Endoscopic excision of breast fibroadenoma through inframammary fold: Feasibility, safety and medium-term outcomes.

INTRODUCTION: Endoscopic-assisted surgery for breast tumors has the advantage of inconspicuous scars, less breast volume loss, and nipple areolar distortion. A novel endoscopic-assisted technique through inframammary fold for excision of fibroadenomas is presented. MATERIALS AND SURGICAL TECHNIQUE: Endoscopic-assisted excision of fibroadenoma(s) through inframammary fold was performed in four patients after informed written consent via three ports (12, 5, and 5 mm). Breast Cancer Treatment Outcome Score-12 (BCTOS-12) was used to evaluate patient satisfaction after surgery. DISCUSSION: No intraoperative and wound complication was noted. On median follow-up of 26.5 months, patients reported satisfactory responses to aesthetic and functional outcomes. No scar related complications were noted. Endoscopic-assisted excision of fibroadenoma through inframammary fold can be a safe and feasible option with good aesthetic outcomes.

The potential mechanism of HIF-1α and CD147 in the development of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis, and the outcomes of common therapy were not favorable. METHODS: The samples of 84 patients with TNBC and 40 patients with breast fibroadenoma were collected in the pathology department specimen library of our hospital. The prognosis of patients was obtained through outpatient follow-up information, telephone and WeChat contacts, and medical records. The mRNA expression was analyzed using bioinformation and quantitative real-time polymerase chain reaction (qPCR). The protein expression was determined by hematoxylin-eosin staining and immunohistochemical staining. The results of survival analysis were visualized using Kaplan-Meier curves. RESULTS: The immunohistochemical staining showed that hypoxia-inducible factor-1alpha (HIF-1α) was mainly distributed in the nucleus and cytoplasm, while CD147 is mainly distributed in cell membrane and cytoplasm. The qPCR results exhibited that the expression level of HIF-1α and CD147 in TNBC tissue was significantly higher than that in breast fibroadenoma tissue. The expression of HIF-1α was related to the histological grade and lymph node metastasis in TNBC, and the expression of CD147 was related to Ki-67, histological grade and lymph node metastasis. There was a positive relationship between the expression of CD147 and HIF-1α. The upregulated expression of CD147 was closely related to the poor prognosis of OS in TNBC. CONCLUSION: CD147 could be a biomarker for the prognosis of TNBC and closely related to the expression of HIF-1α.

Fibroadenoma of the vulva with pseudoangiomatous stromal hyperplasia: A common neoplasm in uncommon site.

Mammary-type tissue in the vulva was first described in 1872 but has been rarely reported in the literature. This tissue was previously considered as ectopic breast tissue that occurs as a result of incomplete regression of the milk line. Similar to native breast tissue, ectopic mammary tissue is hormone-sensitive and can develop benign changes, such as fibroadenoma, as well as malignant changes. A more recent theory suggests that these benign and malignant mammary-type entities arise from mammary-like anogenital glands, which constitute normal vulvar components. We report a case of a 41-year-old woman who presented with a chronic asymptomatic cyst on the left vulva that eventually became uncomfortable, especially on standing. The cyst was located on the labium minus, measuring 1.0 × 0.5 cm, with no identified erythema or other skin abnormalities. Excision of the lesion and subsequent microscopic examination showed a circumscribed mass with a nodular overgrowth of epithelial and stromal components, resembling a mammary fibroadenoma with pseudoangiomatous stromal hyperplasia. We bring to attention this rare diagnosis and the importance of considering it in the presence of a vulvar lesion. The malignant and recurrence potential of mammary-type tissue necessitates excision with clear margins and close monitoring of these patients.

A prediction model based on digital breast pathology image information.

BACKGROUND: The workload of breast cancer pathological diagnosis is very heavy. The purpose of this study is to establish a nomogram model based on pathological images to predict the benign and malignant nature of breast diseases and to validate its predictive performance. METHODS: In retrospect, a total of 2,723 H&E-stained pathological images were collected from 1,474 patients at Qingdao Central Hospital between 2019 and 2022. The dataset consisted of 509 benign tumor images (adenosis and fibroadenoma) and 2,214 malignant tumor images (infiltrating ductal carcinoma). The images were divided into a training set (1,907) and a validation set (816). Python3.7 was used to extract the values of the R channel, G channel, B channel, and one-dimensional information entropy from all images. Multivariable logistic regression was used to select variables and establish the breast tissue pathological image prediction model. RESULTS: The R channel value, B channel value, and one-dimensional information entropy of the images were identified as independent predictive factors for the classification of benign and malignant pathological images (P < 0.05). The area under the curve (AUC) of the nomogram model in the training set was 0.889 (95% CI: 0.869, 0.909), and the AUC in the validation set was 0.838 (95% CI: 0.7980.877). The calibration curve results showed that the calibration curve of this nomogram model was close to the ideal curve. The decision curve results indicated that the predictive model curve had a high value for auxiliary diagnosis. CONCLUSION: The nomogram model for the prediction of benign and malignant breast diseases based on pathological images demonstrates good predictive performance. This model can assist in the diagnosis of breast tissue pathological images.

Double blind randomized controlled trial of efficacy of ormeloxifene for the treatment of fibroadenoma (The FIBROCENT study).

BACKGROUND: We evaluated the effectiveness of Ormeloxifene (Centchroman) on regression of Fibroadenoma in a double-blind randomized controlled trial. METHODS: Patients with biopsy proven Fibroadenoma were enrolled between March 2023 and October 2023 and divided in two arms- Ormeloxifene group and Placebo group. Effectiveness of the treatment was evaluated using USG. No residual mass was defined as complete regression and more than 30% decrease in size was considered as partial regression. RESULTS: A total of 130 consecutive patients with Fibroadenoma were randomized to Ormeloxifene group (n = 65) and Placebo Group (n = 65). Complete regression was observed in 9% (6/65) patients in Ormeloxifene group and 10.8% (7/65) in Placebo Group at the end of 12 weeks (p = 0.49). Twenty one patients taking Ormeloxifene reported adverse events as compared to none in the other group. CONCLUSION: In our study Ormeloxifene was not found to be effective in treatment of fibroadenoma and had concerning side effects.

Using the DNA Integrity Number to Analyze DNA Quality in Specimens Collected from Liquid-Based Cytology after Fine-Needle Aspiration of Breast Tumors and Lesions.

INTRODUCTION: Cancer genome analysis using next-generation sequencing requires adequate and high-quality DNA samples. Genomic analyses were conventionally performed using formalin-fixed paraffin-embedded sections rather than cytology samples such as cell block or smear specimens. Specimens collected from liquid-based cytology (LBC) have the potential to be sources of high-quality DNA suitable for genetic analysis even after long-term storage. METHODS: We collected breast tumor/lesion fractions from 92 residual LBC specimens using fine-needle aspiration (FNA) biopsy, including breast carcinoma (1 invasive carcinoma and 4 ductal carcinomas in situ), papillomatous lesion (5 intraductal papillomas), and fibroepithelial lesion (19 phyllodes tumors and 53 fibroadenomas) samples, and others (1 ductal adenoma, 1 hamartoma, 1 fibrocystic disease, and 7 unknown). DNA was extracted from all samples and subjected to DNA integrity number (DIN) score analysis. RESULTS: Average DIN score collected from 92 LBC specimens was significantly higher score. In addition, high-quality DNA with high DIN values (7.39 ± 0.80) was successfully extracted more than 12 months after storage of residual LBC specimens. CONCLUSION: Residual LBC specimens collected from FNA of the breast were verified to carry high-quality DNA and could serve as an alternate source for genetic analysis.

Atypia Involving Fibroadenomas: Outcomes and Upgrade Rates.

OBJECTIVE: Fibroadenomas (FAs) involved by atypia are rare. Consensus guidelines for management of FAs involved by atypia when diagnosed on image-guided biopsy do not exist because of limited data reporting surgical upgrade rates to ductal carcinoma in situ (DCIS) or invasive malignancy. Therefore, these lesions commonly undergo surgical excision. METHODS: This single-institution retrospective study identified cases of FAs involved by atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and/or lobular carcinoma in situ (LCIS) diagnosed on image-guided biopsy between January 2014 and April 2023 to determine upgrade rates. Cases with incidental atypia adjacent to but not involving FAs were excluded. RESULTS: Among 1736 FAs diagnosed on image-guided biopsy, 32 cases (1.8%) were FAs involved by atypia including 43.8% (14/32) ALH, 28.1% (9/32) ADH, 18.8% (6/32) LCIS, 6.3% (2/32) LCIS + ALH, and 3.1% (1/32) unspecified atypia. The most common imaging finding was a mass. Most cases, 81.3% (26/32), underwent subsequent surgical excisional biopsy. A single case of ADH involving and adjacent to an FA was upgraded to FA involved by low-grade DCIS on excision for an overall surgical upgrade rate of 3.8%. There were no cases upgraded to invasive malignancy. For those omitting surgical excision, there was no subsequent malignancy diagnosis at the FA biopsy site over a mean follow-up of 73 months. CONCLUSION: Cases of radiologic-pathologic concordant FAs involved by atypia have a low upgrade rate of 3.8% and should undergo multidisciplinary review. Larger multi-institutional analysis is needed to determine whether guidelines for excision of atypia should apply to atypia involving FAs.

Surgical management of a giant fibroadenoma during lactation.

Fibroadenomas are the most common breast lesion in women of reproductive age. During pregnancy and lactation, fibroadenomas can undergo rapid growth in response to hormonal stimulus. These changes may prompt further investigation and/or intervention due to the risk of an underlying phyllodes tumour. We present a case of a female patient who underwent surgical excision of a giant fibroepithelial lesion at 4 months post partum while continuing to breastfeed. The lesion was successfully excised while maintaining lactation. A postoperative milk fistula resolved with non-operative management. There is limited literature on the surgical management of breast lesions in lactating women. This case illuminates the surgical management of breast lesions in an often well informed group of patients who may choose to have surgery while lactating in spite of the increased risk of complications. This case also highlights the need for a holistic approach to maintain the overall health of mother and child.

Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Are both distinct epithelial and stromal cells molecular analysis from phyllodes tumors versus fibroadenoma components affected in breast fibroepithelial progression?

PURPOSE: To determine molecular events involved in the tumorigenesis of phyllodes tumors (PT) and the role of each stromal (SC) and epithelial (EC) cell. METHODS: Frozen breast samples enriched with epithelial and stromal cells from three fibroadenomas and 14 PT were retrieved and laser microdissected. Sanger and polymerase chain reaction-based sequencing of exon 2 MED12 and TERT promoter hotspot mutations were performed; 44K microarray platform was used to analyze gene expression. RESULTS: All three fibroadenomas (FAs) presented mutations in MED12, but not in TERT, whose mutation was observed in five of the 14 PTs. EC and SC of each affected tumor displayed identical alterations. Of the total differentially expressed genes (DEG) (EC = 1,543 and SC = 850), 984 were EC-eDEGs and 291 were SC-eDEGs. We found a high similarity of diseases and functions enriched by both cell types, but dissimilarity in the number of enriched canonical pathways. Three signaling canonical pathways overlapping with EC and SC were predicted to be activated in one cell type and inactivated in the other, while no overlap in eDEGs was assigned to them. We also identified 13 EC-eDEGs and five SC-eDEGs enriched networks, in which the SC-eDEGs were able to segregate FA from PT samples. CONCLUSIONS: Identical TERT mutations from both SC and ES origins might affect the PTs tumorigenesis. Gene expression differences suggest coordinated molecular processes between these components with determinant differences acquired by SC, able to fully distinguish PTs from FAs lesions.

Precise diagnosis of breast phyllodes tumors using Raman spectroscopy: Biochemical fingerprint, tumor metabolism and possible mechanism.

BACKGROUND: Breast fibroadenomas and phyllodes tumors are both fibroepithelial tumors with comparable histological characteristics. However, rapid and precise differential diagnosis is a tough point in clinical pathology. Given the tendency of phyllodes tumors to recur, the difficulty in differential diagnosis with fibroadenomas leads to the difficulty in optimal management for these patients. METHOD: In this study, we used Raman spectroscopy to differentiate phyllodes tumors from breast fibroadenomas based on the biochemical and metabolic composition and develop a classification model. The model was validated by 5-fold cross-validation in the training set and tested in an independent test set. The potential metabolic differences between the two types of tumors observed in Raman spectroscopy were confirmed by targeted metabolomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: A total of 204 patients with formalin-fixed paraffin-embedded (FFPE) tissue samples, including 100 fibroadenomas and 104 phyllodes tumors were recruited from April 2014 to August 2021. All patients were randomly divided into the training cohort (n = 153) and the test cohort (n = 51). The Raman classification model could differentiate phyllodes tumor versus fibroadenoma with cross-validation accuracy, sensitivity, precision, and area under curve (AUC) of 85.58 % ± 1.77 %, 83.82 % ± 1.01 %, 87.65 % ± 4.22 %, and 93.18 % ± 1.98 %, respectively. When tested in the independent test set, it performed well with the test accuracy, sensitivity, specificity, and AUC of 83.50 %, 86.54 %, 80.39 %, and 90.71 %. Furthermore, the AUC was significantly higher for the Raman model than that for ultrasound (P = 0.0017) and frozen section diagnosis (P < 0.0001). When it came to much more difficult diagnosis between fibroadenoma and benign or small-size phyllodes tumor for pathological examination, the Raman model was capable of differentiating with AUC up to 97.45 % and 95.61 %, respectively. On the other hand, targeted metabolomic analysis, based on fresh-frozen tissue samples, confirmed the differential metabolites (including thymine, dihydrothymine, trans-4-hydroxy-l-proline, etc.) identified from Raman spectra between phyllodes tumor and fibroadenoma. SIGNIFICANCE AND NOVELTY: In this study, we obtained the molecular information map of breast phyllodes tumors provided by Raman spectroscopy for the first time. We identified a novel Raman fingerprint signature with the potential to precisely characterize and distinguish phyllodes tumors from fibroadenoma as a quick and accurate diagnostic tool. Raman spectroscopy is expected to further guide the precise diagnosis and optimal treatment of breast fibroepithelial tumors in the future.

Breast development and disorders in children and adolescents.

Breast masses are infrequently encountered in pediatric and adolescent populations. Most breast masses in children are benign entities arising from embryological defects which can be managed once breast development is complete. Diagnostic and management dilemmas arise when fibroepithelial lesions of the breast are seen in clinical practice. Differentiation between a fibroadenoma and a phyllodes tumor is important to guide management. Breast cancer in children under 18 years of age is extremely rare and invasive diagnostic testing and aggressive management is only recommended when clinical suspicion of malignancy is very high. Patient and caregiver counseling plays an important role in the management of these diseases. While adult-onset breast diseases have been studied very closely, there is a dearth of literature on pediatric breast anomalies. This review aims to provide a scoping overview of the available literature on benign, fibroepithelial, and malignant lesions of the breast in pediatric and adolescent populations to help guide physicians and surgeons with decision-making regarding the diagnosis and management of pediatric breast diseases.

A rapidly growing fibroadenoma in a pregnant woman: A case report.

BACKGROUND: Fibroadenomas are the most common benign breast lesions in women. They present as a unilateral mass and can rapidly enlarge in size through hormonal changes. Fibroadenomas could be classified as small or giant, and as simple or complex. They are classified as 'giant' when the size exceeds 5 cm and/or weight 500 gram; and as 'complex' if one of the following characteristics is present: cysts with a size >3 mm, epithelial calcifications, sclerosing adenosis and papillary apocrine metaplasia. Giant fibroadenomas can cause compression of surrounding breast tissue or breast asymmetry, requiring surgical excision in order to preserve a normal breast shape. CASE: A 26-year-old pregnant woman was referred with a palpable mass of her right breast. The mass rapidly increased in size to a diameter of 13 cm during the second trimester of her pregnancy. A tru-cut biopsy confirmed a fibroadenoma. The rapid growth and compression of normal breast tissues indicated a lumpectomy during her pregnancy. The mass was easily excised without any consequences for the pregnancy. Pathological examination showed a complex giant fibroadenoma. CONCLUSION: A unique case of a pregnant woman with rapid progression of a fibroadenoma that met the criteria of a complex and giant fibroadenoma, was presented. This case emphasizes the importance of timely surgical intervention, even during pregnancy, to prevent permanent breast tissue damage.

Incidental DCIS within a fibroadenoma.

A female in her early 20s was referred to the breast-endocrine surgeons with a self-detected tender left breast lump on the background of a family history of breast cancer. A physical examination revealed a rubbery and mobile mass in the left upper breast. Ultrasound demonstrated a solid hypoechoic mass with a likely differential diagnosis of fibroadenoma, with a subsequent core needle biopsy (CNB) confirming a fibroadenoma. Given the size and tenderness of the lump, an excisional biopsy was performed. Histology revealed a fibroadenoma with components of low-grade ductal carcinoma in situ, contained within the fibroadenoma and excised with clear margins.Following surgical excision, a multidisciplinary review determined that no further local therapy was required and recommended a genetics referral. This case was interesting as it raised important questions, including what the best surveillance strategies are for female patients with breast cancer within fibroadenoma and determining the risk and probability of missing epithelial atypia via CNB.

Efficacy and safety of vacuum-assisted excision (VAE) of fibroadenomas: experience in a tertiary centre.

PURPOSE: To evaluate the technical success and efficacy rates of US-guided percutaneous vacuum-assisted excision (VAE) of breast fibroadenomas, also assessing procedural complications and long-term patient satisfaction rates. MATERIALS AND METHODS: The institutional database of a tertiary breast cancer referral centre was retrospectively reviewed to retrieve all women with fibroadenomas who underwent US-guided VAE between May 2011 and September 2019. We subsequently included in this study all fibroadenomas with a maximum diameter of 3 cm at US and an available histological confirmation obtained by core-needle biopsy before VAE. Immediately after VAE, technical success (defined as the correct VAE execution) and the occurrence of procedural complications were evaluated. Imaging follow-up (US ± mammography) after 6, 12, 24 and 36 months was performed to evaluate technical efficacy (defined as the absence of fibroadenoma recurrence at 6-month follow-up). Long-term patient satisfaction was evaluated with telephonic interviews in October 2022. RESULTS: We retrospectively included 108 women (median age 46 years) with 110 fibroadenomas diagnosed at core-needle biopsy with a median lesion size at US of 12 mm. Technical success was obtained in 110/110 VAEs (100%). Minor procedural complications (haematomas) occurred in 7/110 VAEs (6%), whereas 8/110 patients had a fibroadenoma recurrence at 6-month follow-up, resulting in a 93% technical efficacy (102/110 VAEs). All patients available for telephonic follow-up (104/104, 100%) reported high satisfaction with VAE results. CONCLUSION: US-guided VAE is a safe and effective procedure for the excision of fibroadenomas, representing a viable alternative to surgery, with a low complication rate and high patient satisfaction.

Cytomorphological patterns of breast lesions among women with palpable breast lumps attending select teaching and referral hospitals in Kenya: a descriptive cross-sectional study.

Introduction: breast lumps account for a greater number of lesions in women attending surgical clinics in the developing world. Breast cancer which mostly presents as a breast lump is the leading cancer in Kenya, with an incidence of 12.5%. The study aims to describe the patterns of breast lesions in women presenting with palpable breast lumps in two major referral hospitals in Kenya. Methods: seven hundred and sixty-eight study participants with palpable lumps underwent fine needle aspiration cytology (FNAC). Sociodemographic data were captured using structured questionnaires. The FNAC materials were evaluated using the International Academy of Cytology Yokohama System (IACYS) and the lesions were classified into five-tier categories. Frequencies and percentages were used to summarize qualitative variables. Results: of 768 smears, 84.8% (n=651) were adequate for evaluation while 15.2% (n=117) were inadequate. Neoplastic lesions comprised 84.5% (n=550) and non-neoplastic 15.5% (n=101). Benign lesions accounted for 83.6% of the lesions followed by breast carcinoma (10.4%). Ductal carcinoma comprised 98.5% of cancerous lesions. The age group most affected with ductal carcinoma and suspicious lesions was 20-34 years (37.3% and 55.6% respectively). Fibroadenoma formed the bulk of the benign lesions identified (44.1%). Suspicious of malignancy was 4.1% (n=27). The age group with the most lesions (47.5%) was 20-34 years. Conclusion: a wide spectrum of breast lesions was established. Such include inflammatory, atypical, benign, suspicious of malignancy, and malignant lesions. Fibroadenoma was a common lesion diagnosed. The age group most affected by malignant lesions was 16-49 years, necessitating enhanced screening of women with breast lumps in our setups.

Differentiation between Phyllodes Tumors and Fibroadenomas through Breast Ultrasound: Deep-Learning Model Outperforms Ultrasound Physicians.

The preoperative differentiation of breast phyllodes tumors (PTs) from fibroadenomas (FAs) plays a critical role in identifying an appropriate surgical treatment. Although several imaging modalities are available, reliable differentiation between PT and FA remains a great challenge for radiologists in clinical work. Artificial intelligence (AI)-assisted diagnosis has shown promise in distinguishing PT from FA. However, a very small sample size was adopted in previous studies. In this work, we retrospectively enrolled 656 breast tumors (372 FAs and 284 PTs) with 1945 ultrasound images in total. Two experienced ultrasound physicians independently evaluated the ultrasound images. Meanwhile, three deep-learning models (i.e., ResNet, VGG, and GoogLeNet) were applied to classify FAs and PTs. The robustness of the models was evaluated by fivefold cross validation. The performance of each model was assessed by using the receiver operating characteristic (ROC) curve. The area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated. Among the three models, the ResNet model yielded the highest AUC value, of 0.91, with an accuracy value of 95.3%, a sensitivity value of 96.2%, and a specificity value of 94.7% in the testing data set. In contrast, the two physicians yielded an average AUC value of 0.69, an accuracy value of 70.7%, a sensitivity value of 54.4%, and a specificity value of 53.2%. Our findings indicate that the diagnostic performance of deep learning is better than that of physicians in the distinction of PTs from FAs. This further suggests that AI is a valuable tool for aiding clinical diagnosis, thereby advancing precision therapy.

Gene Expression Profiling of Fibroepithelial Lesions of the Breast.

Fibroepithelial lesions of the breast (FELs) are a heterogeneous group of neoplasms exhibiting a histologic spectrum ranging from fibroadenomas (FAs) to malignant phyllodes tumors (PTs). Despite published histologic criteria for their classification, it is common for such lesions to exhibit overlapping features, leading to subjective interpretation and interobserver disagreements in histologic diagnosis. Therefore, there is a need for a more objective diagnostic modality to aid in the accurate classification of these lesions and to guide appropriate clinical management. In this study, the expression of 750 tumor-related genes was measured in a cohort of 34 FELs (5 FAs, 9 cellular FAs, 9 benign PTs, 7 borderline PTs, and 4 malignant PTs). Differentially expressed gene analysis, gene set analysis, pathway analysis, and cell type analysis were performed. Genes involved in matrix remodeling and metastasis (e.g., MMP9, SPP1, COL11A1), angiogenesis (VEGFA, ITGAV, NFIL3, FDFR1, CCND2), hypoxia (ENO1, HK1, CYBB, HK2), metabolic stress (e.g., UBE2C, CDKN2A, FBP1), cell proliferation (e.g., CENPF, CCNB1), and the PI3K-Akt pathway (e.g., ITGB3, NRAS) were highly expressed in malignant PTs and less expressed in borderline PTs, benign PTs, cellular FAs, and FAs. The overall gene expression profiles of benign PTs, cellular FAs, and FAs were very similar. Although a slight difference was observed between borderline and benign PTs, a higher degree of difference was observed between borderline and malignant PTs. Additionally, the macrophage cell abundance scores and CCL5 were significantly higher in malignant PTs compared with all other groups. Our results suggest that the gene-expression-profiling-based approach could lead to further stratification of FELs and may provide clinically useful biological and pathophysiological information to improve the existing histologic diagnostic algorithm.