Malignant Heterologous Elements Research Articles

MALIGNANT PHYLLODES TUMORS – A SINGLE HOSPITAL ANALYSIS

Abstract Introduction/Objective Phyllodes tumor (PT), a rare fibroepithelial breast lesion, affects around 1% of breast tumors, primarily in women aged 40–50 years old. The interpretive subjectivity, histological overlap, and limited molecular predictors, necessitate further investigation into their pathogenesis. Prognosis relies on WHO grading based on stromal proliferation. Malignant-PTs are rare and challenging to diagnose, posing a diagnostic challenge with breast sarcomas and metaplastic carcinomas. The study aims to highlight morphological features of malignant-PTs and their correlation on patients’ survival and prognosis. Methods/Case Report Retrospective single-institute study of 33 women who were diagnosed with malignant-PT according to WHO criteria and underwent excision were identified from database spanning 2005-2024. Clinical and pathologic characteristics including biopsy results, histological features, imaging findings, and survival outcomes were analyzed statistically using Kaplan-Meier method. Results (if a Case Study enter NA) Patients aged 28-72 years underwent excision, with a mean of 50 years and tumor sizes ranging 1.1-34 cm with a mean of 11.5 cm. The majority (19 cases) were classified as pT stage I or II, with 14 cases at more advanced stages. Malignant heterologous elements were found in 10 cases (30%). Positive margins were noted in 12 excisions (36%). Besides tumor recurrence in 3 cases (9%) within 33 months post-excision, metastasis was observed in 8 cases, occurring between 4-60 months post-excision. Six patients died from metastasis within 11-62 months post-diagnosis. Conclusion The presence of negative margins and appropriate treatment was associated with a lower risk of recurrence and metastasis. However, they were not linked to enhance survival rates. Survival was primarily correlated to the absence of heterologous components and PT’s staging.

Histomorphological analysis of phyllodes tumors at a tertiary care center

Background: Phyllodes tumors (PT) are rare biphasic neoplastic breast lesions. They account for 0.3–0.5% of female breast tumours1 and have an incidence of about 2.1 per million, the peak of which occurs in women aged 45–49 years. There is sometimes difficulty in dividing tumors into the three recognized grades based on histomorphological features. It is because of the subjective variation and absence of a definitive grading system. More importantly, they do not always correlate with clinical outcome in terms of predicting recurrence, malignant transformation, metastasis, and overall survival. Aims and Objectives: (1) The aim of the study was to study the clinicopathological and histomorphological features of the PT and classify the tumors based on 2019 WHO classification. Materials and Methods: This study was done in the Department of Pathology at Government General Hospital Nizamabad. Total 68 cases are included in this study over a period of 5 years (3 1⁄2 years retrospective and 11/2 year prospective) from 2017 March to 2022 March. PT cases were analyzed based on 2019 WHO classification criteria. The age of the patients, tumor locations, and the relevant details were obtained from the pathology records. Results: Of the 68 PT cases, 53 (78%) were classified as benign, 8 (12%) borderline and 7 (10%) malignant PT based on histomorphological features based on 2019 WHO classification. Conclusion: Our study showed that tumors occurring in older age group with a large tumor size and the presence of malignant heterologous elements, infiltrating borders, and surgical margins <1 cm were usually malignant phyllodes.

Diagnostic concordance of phyllodes tumour of the breast.

Phyllodes tumours (PT) are rare and distinct breast tumours, which span a morphological continuum. Classification into benign, borderline and malignant categories reflects their biology and clinical behaviour and is essential to guide management. This study aims to assess the diagnostic agreement of PT using the UK National Health Service Breast Screening Programme (NHSBSP) breast pathology external quality assurance (EQA) scheme data. Twenty-six PTs were identified in the EQA scheme, which were diagnosed by an average of 607 participants/circulation. Data on diagnostic categories were collected and representative slides were reviewed. The level of concordance between reporting pathologists was assessed. There were 14 benign, six borderline and six malignant PT. The overall rate of diagnosis agreement was 86% when analysed as benign lesions, borderline PT and malignant lesions, which decreased to 79% when diagnosed as PT (irrespective of grade) and to 63% when the diagnosis was further refined to PT categories (benign, borderline and malignant PTs). The highest agreement rate was observed in malignant PT (86%) and the lowest in borderline PT (42%). Malignant heterologous elements, stromal overgrowth and leaf-like architecture are features associated with higher concordance rates. Lower-priority features were stromal expansion, clefting and multinodularity. The concordance of PT diagnosis, as an entity, is high, but its classification into benign, borderline and malignant has variable agreement levels, with borderline tumours having the lowest concordance rate. More research to refine the diagnostic criteria for categorisation of PT is warranted to improve concordance between pathologists.

Retrospective study of malignant phyllodes tumors of the breast: Younger age, prior fibroadenoma surgery, malignant heterologous elements and surgical margins may predict recurrence

PurposeThe potential recurrence rate of malignant phyllodes tumors (MPTs) of the breast is high, and the prognostic factors are still unclear. We therefore aim to study the factors affecting the outcome of MPTs. MethodsA retrospective review of MPT patients treated from 2006 to 2020 at our institution was conducted. Univariate and multivariate Cox proportional hazard models were used to examine the influence of different variables on RFS. Moreover, significant prognostic factors were combined to construct the nomogram to predict the probability of relapse occurring in MPT patients. The 5-year and 10-year RFS rates were estimated using the Kaplan–Meier method. ResultsDuring the study period, 188 MPT patients were identified. The presence of malignant heterologous elements was observed in 23 (12.2%) patients with MPT, and the patients with malignant heterologous elements who received chemotherapy had longer RFS, which could reduce the risk of recurrence (p = 0.022). Recurrence occurred in 56/188 (29.8%) patients, of whom 47 experienced local recurrence and 11 experienced distant metastases. The 5-year and 10-year cumulative RFS rates were 77.5% and 70.1%, respectively. Age (p = 0.041), fibroadenoma surgery history (p = 0.004), surgical margins (p = 0.001) and malignant heterologous elements (p < 0.001) were independent risk factors for postoperative RFS. Subsequently, a nomogram was built, with a C-index of 0.64 (95% CI: 0.629–0.661), to predict the risk of recurrence. ConclusionThe results of this study showed that younger age, fibroadenoma surgery history, malignant heterologous elements and surgical margins <1 cm predict a higher incidence of recurrence in MPT patients. Patients with malignant heterologous elements treated with chemotherapy could have a reduced risk of recurrence.

Abstract P4-06-07: PIK3CA-mutant breast phyllodes tumors show a uniformly aggressive histology and significant mutual exclusivity with MED12 mutation

Abstract Introduction: De-regulation of the class I phosphoinositide 3’-kinase (PI3K) pathway has long been known to contribute to the development and progression of many tumors. However, the FDA only recently approved the first selective inhibitor of PIK3CA, the p110-alpha catalytic subunit of PI3K, specifically for use in treatment of a subset of PIK3CA-mutant breast carcinomas. Given the emergence of this therapeutic class of agents, we sought to identify other subsets of breast tumors that may be driven largely by PIK3CA mutations and which therefore could be candidates for these therapies. In breast fibroepithelial neoplasms, mutations in PIK3CA have been occasionally reported in borderline and malignant phyllodes tumors. In contrast, mutations in MED12 are common and recurrent across the entire spectrum of benign and malignant breast fibroepithelial tumors, and are enriched in borderline/malignant phyllodes cases that still have benign fibroadenoma-like areas. In the current study, we sought to define the histologic and molecular features of PIK3CA-mutant phyllodes tumors. Methods: From 2014 to 2019, we analyzed clinical tumor samples using comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform. We searched our case archive to find breast phyllodes tumors with known or likely pathogenic alterations in PIK3CA and other known tumor-related genes. All cases were clinically advanced. We reviewed pathology reports, histopathology, and patient clinical data. Results: We identified 12 (16%) of 76 breast phyllodes tumors in our case archive as PIK3CA-mutant. Median patient age for PIK3CA-mutant phyllodes tumors was 56 years. Cases consisted of 6 primary tumors, 2 local recurrences, and 4 lung metastases. Primary tumor size measured from 38 to 220 mm (median 100 mm; mean 114 mm). Digital slides were available for histology review in 9 cases. Cases showed uniformly malignant histology, with no benign or fibroadenoma-like regions. 3 cases showed malignant heterologous elements. Compared to the rest of our breast phyllodes tumor cohort, PIK3CA-mutant cases showed significantly fewer pathogenic genomic alterations in MED12 (8% vs. 55%, p=0.0037) and TP53 (17% vs. 56%, p=0.0245), as well as a trend to fewer mutations in RB1 (0% vs. 22%, p=0.11). The other most frequently mutated genes in the PIK3CA-mutant group were TERTp (70%), CDKN2A (67%), and NF1 (50%). Conclusions: PIK3CA-mutant phyllodes tumors define a unique subset of tumors characterized by aggressive histologic features and largely lacking the MED12 mutations seen in many fibroepithelial neoplasms. These findings provide compelling rationale for comprehensive genomic profiling of advanced cases of this disease in an effort to inform therapeutic options including clinical trials of PI3K-targeted agents in this setting. Citation Format: Erik A Williams, Ethan S Sokol, Dean C Pavlick, Nikunj Shah, Julia A Elvin, Jo-Anne Vergilio, Jonathan K Killian, Nhu Ngo, Douglas Lin, Vincent A Miller, Jeffrey S Ross. PIK3CA-mutant breast phyllodes tumors show a uniformly aggressive histology and significant mutual exclusivity with MED12 mutation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-07.

Heterologous sarcomatoid pleural mesothelioma with osteosarcomatous differentiation: a report of autopsy case that accomplished trimodality therapy and review of the literature

Heterologous mesothelioma is a very rare subtype of sarcomatoid mesothelioma characterized by the presence of malignant heterologous elements. A 69-year-old man with a strong history of asbestos exposure presented with a 5-cm mass in his chest wall, destroying the right 5th rib and spreading along the parietal pleura, on a CT. Biopsy revealed heterologous mesothelioma with osteosarcomatous elements, following which left extrapleural pneumonectomy was performed with combined resection of pericardium, hemidiaphragm, and 4th, 5th, and 6th costal segments. A small cytokeratin-positive epithelioid component in the resected tumor definitively confirmed the diagnosis. Post-operative chemotherapy and intensity-modulated radiotherapy were undertaken. After 12-month disease-free period post treatment, rapid intraperitoneal recurrence resulted in death. Autopsy revealed no tumors in the left thorax. We present here a case of heterologous osteosarcomatous pleural mesothelioma that followed a unique clinical course after trimodality therapy. In addition, literature of 54 cases of the similar heterologous mesothelioma was reviewed.

Size and heterologous elements predict metastases in malignant phyllodes tumours of the breast.

Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms comprising 0.3-1.0% of all primary breast tumours. The majority of PTs are benign and generally well managed with surgery. However, malignant PTs, and occasionally borderline PTs, can behave in a clinically aggressive manner by metastasizing to distant organs. Although distant metastasis is rare, the prognosis of patients with metastasis is dismal as many are unresponsive to standard chemotherapy and the risk of death is high. In this study, we correlated clinicopathological parameters to survival outcomes in a cohort of patients diagnosed with malignant PTs in our institution. The study cohort comprised 83 cases of malignant PTs diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 1994 to 2015. Clinicopathological features and follow-up were obtained from hospital records. Metastasis-free survival (MFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared between groups using the log-rank test. Cox regression was carried out to identify factors predictive for metastasis. Mean and median age of patients was 48years (range 21-71years). Tumour size measured from 30 to 220mm (mean 90mm, median 77mm). Follow-up data was available for 68 patients. Mean and median follow-up was 90 and 57months, respectively, with a maximum of 291months. Distant metastasis occurred in 16 out of 68 patients (23.5%). The most common site of metastasis was the lung. Malignant heterologous elements were observed in 16 (19.3%) cases. Individual clinicopathological parameters had no impact on outcome. On Kaplan-Meier analysis, women with large tumours and presence of malignant heterologous elements showed trends for poorer MFS (p=0.217 and p=0.566, respectively). However, the combination of large tumours (≥90mm) containing malignant heterologous elements disclosed significantly worse MFS (p=0.043) and a trend for poorer OS (p=0.238). On multivariate analysis, large tumours harbouring malignant heterologous elements independently predicted metastasis (95% CI 1.041-12.517, HR 2.434, p=0.049). Our study demonstrates that tumour size and presence of malignant heterologous elements predicted metastasis in malignant PTs. Further work needs to be done in determining if protein biomarkers and genomic aberrations are able to additionally refine metastatic risk and define therapeutic targets.

Sarcomatoid urothelial carcinoma with chondrosarcomatous differentiation of the ureter: A case report and review of the literature.

Sarcomatoid urothelial carcinoma of the urinary tract is associated with poor prognosis. The majority of sarcomatoid urothelial carcinomas are found in the urinary bladder, while a small minority have been shown to arise from the ureter. In the present case, a 72-year-old male patient was diagnosed with sarcomatoid urothelial carcinoma with chondrosarcomatous differentiation of the left ureter, and subsequently underwent nephroureterectomy and retroperitoneal lymph node dissection. Two lymph nodes from the renal hilum and one paraaortic lymph node were also found to have metastatic involvement; however, the patient refused to receive chemotherapy or radiotherapy and succumbed to bone and omentum metastasis at 6 months after the initial diagnosis. Sarcomatoid urothelial carcinoma of the ureter is uncommon. Even rarer is the presence of malignant heterologous elements, such as chondrosarcoma. The present study reports a rare case of sarcomatoid urothelial carcinoma with chondrosarcomatous differentiation of the ureter, as well as a review of the literature, in order to demonstrate the aggressive nature of this particular malignancy.

Spindle Cell Carcinoma of the Vulva

Spindle cell or sarcomatoid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma of the vulva (SCCV) with only 12 well-documented cases reported to date. Morphologically tumors may be biphasic or monophasic, and uncommonly include heterologous elements. Only 1 reported vulval tumor has previously been investigated for human papillomavirus DNA content. We describe 4 women with spindle cell (sarcomatoid) SCCV, 3 of which occurred de novo and 1 followed radiotherapy for previous SCCV. The tumors in all 4 women arose in a background of lichen sclerosus, and 3 were associated with vulval intraepithelial neoplasia differentiated (simplex) type. All tumors were negative for human papillomavirus DNA on polymerase chain reaction analysis. One case is the second reported with malignant heterologous elements described in the vulva. These tumors seem to be more aggressive than conventional SCCV.

Malignant mesothelioma with heterologous elements: clinicopathological correlation of 27 cases and literature review

Only a small number of malignant mesotheliomas with heterologous elements have been described. There are currently no criteria for diagnosis and little data regarding prognosis. We suggest that the term heterologous mesothelioma should be reserved for tumours that show malignant heterologous elements, notably osteosarcomatous, chondrosarcomatous, or rhabdomyoblastic elements but have immunohistochemical and clinical characteristics of mesothelioma. We identified 27 such cases and characterized the clinical and pathological characteristics of these tumours. In our series, 89% originated in the pleura, and 11% from the peritoneal cavity. The median age at diagnosis was 68 years, ranging from 27 to 85 years. Of these cases, 93% occurred in males and 7% in women. Of the 27 mesothelioma cases 16 (59%) were sarcomatoid, 10 (37%) were biphasic, and one was reported as epithelioid; 40% (11 cases) showed osteosarcomatous elements only, 19% showed areas of rhabdomyosarcoma only, 19% contained areas of chondrosarcoma only, and 22% exhibited osteochondromatous elements. Immunohistochemical labelling for cytokeratins was present in the majority of cases. Exposure to asbestos was identified in all the 17 cases for which an exposure history was available (63%). Median survival was 6 months after diagnosis, similar to the survival seen in sarcomatoid mesotheliomas. The differential diagnosis includes primary and secondary pleural sarcomas, including osteosarcomas and chondrosarcomas. Immunohistochemical labelling for cytokeratins is helpful in the distinction, but lack of labelling for cytokeratins in a spindle cell/sarcomatoid tumour does not exclude the diagnosis of mesothelioma, irrespective of the presence of heterologous elements. We suggest that if the anatomical distribution conforms to that of mesothelioma, a diagnosis of heterologous mesothelioma should be made in preference to a diagnosis of primary pleural osteosarcoma or chondrosarcoma, regardless of cytokeratin positivity, as for conventional non-heterologous sarcomatoid mesothelioma.

Carcinoma sarcomatoide renal con elementos heterólogos malignos: A propósito de un caso

The sarcomatoid pattern represents the histological type of renal carcinoma with the poorest prognosis, receiving the grade 4 of the Furhman classification consistently.We report the case of a 80-year-old male who underwent nephroureterectomy with the pathologic diagnosis of sarcomatoid renal carcinoma with areas of chondro and osteosarcoma, as well as squamous cell differentiation. It is an exceptional case because it is rare to find all these elements in the same tumor.The study of the surgical specimen enables in most cases the identification of some of the classic histological patterns of renal carcinoma, nevertheless an immunohistochemical study is of great value for proper classification of the neoplasia and differential diagnosis with other renal lesions, mainly sarcomas.The presence of malignant heterologous elements, as in our case, will confirm the prognosis of these neoplasias, which really don't have an effective treatment.