosis. The few reported cases have described a poor prognosis. Therefore, we present a case of MPT with chondroblastic osteosarcomatous differentiation to contribute to the dearth of literature examining this entity.

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Breast carcinoma is the most common cancer in women. Nineteen different subtypes of breast carcinomas are recognized in the current WHO classification of breast tumors. Except for these subtypes, there are a number of carcinomas with special morphologic and immunohistochemical features that are not included in the 5th WHO classification, while others are considered special morphologic patterns of invasive breast carcinoma of no special type. In this manuscript, we systematically review the literature on four different subtypes of invasive breast carcinoma, namely lymphoepithelioma-like breast carcinoma, breast carcinoma with osteoclast-like giant cells, signet-ring breast carcinoma, and metaplastic breast carcinoma with melanocytic differentiation. We describe their clinicopathological characteristics, focusing on the differential diagnosis, treatment, and prognosis.

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The differential diagnosis of malignant spindle cell neoplasms in the breast most frequently rests between malignant phyllodes tumor (MPT) and metaplastic carcinoma (MBC). Diagnosis of MPT can be challenging due to diffuse stromal overgrowth, keratin (CK) and/or p63 immunopositivity, and absent CD34 expression, which can mimic MBC, especially in core biopsies. Distinction of MPT from MBC has clinical implications, with differences in surgical approach, chemotherapy, and radiation. In this study, we evaluated MPT (78 tumors, 64 patients) for stromal CK, p63, and CD34 expression and profiled a subset (n=31) by targeted next-generation DNA sequencing (NGS), with comparison to MBC (n=44). Most MPT (71%) were CK+ and/or p63+, including 32% CK+ (25/77 focal) and 65% p63+ (32/66 focal, 10/66 patchy, 1/66 diffuse). Thirty-percent of MPT expressed both CK and p63 (20/66), compared to 95% of MBC (40/42, p<0.001). CK and/or p63 were positive in CD34+ and CD34- MPT. Recurrent genetic aberrations in MPT involved TERT, TP53, MED12, CDKN2A, chromatin modifiers, growth factor receptors/ligands, and PI-3K and MAPK pathway genes. Only MED12 (39%, 12/31) and SETD2 (13%, 4/31) were exclusively mutated in MPT and not MBC (p<0.001 and p=0.044, respectively), whereas PIK3R1 mutations were only found in MBC (35%, 13/35, p<0.001). Comparative literature review additionally identified ARID1B, EGFR, FLNA, NRAS, PDGFRB, RAD50, and RARA alterations enriched or exclusively in MPT versus MBC. MED12 was mutated in MPT with diffuse stromal overgrowth (53%, 9/17), CD34- MPT (41%, 7/17), and CK+ and/or p63+ MPT (39%, 9/23), including 36% of CD34- MPT with CK and/or p63 expression. Overall, MED12 mutation and/or CD34 expression were observed in 68% (21/31) MPT, including 61% (14/23) of CK+ and/or p63+ tumors. Our results emphasize the prevalence of CK and p63 expression in MPT and demonstrate diagnostic utility of NGS, especially in MPT with confounding factors that can mimic MBC.

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Metaplastic thymoma (MT), a rare subtype of thymic epithelial tumors (TETs), harbors YAP1::MAML2 fusions. Poroma, a skin tumor, also carries these fusions and exhibits a unique staining pattern for YAP1 immunohistochemistry (IHC), namely, a YAP1 N-terminus (YAP1[N])-positive but YAP1 C-terminus (YAP1[C])-negative pattern. In this context, MT was recently reported to lack YAP1(C) expression exclusively among TET subtypes. However, a lack of information about YAP1(N) expression in that study and another report that wild-type YAP1 expression was diminished in type B3 thymoma and thymic carcinoma warrants further studies for YAP1 expression in TETs. Thus, we immunohistochemically examined YAP1(N) and YAP1(C) staining patterns in our TET samples, including 14 cases of MT. In addition, 11 of the 14 MT cases were genetically analyzed with the formalin-fixed paraffin-embedded tissues if they harbored YAP1::MAML2 fusions. MT consistently exhibited YAP1(N)-positive and YAP(C)-negative staining, whereas type B3 thymoma and thymic carcinoma showed relatively heterogeneous staining patterns for YAP1(N) and YAP1(C) and were sometimes negative for both antibodies. Furthermore, a lower expression of YAP1 was found in type B3 compared to B2 thymomas. Among genetically analyzed 11 MT cases, 6 cases showed YAP1::MAML2 fusions, whereas the analysis failed in 5 very old cases due to poor RNA quality. These results indicate that IHC of both YAP1(N) and YAP1(C) is recommended to obtain staining patterns almost unique to MT. The biological significance of YAP1 in high-grade TETs warrants further investigation.

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Background: Metaplastic thymoma (MT), an exceedingly rare variant of primary thymic epithelial neoplasms, is distinguished by its indolent progression and unique histopathological profile. It presents a biphasic pattern characterized by solid epithelial and spindle cell components, potentially leading to diagnostic confusion with type A thymomas or the type A component of type AB thymomas. Accurate diagnosis is pivotal for optimal therapeutic strategies and prognostication. Case Description: We document an exceptional case of a 32-year-old woman, incidentally discovered to have a mediastinal nodule in the middle compartment on chest computed tomography (CT). The lesion was excised via video-assisted thoracoscopic surgery. Histological evaluation revealed a biphasic cellular architecture comprising epithelioid and spindle cells. Immunohistochemical analysis demonstrated significant positivity for CK5/6 and P40 in epithelial cells, and vimentin and epithelial membrane antigen in spindle cells, with a low proliferation index marked by Ki-67. Noteworthy, fluorescence in situ hybridization (FISH) analysis identified a YAP1::MAML2 gene fusion, with a predominant pattern suggestive of fusion gene presence, thus corroborating the diagnosis of MT. Conclusions: This report underscores the critical role of a multifaceted diagnostic approach, including histopathological, immunohistochemical, and genetic analyses, in the identification of MT. The detection of the YAP1::MAML2 gene fusion through FISH analysis provides a robust diagnostic marker, highlighting the necessity for clinical and pathological vigilance for this rare tumor.

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Presented are three casuistics of seemingly identical breast lesions which even by adopting advanced laboratory techniques may represent diagnostic challenge. Microscopic features of some bland spindle cell lesions of different histogenesis (epithelial or mesenchymal) are misleading and a potential source of unaware errors, which might affect optimal therapeutic strategy. In the setting of three diverse entities (low-grade spindle cell metaplastic carcinoma, desmoid fibromatosis and phyllodes tumor) is documented both demanding diagnostic algorithm and revealing molecular landscape on one side as well as evolving predictive/prognostic parameters on the other one. Close interdisciplinary cooperation is inevitable for accurate interpretation/understanding of revealed diagnostic facts which is required for adjustment of competent rational and individualized therapy.

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Metaplastic breast carcinoma (MBC) represents a rare subtype of breast cancer, characterized by poor prognostic indicators that have been recently identified. Clinical and radiological presentations often mimic other breast cancer types, necessitating immunohistochemistry (IHC) for accurate diagnosis. In this study, we report a case involving a 31-year-old female presenting with a painless, fixed, non-inflammatory mass in the left breast, which was confirmed as MBC. Treatment encompassed lumpectomy, chemotherapy, radiotherapy, and subsequent hormonal therapy. Understanding this rarely reported yet aggressive form of breast cancer holds significant importance for clinicians, enabling them to promptly establish a diagnosis and implement effective management strategies.

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BACKGROUND: Metaplastic breast cancer (MBC) is a rare type of breast carcinoma with clinicopathological differences. The prognosis and treatment strategies for MBC are usually conflicting. In this study, we aim to present the clinicopathologic features, treatment strategies, and prognosis of our MBC patients. MATERIAL AND METHODS: In our retrospective study, 18 metaplastic breast cancer patients treated in our institution between January 2005 and December 2022 were evaluated. Demographic and clinicopathological characteristics, surgical and systemic treatment options, locoregional recurrences, distant metastases, and overall survival (OS) of the MBC patients were retrieved from the patient files. RESULTS: All patients were female; the median age was 54.42 ± 12.37 years. Most of the patients (n = 15, 83.33%) presented with palpable masses. Tumors were mostly triple-negative, with a high grade and a high Ki­67 proliferation index. Spindle cell carcinoma and MBC with mesenchymal differentiation were the most common subtypes. Most of the patients underwent mastectomy (n = 11, 61.11%); breast-conserving surgery (BCS) was performed on seven (38,88%) patients. Lymph node positivity was detected in six of 18 patients (33.33%). Fewer patients (n = 4, 22.22%) received neoadjuvant chemotherapy. While local recurrence developed in two out of seven patients (28.57%) who underwent BCS, there was no local recurrence in patients who had mastectomy. The OS time varied according to tumor size and the presence of lymph node metastases (p <0.001; p = 0.005). CONCLUSION: Metaplastic breast cancer is genetically heterogeneous and resistant to conventional treatment strategies. Mastectomy is still the surgical treatment method that is performed more frequently and provides better local control for patients with metaplastic breast cancer.

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Metaplastic breast carcinoma (MBC) and gynecologic carcinosarcoma (GCS) are rare, clinically aggressive cancers that demonstrate epithelial components and mesenchymal or sarcomatoid components. In this study, we assessed PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in MBC and GCS. Overall, PD-L1 positivity using the SP142 clone was seen in 50 % of MBC and 51.9 % of GCS cases, with PD-L1 expression in tumor cells significantly higher in MBC cases (p = 0.034), and PD-L1 expression in immune cells similar in MBC and GCS cases. PD-L1 expression was significantly higher in epithelial components than in mesenchymal components in both MBC and GCS cases (p = 0.0005). TILs were low in the majority of MBC and GCS cases (≥ 10 %) and generally correlated with PD-L1 expression; however, many PD-L1 positive cases with low TILs were seen. PD-L1 expression using the 22C3 clone was additionally assessed, with positivity seen in 62.9 % of MBC cases and 30 % of GCS cases. Concordance between SP142 and 22C3 results was seen in 62.5 % of MBC cases and 80 % of GCS cases. Overall, our findings suggest that a subset of MBC and GCS cases may benefit from immune checkpoint inhibitor therapy. Our findings also illustrate unique aspects of PD-L1 expression patterns in these tumors which may harbor additional prognostic and therapeutic significance.

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Metaplastic thymoma is a rare thymic neoplasm that has generally been considered to follow a benign to indolent clinical course; however, 3 metaplastic thymomas with high-grade malignant transformation to sarcomatoid carcinoma have been reported. In recent years, both conventional metaplastic thymomas and this subset showing malignant transformation have been associated with recurrent YAP1::MAML2 fusions. We report a metaplastic thymoma showing transformation to squamous cell carcinoma, that to our knowledge is the fourth reported in the literature with transition to overtly malignant features and the first showing pure carcinomatous transformation, and in which YAP1::MAML2 fusion was demonstrated via next generation sequencing.

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A 62-year-old male presented with pain and haematuria starting 3 months before. The computed tomography showed focal and mural bladder thickening with ureteropelvic dilatation. The following transurethral bladder resection revealed a high-grade muscle-invasive urothelial carcinoma. In the subsequent cystoprostatectomy we found the same tumour, but adding focal tumour-associated stromal osseous metaplasia. Ossifying metaplasia is an extremely rare feature in urothelial carcinoma, with a few reported cases and represents a diagnostic challenge, mimicking radiotherapy-induced sarcoma or sarcomatoid carcinoma. (AU)

Varón de 62 años que consulta por dolor y hematuria desde hace 3 meses. En la tomografía computarizada se observó un engrosamiento focal y mural de la vejiga con dilatación ureteropélvica. La resección vesical transuretral reveló un carcinoma urotelial infiltrante de alto grado músculo-invasivo. En la cistoprostatectomía posterior encontramos el mismo tumor, pero añadiendo focos de metaplasia ósea estromal asociada al tumor. La metaplasia osificante es una característica extremadamente rara en el carcinoma urotelial, con algunos casos informados, y representa un desafío diagnóstico, ya que simula un sarcoma inducido por radioterapia o un carcinoma sarcomatoide. (AU)

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INTRODUCTION: Metaplastic breast carcinoma (MBC) is a rare form of breast cancer, comprising less than 1 % of all breast malignancies. Osseous differentiation is an extremely rare subtype of MBC, accounting for only 0.003-0.12 % of all breast cancer cases. CASE PRESENTATION: We report a case of advanced-stage metaplastic breast carcinoma with osseous differentiation. The patient received neoadjuvant chemotherapy, but then the tumor progressed to metastasis. Despite palliative surgery, and chemotherapy, the disease did not respond; the patient died shortly later. CLINICAL DISCUSSION: Metaplastic breast carcinoma with osseous differentiation often rapidly progressive, resistant to chemotherapy, and associated with a poor prognosis. Some studies in the literature suggest that MBC tends to spread through the blood rather than lymphatic spread and therefore leads to lung and bone metastases. CONCLUSION: These findings suggest that the role of neoadjuvant chemotherapy in this histopathological group is limited and its use should be carefully considered.

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Metaplastic thymoma is a rare biphasic thymic tumor with indolent behavior and recurrent YAP1::MAML2 gene rearrangement. Although the diagnosis of this tumor is usually straightforward based on hematoxylin and eosin (H&E) findings alone, cases with scant spindle-cell ("pseudosarcomatous stroma") components can be easily confused with more commonly occurring type A thymoma. We present a case of metaplastic thymoma with a sparse stroma-like spindle-cell component, discussing its histological and immunohistochemical hints and drawing attention to the visual similarity to type A thymoma. This is also the first published case of metaplastic thymoma with associated psoriasis.

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Sclerosing lesions of the breast encompass a spectrum of benign and malignant entities and often pose a diagnostic challenge. Awareness of key morphologic features and pitfalls in the assessment of morphology and immunophenotype is essential to avoid over- or underdiagnosis and ensure optimal clinical management. This review summarizes nonneoplastic sclerosing lesions such as radial scar/complex sclerosing lesion, sclerosing adenosis, sclerosing intraductal papilloma, sclerosing variants of ductal adenoma and nipple adenoma, and fibroadenoma with extensive sclerosis, including their clinical presentation, characteristic morphology, differential diagnostic considerations, appropriate immunohistochemical work-up, when needed, and the clinical significance. In addition, atypical or neoplastic entities (such as atypical ductal hyperplasia, ductal carcinoma in situ, low-grade adenosquamous carcinoma, and fibromatosis-like metaplastic carcinoma) that can involve these sclerosing lesions are also briefly discussed.

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BACKGROUND: Metaplastic breast carcinomas are a rare variant group of breast carcinomas. They are usually high-grade and triple-negative tumors. They often present with large primary tumor sizes. However, the involvement of axillary lymph nodes is infrequent at the time of diagnosis. Metaplastic breast carcinomas are associated with a worse prognosis and a poorer response to chemotherapy in comparison with other non-metaplastic triple-negative breast cancers. Up until this point, there are no specific treatment recommendations for metaplastic breast carcinomas beyond those intended for invasive breast cancer in general. CASE PRESENTATION: A 40-year-old woman complained of a palpable mass in her left axilla. On ultrasonography, the mass was solid, spindle-shaped, hypoechoic with regular borders, and exhibited decreased vascularity. At first, the mass appeared to be of a muscular origin. There was not any clinical nor ultrasonic evidence of a primary breast tumor. On magnetic resonance imaging, the axillary mass was a well-defined with regular borders, measuring 24 × 35 mm. Needle biopsy showed a spindle cell tumor with mild to moderate atypia. The subsequent surgical resection revealed a spindle cell neoplasm within a lymph node, favoring a metastatic origin of the tumor. The tumor cells lacked expression of estrogen, progesterone, and HER2 receptors. PET-CT scan indicated pathological uptake in the left breast. Accordingly, the patient was diagnosed with metaplastic breast cancer that had metastasized to the axillary lymph node. She commenced a combined chemotherapy regimen of doxorubicin and cyclophosphamide. After six treatment cycles, she underwent left modified radical mastectomy with axillary lymph node dissection. Pathological examination of the specimens revealed a total burn-out tumor in the breast due to excellent treatment response. There were no residual tumor cells. All dissected lymph nodes were free of tumor. At the one-year follow-up, the patient showed no signs of tumor recurrence. CONCLUSION: This report sheds light on a distinctive presentation of metaplastic breast carcinoma, emphasizing the need for vigilance in diagnosing this rare and aggressive breast cancer variant. In addition, the patient's remarkable response to chemotherapy highlights potential treatment avenues for metaplastic breast cancer.

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Metaplastic breast cancer is a rare, aggressive, and chemotherapy-resistant subtype of breast cancers, accounting for less than 1% of invasive breast cancers, characterized by adenocarcinoma with spindle cells, squamous epithelium, and/or mesenchymal tissue differentiation. The majority of metaplastic breast cancers exhibit the characteristics of triple-negative breast cancer and have unfavorable prognoses with a lower survival rate. This subtype often displays gene alterations in the PI3K/AKT pathway, Wnt/ß-catenin pathway, and cell cycle dysregulation and demonstrates epithelial-mesenchymal transition, immune response changes, TP53 mutation, EGFR amplification, and so on. Currently, the optimal treatment of metaplastic breast cancer remains uncertain. This article provides a comprehensive review on the clinical features, molecular characteristics, invasion and metastasis patterns, and prognosis of metaplastic breast cancer, as well as recent advancements in treatment strategies.

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