Integrating single-cell and spatial transcriptomes reveals COL4A1/2 facilitates the spatial organisation of stromal cells differentiation in breast phyllodes tumours.

BACKGROUND: Breast phyllodes tumours (PTs) are a unique type of fibroepithelial neoplasms with metastatic potential and recurrence tendency. However, the precise nature of heterogeneity in breast PTs remains poorly understood. This study aimed to elucidate the cell subpopulations composition and spatial structure and investigate diagnostic markers in the pathogenesis of PTs. METHODS: We applied single-cell RNA sequencing and spatial transcriptomes on tumours and adjacent normal tissues for integration analysis. Immunofluorescence experiments were conducted to verify the tissue distribution of cells. Tumour cells from patients with PTs were cultured to validate the function of genes. To validate the heterogeneity, the epithelial and stromal components of tumour tissues were separated using laser capture microdissection, and microproteomics data were obtained using data-independent acquisition mass spectrometry. The diagnostic value of genes was assessed using immunohistochemistry staining. RESULTS: Tumour stromal cells harboured seven subpopulations. Among them, a population of widely distributed cancer-associated fibroblast-like stroma cells exhibited strong communications with epithelial progenitors which underwent a mesenchymal transition. We identified two stromal subpopulations sharing epithelial progenitors and mesenchymal markers. They were inferred to further differentiate into transcriptionally active stromal subpopulations continuously expressing COL4A1/2. The binding of COL4A1/2 with ITGA1/B1 facilitated a growth pattern from the stroma towards the surrounding glands. Furthermore, we found consistent transcriptional changes between intratumoural heterogeneity and inter-patient heterogeneity by performing microproteomics studies on 30 samples from 11 PTs. The immunohistochemical assessment of 97 independent cohorts identified that COL4A1/2 and CSRP1 could aid in accurate diagnosis and grading. CONCLUSIONS: Our study demonstrates that COL4A1/2 shapes the spatial structure of stromal cell differentiation and has important clinical implications for accurate diagnosis of breast PTs.

Malignant phyllodes tumour of the breast with early recurrence in a young patient.

A young woman in her 20s was found to have a left breast malignant phyllodes tumour by ultrasound-guided core needle biopsy, after identifying a palpable lump. She then underwent lumpectomy excision with >1 cm gross margins; however, final pathology demonstrated <1 cm margins at the superior margin. She then underwent re-excision of superior and medial margins to ensure at least a 1 cm margin. Biopsy tract was not excised at initial or re-excision surgery. Approximately 6 weeks after completion lumpectomy, the patient noted a new palpable mass near the previous biopsy site and underwent punch biopsy. Final pathology of this new mass was concordant with early recurrence. The patient then underwent lumpectomy of the new mass along with excision of the overlying skin and biopsy tract with >1 cm margins.

Benign phyllodes tumour in a transgender woman receiving hormonal therapy.

We present a case of a transwoman taking hormonal feminisation therapy for over 20 years, who underwent surgical excision of a benign phyllodes tumour of the breast. Hormones progesterone and oestrogen act on breast epithelium to increase proliferation. For ciswomen, endogenous and exogenous oestrogen exposure over a lifetime is associated with increased risk for certain benign and malignant breast pathologies. Transwomen taking hormonal therapy may also be at an increased risk of breast disease.

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.

Surgical Management and System Therapy of the Most Giant Known Malignant Metastatic Breast Phyllodes Tumor: A Case Report and Review of the Literature.

INTRODUCTION: Phyllodes tumors belong to uncommon fibroepithelial breast tumors with a range of biological behaviors. Phyllodes tumors are responsible for less than 1 percent of all neoplasms of the breast. CASE PRESENTATION: A 66-year-old woman presented to our Breastcancer Unit in March 2021 because of a huge mass of her left breast with bleeding out of a tumor necrosis. Five years ago in 2016, a benign phyllodes tumor was diagnosed externally. When we started the treatment, the tumor had a weight of 18.6 kg. CONCLUSION: We describe the surgical management and the systemic treatment of metastatic disease.

Real-world data on malignant and borderline phyllodes tumors of the breast: A population-based study of all 921 cases in the Netherlands (1989 -2020).

AIM: The aim of our study is to analyze patterns in treatment and outcome in a population-based series of patients with borderline and malignant phyllodes tumors (PT). MATERIAL AND METHODS: Data on all patients with a borderline or malignant PT (1989-2020) were extracted from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga) and retrospectively analyzed. RESULTS: We included 921 patients (borderline PT n = 452 and malignant PT n = 469). Borderline PT patients more often had breast-conserving surgery (BCS) as final surgery (81 vs. 46%). BCS rates for borderline PT increased over time (OR 1.08 per year, 95%CI 1.04 - 1.13, P < 0.001). In malignant PT adjuvant radiotherapy was given in 14.7%; this rate increased over time (OR 1.07 per year, 95%CI 1.02 - 1.13, P = 0.012). Local recurrence rate (5-year estimate of cumulative incidence) was 8.7% (95%CI 6.0-11.4) for borderline PT and 11.7% (95%CI 8.6-14.8) for malignant PT (P = 0.187) and was related to tumor size ≥ 20 mm (HR 10.6 (95%CI 1.5-76.8) and positive margin (HR 3.0 (95%CI 1.6-5.6), p < 0.001), but not to negative margin width (HR 1.3 ( 95%CI 0.7-2.3), p = 0.350)). Distant metastasis occurred only in malignant PT with a 5-year cumulative incidence of 4.7% (95%CI 3.3 - 6.1). CONCLUSION: This population-based series showed an increase in BCS in borderline PT and an increase in adjuvant radiotherapy in malignant PT over time. We identified malignant PT, BCS, larger tumor size and positive final margins as possible risk factors for local recurrence. Small but negative margins can be accepted.

Adenomyoepithelial adenosis mimicking phylloides: A diagnostic dilemma.

Benign proliferative breast diseases are well recognized in young females. Benign biphasic proliferation of epithelial and myoepithelial cells has been observed, among which adeno-myoepithelial adenosis is one of the rare morphologies published in the literature with the tendency to recur and poses a risk for low-grade malignant transformation. Here, we report a case of a young female who had a history of recurrent breast lump mimicking phyllodes tumor and eventually diagnosed as adeno-myoepithelial adenosis on histopathological examination. Benign proliferative breast diseases are well recognized in young females. Benign biphasic proliferation of epithelial and myoepithelial cells has been observed, among which adeno-myoepithelial adenosis is one of the rare morphologies published in the literature with the tendency to recur and poses a risk for low-grade malignant transformation. Here, we report a case of a young female who had a history of recurrent breast lump mimicking phyllodes tumor and eventually diagnosed as adeno-myoepithelial adenosis on histopathological examination.

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.

Malignant phyllodes tumor and invasive lobular breast carcinoma: Morpho-molecular characterization of an uncommon collision tumor and review of the literature.

Phyllodes tumor (PT) of the breast is a biphasic neoplasia composed of mesenchymal and epithelial cells. PTs are graded as benign, borderline or malignant according to histological criteria. Invasive lobular carcinoma (ILC) is a special breast cancer subtype defined by non-cohesive growth and loss of E-cadherin. PT is treated by resection. ILC is treated by resection and adjuvant endocrine therapy with or without chemotherapy. Collision tumors composed of PT and concurrent ILC are rare. Due to their dissociated growth, ILC cells may escape histologic detection when admixed with PTs. Here we report the case of a 71-years-old female diagnosed with a PT/ILC collision tumor. The patient presented with a tumor in the right breast. A core needle biopsy showed mesenchymal spindle cell proliferates suspicious for a PT. The resection specimen confirmed a malignant PT with stromal overgrowth. Unexpectedly, the resection specimen also revealed sparse infiltrates of ILC admixed with the PT. Immunohistochemistry of mesenchymal PT cells and ILC cells was consistent with the histomorphological diagnosis. Molecular analyses demonstrated a IDH1 variant of unknown significance and GNAS gene mutation in microdissected PT tissue. ILC tissue showed wild-type IDH1 and GNAS, but harbored CDH1/E-cadherin and TP53 gene mutations, arguing against clonal relatedness of the two lesions. Review of the literature identified six reported PT/ILC collision tumors, involving three benign, two borderline and one malignant PT. In summary, this is the second report on a malignant PT/ILC collision tumor. Correct histologic diagnosis of PT/ILC collision tumors is clinically relevant, because adjuvant endocrine therapy is mandatory for ILC.

Multidisciplinary Management of Phyllodes Tumours and Breast Sarcoma: A Cross-sectional Survey of Clinical Practice across the UK and Ireland.

AIMS: Phyllodes tumours and breast sarcomas are uncommon tumours and their rarity poses significant challenges in diagnosis and management. This cross-sectional study was conducted to evaluate the multidisciplinary clinical practice for these tumours across the UK and Ireland, with the aim of identifying gaps in knowledge and providing direction for establishing national guidelines. MATERIALS AND METHODS: An international survey was adapted and circulated to breast and/or sarcoma surgeons and oncologists in the UK and Ireland through national organisations. Multidisciplinary team (MDT) responses were analysed anonymously. RESULTS: Twenty-eight MDTs participated in this study, predominately from high-volume units (85.5%). Although only 43% of the surveyed units were part of a trust that holds a sarcoma MDT, 68% of units managed malignant phyllodes and angiosarcoma, whereas 64.5% managed soft-tissue sarcoma of the breast. Across all subtypes, axillary surgery was recommended by 14-21% of the MDTs and the most recommended resection margins for breast surgery were 'no tumour on ink' in benign phyllodes (39%) and 10 mm in the remaining subtypes (25-29%). Immediate breast reconstruction was supported by 11-18% of MDTs for breast sarcoma subtypes, whereas 36% and 32% advocated this approach in benign and borderline phyllodes tumours, respectively. Adjuvant radiotherapy and chemotherapy were recommended by up to 29% and 11% of the MDTs, respectively. CONCLUSION: The results of this study demonstrate a wide variation in clinical practice across the surveyed MDTs. As only 28 MDTs participated in our study, with under-representation from low-volume units, our results might be an underestimation of the variability in practice across the UK and Ireland. This multi-institutional study sheds light on controversial aspects in the management of phyllodes tumours and breast sarcoma, identifies the need for national guidelines to inform best practice, and calls for the centralisation of the management of breast sarcoma within specialist centres.

Margin status impact on recurrence of phyllodes tumors in high-risk groups: a retrospective observational study.

BACKGROUND: Phyllodes tumor (PT) is an fibroepithelial tumor with potential for local recurrence. The optimal margin for surgical resection of PT is still debated, particularly in cases of positive margins. This study aimed to identify the risk factors for phyllodes tumor recurrence and the effect of a free margin on tumor recurrence by considering these risk factors. MATERIALS AND METHODS: This is a retrospective observational study of patients diagnosed with PT who had undergone surgical management. The data were collected from medical records from 2001 to 2020 in the breast clinic of Shahid Motahhari Clinic of Shiraz. Patients were followed up for at least 3 years after the operation to be checked for local recurrence or distant metastasis at regular intervals. RESULTS: This retrospective study included 319 patients with PT who underwent surgical management. Of these patients, 83.9% (n = 267), 7.6% (n = 24), and 8.5% (n = 27) were classified as benign, borderline, and malignant, respectively. 8.8% of all patients and 7.6% of non-malignant cases experienced local recurrence, and risk factors for recurrence included oral contraceptive use, smoking, size > 4 cm, stromal overgrowth, and stromal cell atypia. A negative surgical margin decreased the prevalence of recurrence in tumors > 4 cm and with stromal overgrowth significantly. CONCLUSION: The study found that a negative margin in all patients did not reduce the recurrence rate in benign and borderline phyllodes tumors, suggesting close follow up as a reasonable alternative. However, a negative margin may be effective in reducing recurrence in certain high-risk groups.

Stromal Ki67 Expression Might be a Useful Marker for Distinguishing Fibroadenoma From Benign Phyllodes Tumor of the Breast.

Background. Fibroadenoma (FA) and benign phyllodes tumor (PT) of the breast often have similar appearances on imaging. While an exact diagnosis of biopsy specimens is required to choose adequate treatment, including surgical procedures, it is sometimes difficult to pathologically differentiate these 2 tumors due to histological resemblances. To elucidate markers for distinguishing FA from benign PT, we analyzed clinical samples immunohistochemically. Methods. We retrospectively investigated 80 breast fibroepithelial lesions. As a discovery set, 60 surgical excision samples (30 FA and 30 benign PT) were examined. Twenty biopsy samples (10 FA and 10 benign PT) were examined as a validation set. To determine targets for immunohistochemistry, we first tested some proteins based on previous reports. As a result, Ki67 was chosen for differentiating FA and PT; thus further examinations were conducted with this protein. Results. Among the proteins examined, stromal Ki67 was significantly higher in PT than in FA. Benign PT had significantly higher stromal Ki67 expression both at random and at hotspots (p < .001 and <.001, respectively). The receiver operating characteristic curve analysis identified 3.5% and 8.5% (at random spots and hotspots, respectively) as the optimal cutoff values of stromal Ki67 for distinguishing between these 2 tumors. In the validation cohort employing needle biopsy specimens, we confirmed that these 2 cutoff values properly classified these 2 tumors (p = .043 and .029, respectively). Conclusion.We revealed that stromal Ki67 might be a potential marker for distinguishing FA from benign PT.

Clinical and radiological evaluation of a phyllodes tumor of the breast: a case report.

Phyllodes tumors (PTs) are rare breast tumors characterized by varying biological behavior and heterogeneous clinical findings. As a result, accurately diagnosing PTs preoperatively is challenging, often leading to misdiagnosis. A 49-year-old patient presented with a steadily growing right breast mass that had persisted over a 10-year period. Breast mammography and ultrasonography results indicated the presence of a PT. Following a lumpectomy, the patient was diagnosed with a borderline PT. However, nearly 1 year later, she was readmitted due to the recurrence of a palpable mass at the site. Consequently, 1 year and 8 months after the initial operation, she underwent thoracoscopic lobectomy to address solitary lung metastases. Subsequently, the patient experienced brain metastasis and massive hemorrhage 14 months later. Long-term follow-up was recommended. This case study presents an instance of borderline PT with clinical and imaging features that are crucial for guiding clinical operations and evaluating patient prognosis.

Epithelial Carcinomas Arising within Phyllodes Tumours of the Breast: A Review of Their Pathological Characteristics.

Epithelial proliferation is a common feature of phyllodes tumours (PTs), but epithelial malignancy is rare. This review seeks to further our understanding of epithelial malignancy within PTs by analysing their histopathological characteristics in previously reported cases and providing an overview of studies on their pathological features. PubMed and DeepDyve were searched for case reports, case series, and literature reviews of in situ and invasive carcinoma within PTs. Only cases where the carcinoma was within the PT were included. Cases of synchronous carcinoma in the ipsilateral or contralateral breast were excluded. Ninety-eight cases of in situ or invasive carcinoma within a PT were identified. Across the grades of PTs, there was a similar proportion of invasive carcinomas compared to in situ lesions. Malignant PT correlates with a higher likelihood of epithelial malignancy, and molecular studies support a possible causal pathophysiological relationship. This higher likelihood may suggest interactions between malignant stroma and the transforming epithelium that could potentially play a significant role in the phenomenon, which remains to be elucidated. Encasement within a PT likely improves the prognosis of breast carcinoma due to earlier detection. The presence of carcinoma within a malignant PT has uncertain prognostic implications. Thorough sampling of all PTs is recommended for appropriate prognostication and management.

Primary malignant phyllodes tumors of the breast: A retrospective analysis from a referral center.

BACKGROUND: The treatment for primary malignant phyllodes tumors of the breast (B-MPT) consists of wide local excision with negative margins (≥1 cm). However, because of their rarity, prognostic factors, type of surgery and adjuvant treatments are still a matter of debate. METHODS: We conducted a single-center retrospective study to describe outcomes and prognostic factors of patients with primary B-MPT, who underwent breast surgery from January 2000 to December 2021. The primary endpoint was the cumulative incidence of any recurrence. Secondary endpoints were the cumulative incidences of distant and local recurrences. RESULTS: 131 patients were included, of whom all received surgery, 5 adjuvant anthracycline-based chemotherapy and 15 radiation therapy. After a median follow-up of 6.4 years, the cumulative incidences at 5-years of any, local and distant recurrences were of 26% (95% Confidence Interval [CI], 4-34%), 16% (95%CI, 10-24%) and 10% (95%CI, 5.3-16%), respectively. Tumor size ≥ 5 cm was associated with higher distant recurrences (p = 0.05); instead, among small tumors (<5 cm), distant recurrences were higher in those with heterologous differentiation and/or multifocal disease (p = 0.06). Type of breast surgery (mastectomy vs. lumpectomy/excision) was not found to be significantly associated with distant (p = 0.32) or local (p = 0.17) recurrence, even after controlling local recurrence incidence for negative pathologic prognostic factors (p = 0.17). CONCLUSIONS: The natural history of B-MPT is burdened by local and distant recurrences. Pathologic prognostic factors (i.e., tumor size, heterologous differentiation and multifocal disease) more than the type of wide breast surgery (mastectomy vs. lumpectomy) seem to represent the most significant prognostic factor for recurrences.

Malignant phyllodes tumour with lymph node metastasis: a diagnostic conundrum resolved by next generation DNA sequencing.

A malignant neoplasm with spindle cell and chondroid differentiation in the breast, metastatic to lymph node. In this context, a metaplastic carcinoma is typically favored given the exceptional nature of lymph node metastases in malignant phyllodes tumors (MPT). However, we demonstrate pathognomonic hotspot mutations in MED12 and the promoter of the TERT gene by targeted next-generation DNA sequencing, supporting a diagnosis of MPT.

Malignant Phyllodes Tumor in a Pubertal Girl: A Report of a Case.

BACKGROUND: Malignant phyllodes tumor (MPT) is a rare breast disease that is extremely rare in children. A few cases of pediatric malignant phyllodes tumors have been reported, including some with a poor prognosis. CASE: A 14-year-old girl presented with a growing lump on her right breast. On the basis of imaging tests and a core needle biopsy, MPT was diagnosed, and right mastectomy was performed. The postoperative course was uneventful. SUMMARY AND CONCLUSION: MPT is an infrequent disease in adult females and is extremely rare in pubertal females. It occasionally shows rapid growth, metastasis, and recurrence with a poor prognosis. Early surgical resection is necessary to obtain a cure. When a rapidly growing breast tumor is observed in pubertal females, MPT should be considered.

Surgical Bedside Electrochemotherapy for Local Control of a Recurrent Phylloid Malignant Breast Tumor: A Case Report.

BACKGROUND: We present the case of a recurrent malignant phyllodes tumor of the breast, after mastectomy and radiotherapy, in which electrochemotherapy (ECT) was applied to the tumor bed, to achieve better local control. CASE REPORT: A 66-year-old woman with a large malignant phyllodes tumor of the right breast with a size of 40 cm underwent right radical mastectomy and right axillary lymph node sampling. One month after surgery, with histologically clear margins, the woman presented with multiple small oval masses in the upper portion of the chest wall, indicating rapid disease progression. A second radical excision with clear margins was performed, followed by adjuvant radiotherapy. Two months after the end of treatment, a new 3-cm mass was present in the right axillary extension. The patient underwent a third extensive debulking surgery. At the end of the resection, ECT was applied on the tumor bed along the extensive skin flaps and resection margins. After eight months of follow-up, breast magnetic resonance imaging and total body computed tomography showed disease recurrence in the anterior portion of the right serratus muscle and in the lungs bilaterally. The area undergoing previous ECT showed no disease recurrence. The patient received two lines of palliative chemotherapy. She died 28 months after diagnosis. At the time of death, the large area treated with ECT was geometrically spared from local disease progression. CONCLUSION: This case report suggests the potential efficacy of ECT at the operating bedside to increase local control in aggressive malignancies.

A case report of a patient with ductal carcinoma and a malignant phyllodes tumor in situ in 2 separate breasts.

RATIONALE: Breast malignant phyllodes tumors (MPT) are quite uncommon. It is rarely reported that they occur in conjunction with breast cancer. We detailed a case in which an MPT and ductal carcinoma in situ carcinoma occurred simultaneously in 2 different breasts. PATIENT CONCERNS: A 79-year-old female patient was seen for a rapidly growing lump in the upper left quadrant of her breast. The lump was described as huge, hard, irregular, and palpable. MRI of the breasts revealed a big mass in the left breast and a smaller lump in the right. DIAGNOSIS: Ductal carcinoma in situ with breast MPT. INTERVENTIONS: We performed a double mastectomy. Post-operative endocrine treatment was suggested. OUTCOMES: During the 18-month follow-up period, no signs of recurrence or metastasis were seen. The ultrasound examination of the chest wall showed no abnormality. Bilateral axillary and supraclavicular ultrasonography showed no lymphadenectasis and a CT scan of the lungs showed no suspicious cancer nodules. LESSONS: It is possible for MPT and ductal carcinoma in situ to occur simultaneously in different breasts. Surgeons need to integrate clinical observations, imaging tools, and patient history to make an early diagnosis. Before undergoing surgery, a thorough examination of both breasts is required.

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.