Publications by authors named "Julia Y Tsang"

73 Publications

The International Academy of Cytology Yokohama System for Reporting Breast Cytopathology showed improved diagnostic accuracy.

Cancer Cytopathol 2021 May 24. Epub 2021 May 24.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.

Background: The aim of the International Academy of Cytology Yokohama System for Reporting Breast Fine Needle Aspiration Biopsy Cytopathology is to improve cytology practice. This study assessed cytologic diagnoses made with the system and its efficacy when it was applied by pathologists with different levels of experience.

Methods: In all, 1080 cases of breast fine-needle aspiration biopsy (FNAB) over a period of 16 years were reviewed and reclassified with the system. The category distribution and the diagnostic performance were compared with the original diagnoses. The concordance rates for diagnoses from pathologists with different levels of experience were also determined.

Results: The distribution of cytologic diagnoses made with the system was as follows: 11.7% were insufficient, 56.6% were benign, 20.1% were atypical, 6.1% were suspicious for malignancy, and 5.6% were malignant. The rates for the insufficient and atypical categories were lower than the original diagnosis rates (13.1% and 23.8%, respectively). Overall, 120 cases (11.1%) were recategorized. Among those recategorized as benign, suspicious, or malignant with follow-up data, 96.7% were correctly reclassified. A significant improvement in diagnostic performance was found with the system (P < .001). Such improvement was also seen in problematic breast lesions, including fibroepithelial lesions, papillary lesions, and low-grade carcinomas. Pathologists with intermediate experience showed a higher concordance with an expert pathologist in the diagnoses than those with short experience (κ, 0.838 vs 0.634).

Conclusions: The system effectively categorized the diagnoses, and the diagnostic performance of FNAB reporting was improved. The structured reporting also enhanced the reproducibility of reporting by pathologists with intermediate experience and, to some extent, those with short experience.
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http://dx.doi.org/10.1002/cncy.22451DOI Listing
May 2021

Clinicopathologic and genetic features of metaplastic breast cancer with osseous differentiation: a series of 6 cases.

Breast Cancer 2021 May 3. Epub 2021 May 3.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Aims: Metaplastic breast cancer (MBC) comprises a heterogeneous group of tumors, of which MBC with osseous differentiation (MBC-OD) is extremely rare that only few cases have been reported. This study aimed to present the clinicopathologic and molecular features of MBC-OD.

Methods: We collected 6 cases of MBC-OD from five different centers and described its clinicopathologic and molecular characteristics based on the next-generation sequencing. Another 11 cases from the literature were also reviewed to better characterize the tumor.

Results: The tumor primarily showed an osteosarcoma-like appearance, which composed of high cellularity with spindle cells and osteoblast-like cells producing coarse lace-like neoplastic bone (4/6) or osteoid matrix (6/6). 55 somatic mutations including 39 missenses (70.9%), 9 frameshifts (16.4%), 3 splice sites (5.5%), 3 in-frame InDels (5.5%) and 1 nonsense (1.8%) were identified. TP53 was the most frequently mutated genes (5/6, 83.3%), followed by RB1 (3/6, 50.0%), BCOR (2/6, 33.3%), MED12 (2/6, 33.3%), PIK3CA (2/6, 33.3%), and TET2 (2/6, 33.3%). Genetic alterations suggesting therapies with clinical benefit, including mTOR inhibitors, tyrosine kinase inhibitors (TKI), and poly-ADP ribose polymerase inhibitor (PARPi), were observed in five cases. The median follow-up was 21 months (range, 3-80 months). Local recurrence was observed in two cases and three patients displayed distant metastasis. Two patients died of the disease at 3 months and 7 months, respectively.

Conclusions: Based on this series, MBC-OD is a highly aggressive breast tumor with osteosarcoma-like morphology and a high incidence of recurrent disease showing specific genetic profiles.
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http://dx.doi.org/10.1007/s12282-021-01246-9DOI Listing
May 2021

SETD2 alterations and histone H3K36 trimethylation in phyllodes tumor of breast.

Breast Cancer Res Treat 2021 Jun 12;187(2):339-347. Epub 2021 Apr 12.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong SAR.

Purpose: SETD2 is one of the key epigenetic regulatory genes involved in histone modifications. Its alterations were potentially oncogenic and commonly found in cancers. Interestingly, SETD2 is one of the most frequent mutated genes found exclusively in phyllodes tumor of the breast (PT). However, little has been done to further characterize SETD2 alterations in PT.

Methods: In this study, we examined the alterations of SETD2 gene and protein expression in a large cohort of PTs. Their correlations with SETD2 downstream target, H3K36me3 expression, and clinicopathologic features in PT were also assessed.

Results: SETD2 mutation was found in 15.9% of our cases and was mostly predicted to be damaging mutations. Interestingly, SETD2 mutations were associated with lower H3K36me3 expression, particularly those with damaging mutations (p = .041). Neither SETD2 mutations nor H3K36me3 expression was associated with PT grading and other clinicopathological features. By contrast, the SETD2 protein expression cannot reflect its mutation status and showed a different trend of clinicopathological correlations from H3K36me3.

Conclusions: Our findings may suggest a potential involvement of epigenetic regulation via SETD2 alterations and downstream H3K36me3 on PT development. SETD2 mutations may occur early in the pathogenic process of PTs and its loss per se may not be sufficient for progression to malignancy. Exclusive alterations of SETD2 in PT can be used as markers for the diagnosis of fibroepithelial lesions. The association of H3K36me3 with SETD2 mutations may also indicate the value of evaluation of H3K36me3 expression in the diagnosis of fibroepithelial lesions.
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http://dx.doi.org/10.1007/s10549-021-06181-zDOI Listing
June 2021

Papillary lesions of the breast: A systematic evaluation of cytologic parameters.

Cancer Cytopathol 2021 Feb 9. Epub 2021 Feb 9.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.

Background: The cytologic diagnosis of papillary lesions of the breast is challenging because of the diverse morphology, including epithelial hyperplasia, atypia, low-grade malignancy, and neuroendocrine differentiation; also, traditional malignant features such as necrosis and myoepithelial cell loss can be lacking. Thus, the diagnostic criteria for papillary lesions may differ from those for other breast lesions. This study evaluated various cytologic parameters in a large cohort to identify useful diagnostic features.

Methods: Cytologic preparations of papillary lesions with histologic follow-up were reviewed for features related to cellularity, epithelial cohesiveness, cellular and stromal architecture, cytomorphology, and background. Corresponding histologic slides were also reviewed.

Results: In all, 153 cases were included. Epithelial discohesion, solid and cribriform patterns, atypical nuclear features, and mitoses (P ≤ .001 to P = .017) were associated with malignancy. Cell balls, monolayer sheets, and features of cystic change (P < .001 to P = .016) were associated with benign lesions. Complex (P = .031) and slender (P = .026) papillae and neuroendocrine features (P < .001) were associated with malignancy. Hemorrhage, background, and infiltrating neutrophils (P < .001 to P = .025) were associated with malignancy; fibrotic broad papillary stromal fragments (naked papillary fronds [NPFs]; P = .043) were associated with benignity. The presence of any single parameter, including the absence of myoepithelial cells within epithelial structure, the presence of cytoplasmic granules, an increased amount of cytoplasm, and a nuclear to cytoplasmic (N/C) ratio greater than 0.7, which were identified by principal component analysis, yielded a sensitivity of 95.1% and a specificity of 100.0% in predicting malignancy.

Conclusions: Methodological assessment of multiple features is recommended. Myoepithelial cells, cytoplasmic granules, the amount of cytoplasm, and the N/C ratio are key features for diagnosis.
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http://dx.doi.org/10.1002/cncy.22412DOI Listing
February 2021

Breast cancer with neuroendocrine differentiation: an update based on the latest WHO classification.

Mod Pathol 2021 Jun 2;34(6):1062-1073. Epub 2021 Feb 2.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong SAR.

Breast cancers with neuroendocrine (NE) differentiation are very heterogeneous, comprising broadly cancers that are morphologically similar to NE tumors (NET) of other anatomic sites, infiltrating breast carcinomas, no special type (IBC-NST) and other special subtypes with NE morphology and/or NE markers expression. Depending on the classification schemes, they are variably included into "NE breast cancers". The latest WHO classification harmonized NE breast cancers with NE neoplasms (NEN) of other organ systems, defined NEN into well-differentiated NET (low Nottingham grade) and poorly-differentiated NE carcinoma (NEC) (high Nottingham grade). Other IBC with NE differentiation are diagnosed based on solely the non-NEN component. Due to the changes in diagnostic criteria, variable results were obtained in the previous studies on NE breast cancers. Hence, the clinical value of NE differentiation in breast cancers is not well investigated and understood. In this review, the current understanding in the pathogenesis, clinical, prognostic, immunhistochemical, and molecular features of "NE breast cancers" is summarized. Controversial issues in their diagnosis and classification are also discussed.
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http://dx.doi.org/10.1038/s41379-021-00736-7DOI Listing
June 2021

Re: INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer: author reply.

Pathology 2021 Feb 28;53(2):293-294. Epub 2020 Dec 28.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.12.002DOI Listing
February 2021

INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.

Pathology 2021 Feb 17;53(2):170-178. Epub 2020 Sep 17.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, New Territories, Hong Kong. Electronic address:

Insulinoma associated protein 1 (INSM1) is a relatively new marker of neuroendocrine differentiation. It has been shown to have a high sensitivity for neuroendocrine tumours arising from different organs. This study evaluated INSM1 as a marker for neuroendocrine differentiation in infiltrating breast cancers (IBC). The expression of INSM1, together with other neuroendocrine markers (synaptophysin, chromogranin and CD56) was assessed in a large IBC cohort using tissue microarray by immunohistochemistry. Overall, 13.1%, 4.6%, 7.0% and 6.5% of the cases were positive for synaptophysin, chromogranin, INSM1 and CD56, respectively. INSM1 expression showed similar clinicopathological and biomarker profiles as chromogranin and synaptophysin. They were associated positively with luminal profile (p<0.001) and hormone receptors expression (p≤0.015), but negatively with HER2 (p≤0.044) and high molecular weight cytokeratins (p≤0.047). Using synaptophysin and/or chromogranin to define neuroendocrine differentiation, INSM1 showed a sensitivity of 37.3%, and was more sensitive than chromogranin (33.5%) and CD56 (16.4%) but less than synaptophysin (94.6%). Interestingly, INSM1 expression segregated IBC with neuroendocrine differentiation into different prognostic subgroups, particularly within luminal B subtype. Among the synaptophysin/chromogranin+ luminal B cancers, INSM1 expression was associated with significantly better survival (DFS: χ=8.009, p=0.004; BCSS: χ=3.873, p=0.049). Multivariate analysis showed that synaptophysin/chromogranin+ INSM1- status was an independent adverse factor for DFS (HR=2.282, 95%CI=1.196-4.356, p=0.012) in the luminal B subtype. Our data supported the usefulness of INSM1 in detecting neuroendocrine differentiation in IBC. Furthermore, INSM1 expression suggested a favourable prognostic impact; thus, it could be useful for stratifying neuroendocrine tumours with different prognosis.
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http://dx.doi.org/10.1016/j.pathol.2020.07.004DOI Listing
February 2021

SALL4 promotes tumor progression in breast cancer by targeting EMT.

Mol Carcinog 2020 10 24;59(10):1209-1226. Epub 2020 Aug 24.

Department of Applied Biology and Chemical Technology, State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong SAR.

Sal-like protein 4 (SALL4) is overexpressed in breast cancer and might contribute to breast cancer progression, but the molecular mechanism remains unknown. Here, we found that within a group of 371 ethnic Chinese breast cancer patients, SALL4 was associated with lower grade (P = .002) and progesterone receptor positivity (P = .004) for overall cases; lower Ki67 (P = .045) and high vimentin (P = .007) for luminal cases. Patients with high SALL4 expression in lymph node metastasis showed a significantly worse survival than those with low expression. Knockout of SALL4 in a triple-negative breast cancer cell line MDA-MB-231-Red-FLuc-GFP led to suppressed ability in proliferation, clonogenic formation, migration, and mammosphere formation in vitro, tumorigenicity and lung colonization in vivo. On the other hand, overexpression of SALL4 enhanced migration and mammosphere formation in vitro and tumorigenicity in vivo. Mechanistically, there was a positive correlation between SALL4 expression and mesenchymal markers including Zinc finger E-box binding homeobox 1 (ZEB1), vimentin, Slug, and Snail in vivo. Chromatin immunoprecipitation experiment indicated that SALL4 can bind to the promoter region of vimentin (-778 to -550 bp). Taken together, we hypothesize that SALL4 promotes tumor progression in breast cancer by inducing the mesenchymal markers like vimentin through directly binding to its promoter. Increased SALL4 level in metastatic lymph node relative to the primary site is an important poor survival marker in breast cancer.
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http://dx.doi.org/10.1002/mc.23250DOI Listing
October 2020

Combined SOX10 GATA3 is most sensitive in detecting primary and metastatic breast cancers: a comparative study of breast markers in multiple tumors.

Breast Cancer Res Treat 2020 Nov 1;184(1):11-21. Epub 2020 Aug 1.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

Purpose: For invasive breast cancer (IBC), high SOX10 expression was reported particularly in TNBC. This raised the possibility that SOX10 may complement other breast markers for determining cancers of breast origin.

Methods: Here, we compared the expression of SOX10 with other breast markers (GATA3, mammaglobin and GCDFP15) and their combined expression in a large cohort of IBC together with nodal metastases. We have also evaluated the expression of GATA3 and SOX10 in a wide spectrum of non-breast carcinomas to assess their value as breast specific markers.

Results: Compared with other markers, SOX10 showed lower overall sensitivity (6.5%), but higher sensitivity in TNBC (31.4%) than other breast markers including GATA3 (29.7% for TNBC). Its expression demonstrated the highest concordance between the paired IBC and nodal metastases (96.4%, κ = 0.663) among all the breast markers. More importantly, SOX10 identified many GATA3-negative TNBC, thus the SOX10/GATA3 combination was the most sensitive marker combination for IBC (86.6%). For non-breast carcinoma, a high SOX10/GATA3 expression rate was found in melanoma (77.9%, predominately expressed SOX10), urothelial carcinoma (82.0%, predominately expressed GATA3) and salivary gland tumors (69.4%). Other carcinomas, including cancers from lungs, showed very low expression for the marker combination.

Conclusions: The data suggested that SOX10/GATA3 combination can be used for differentiating metastases of breast and multiple non-breast origins. However, the differentiation with melanoma and urothelial tumors required more careful histologic examination, thorough clinical information and additional site-specific IHC markers. For salivary gland tumors, the overlapping tumor types with IBC renders the differentiation difficult.
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http://dx.doi.org/10.1007/s10549-020-05818-9DOI Listing
November 2020

The significance of highlighting the oestrogen receptor low category in breast cancer.

Br J Cancer 2020 10 27;123(8):1223-1227. Epub 2020 Jul 27.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

The latest ASCO/CAP guideline has recommended to report oestrogen receptor (ER) low cases (ER; 1-10%) as "ER low positive category", prompting us to compare the clinicopathologic features, biomarkers, survival and treatment of the ER cases with other subgroups (ER negative (ER) and ER high (ER)). ER cases revealed more similar clinicopathologic and biomarker profiles (including younger age, larger tumour, high proliferation, HER2 and basal markers expression) to ER than ER cancers. The ER cases receiving hormonal therapy showed a similarly poor outcome as ER cancers. However, majority of ER cases were downstaged to stage I in the 8th AJCC pathological prognostic staging, highlighting a risk of potential under treatment. Overall, our data highlighted the differences of ER from other ER cases and their management should be considered separately.
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http://dx.doi.org/10.1038/s41416-020-1009-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555863PMC
October 2020

Axillary Nodal Metastasis with Papillary Morphology: An Uncommon Origin.

Acta Cytol 2020 11;64(6):612-616. Epub 2020 Jun 11.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong,

Background: Metastases to axillary lymph nodes are commonly and readily confirmed by fine needle aspiration cytology (FNAC). Most likely, these arise from breast primaries. However, the diagnosis can become complicated when unusual cytomorphology is encountered.

Case: We report a 60-year-old woman presenting with bilateral axillary lymphadenopathies but without breast lesions. History showed increasing CA-125 levels. FNAC yielded carcinoma cells showing prominent papillary pattern, being composed of mild to moderately differentiated malignant cells, with focal abortive glandular formation and squamous metaplasia. IHC stains were done and the tumor cells were PAX-8 positive, but GATA-3 and GCDFP-15 negative. Coupled with the clinical history, a diagnosis of metastatic endometrioid adenocarcinoma was made.

Conclusion: Nodal metastases with papillary cytomorphology can rarely arise from nonbreast primaries. The presence of papillary pattern, particularly in the absence of a clinically detectable breast lesion, should raise the possibility of a metastasis. Correlation with patient history, imaging findings and judicious use of IHC studies are crucial for a correct diagnosis.
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http://dx.doi.org/10.1159/000508241DOI Listing
November 2020

The Clinical Significance of Neuroendocrine Features in Invasive Breast Carcinomas.

Oncologist 2020 09 16;25(9):e1318-e1329. Epub 2020 Jun 16.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

The latest World Health Organization (WHO) classification categorized invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiations into neuroendocrine neoplasms (including well-differentiated neuroendocrine tumor [NET] and poorly differentiated neuroendocrine carcinoma [NEC]) and IBC no special type with NE features (IBC-NST-NE). However, little is documented of the clinical significance of this classification; also the precise thresholds and choices of NE markers were variable. In the current study, a large cohort of patients with IBC with NE differentiation were morphologically classified based on the WHO criteria and the clinical relevance of expression of different NE markers (synaptophysin [SYN], chromogranin [CG], and CD56) was evaluated. Among 1,372 IBCs, 52 NET (3.8%) and 172 IBC-NST-NE (12.5%) were identified. Compared with the IBC-no NE cases, NET and IBC-NST-NE were similarly associated with positive estrogen receptor (ER) expression and lower grade (p < .001). For patient outcome, IBC-NST-NE, but not NET, demonstrated significantly worse survival than the IBC-no NE cases. Based on high (≥50%) and low (<50%) expression for each NE marker, independent poor disease-free survival for SYN CG and SYN CG cancers (IBC-no NE cases as references, hazard ratio [HR], ≤1.429; p ≤ .026) was found. Interestingly, SYN and CG expression correlated with each other and they shared similar clinicopathologic characteristics; but not with with CD56. In addition, CD56-only positive cases were associated with hormone receptors negativity and basal markers positivity (p ≤ .019), and patients' outcome was similar to IBC-no NE cancers. Our findings suggested that NE markers expression may provide information to fine tune treatment strategy. The relevance of CD56 as NE marker requires further studies. IMPLICATIONS FOR PRACTICE: Invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiation are heterogeneous in clinicopathologic parameters, biomarker expression, and prognosis. However, there are no specific therapies targeting NE differentiation, and all carcinomas with any NE differentiation are treated similarly as other IBCs. The results of this study suggest that stratification based on NE marker expression levels may provide added prognostically pertinent information, aiding better treatment strategy. In addition, CD56-only positive carcinomas showed a different clinicopathologic and biomarker expression profile compared with those with chromogranin and synaptophysin expression. Relevance of CD56 as an NE marker requires further studies.
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http://dx.doi.org/10.1634/theoncologist.2020-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485343PMC
September 2020

Sry-related high-mobility-group/HMG box 10 (SOX10) as a sensitive marker for triple-negative breast cancer.

Histopathology 2020 Dec 12;77(6):936-948. Epub 2020 Sep 12.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

Aims: Confirmation of a breast origin for triple-negative breast cancer (TNBC) is sometimes problematic. The traditional breast markers GATA-binding protein 3 (GATA3), mammaglobin (MGB) and gross cystic disease fluid protein 15 (GCDFP15) have shown limitations in identifying TNBC. Here, we aimed to examine the diagnostic potential of the newly proposed TNBC marker, Sry-related high-mobility-group/HMG box 10 (SOX10).

Methods And Results: We analysed and compared SOX10 expression with GATA3, MGB and GCDFP15 expression in a test cohort of 1838 invasive breast cancers (IBCs) by using tissue microarrays. The findings from the test cohort were further examined with a validation cohort of 42 TNBCs in whole sections. The overall expression rates of SOX10, GATA3, MGB and GCDFP15 were 6.9%, 83.1%, 47.0%, and 34.8%, respectively. Among the TNBCs within this cohort, the expression rates of SOX10, GATA3, MGB and GCDFP15 were 31.3%, 34.5%, 27.9%, and 25.2%, respectively. SOX10 was strongly associated with TNBC (P < 0.001), whereas all other traditional markers were associated with non-TNBC (P < 0.001 for all). In addition, SOX10 was more correlated to basal-like breast cancer (BLBC) (P = 0.001) than five-marker-negative subtype among the TNBCs. A high expression rate of SOX10 (81%) was confirmed in the validation cohort. Additionally, SOX10 expression was inversely correlated with GATA3 and GCDFP15 expression, so they may complement each other in TNBC detection. The SOX10-GATA3 combination yielded a sensitivity of 60.3% for TNBC detection in the test cohort.

Conclusion: SOX10 is a reliable marker for identifying TNBC, and complements GATA3. The SOX10-GATA3 combination may be used as a sensitive TNBC marker.
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http://dx.doi.org/10.1111/his.14118DOI Listing
December 2020

Improved Prognostication for the Updated AJCC Breast Cancer Pathological Prognostic Staging Varied in Higher-Stage Groups.

Clin Breast Cancer 2020 06 20;20(3):253-261.e7. Epub 2020 Mar 20.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Electronic address:

Background: In addition to TNM-based anatomical staging (AS), a novel pathological prognostic staging (PPS) has been proposed by the American Joint Committee on Cancer (AJCC). PPS demonstrated better prognostication, but its superiority in breast cancer subtypes and related to staging discrepancies between AS and PPS are not clear.

Methods: A cohort of 1729 patients with breast cancer was staged into AS and PPS according to the latest AJCC staging. Patient characteristic and restaging outcomes were compared.

Results: Compared with AS, 799 and 135 cases were upstaged and downstaged respectively in PPS, mostly involved stage I cases. For the overall cohort, PPS demonstrated superior prognostic power over AS in both disease-free survival (DFS) and breast cancer-specific survival. However, such superiority was found mainly in estrogen receptor (ER)/progesterone receptor (PR)+ but not ER-PR- cancers. Comparing the restaged cases within the same PPS, PPS 1A cases showed similar survival irrespective of the original AS. Interestingly, in other PPS groups (PPS 1B and higher), there was a difference in outcome among patients with same PPS but different AS. Within PPS 1B patients, downstaged cases from higher AS showed worse DFS (3A>1B vs. 2A>1B: χ = 4.732, P = .030).

Conclusions: PPS may provide a more accurate prognostication, mostly among ER/PR+ cancers and with PPS 1A patients. Patients restaged to higher PPS stages showed significant differential survival even within the same PPS. Also, only limited improvement was observed for ER-PR- cancers. Caution needs to be exercised in using PPS for patient prognostication, as in some cases the outcome can be variable with the same PPS.
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http://dx.doi.org/10.1016/j.clbc.2020.01.011DOI Listing
June 2020

Co-expression of HLA-I loci improved prognostication in HER2+ breast cancers.

Cancer Immunol Immunother 2020 May 13;69(5):799-811. Epub 2020 Feb 13.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

The underlying basis for cancer immune evasion is important for effective immunotherapy and prognosis in breast cancers. Human leucocyte antigens (HLA)-I comprising three classical antigens (HLA-A, -B and -C) is mandatory for anti-tumor immunity. Its loss occurred frequently in many cancers resulting in effective immune evasion. Most studies examined HLA-I as a whole. Alterations in specific locus could have different clinical ramifications. Hence, we evaluated the expression of the three HLA-I loci in a large cohort of breast cancers. Low expression of HLA-A, -B and -C were found in 71.1%, 66.3%, and 60.2% of the cases. Low and high expression in all loci was found in 48.3% and 17.9% of the cases respectively. The remaining showed high expression in one or two loci. Cases with all HLA high expression (all HLA high) was frequent in the ER-HER2- (27.4%) and ER-HER2+ (23.1%) cases and was associated with characteristic pathologic features related to these tumor (higher grade, necrosis, high tumor infiltrating lymphocyte (TIL), pT stage, low hormonal receptor, high basal marker expression) (p ≤ 0.019). Interestingly, in HER2+ cancers, only cases with all HLA high and high TIL showed significantly better survival. In node positive cancers, concordant high HLA expression in primary tumors and nodal metastases was favorable prognostically (DFS: HR = 0.741, p < 0.001; BCSS: HR = 0.699, p = 0.003). The data suggested an important clinical value of a combined analysis on the co-expression HLA-I status in both primary and metastatic tumors. This could be a potential additional key component to be incorporated into TIL evaluation for improved prognostication.
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http://dx.doi.org/10.1007/s00262-020-02512-zDOI Listing
May 2020

AJCC 8th edition prognostic staging provides no better discriminatory ability in prognosis than anatomical staging in triple negative breast cancer.

BMC Cancer 2020 Jan 6;20(1):18. Epub 2020 Jan 6.

Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: We retrospectively compared the prognostic value between the AJCC 8th edition anatomic (AS) and prognostic staging (PS) system for triple negative breast cancer (TNBC) in a cohort from two involved institutions and a large population database.

Methods: Clinicopathological data of TNBCs were identified in two involved institutions (SYSUCC-PWH cohort). Data from SEER database during 2010-2015 was also accessed. We restaged all cases into AS and PS group according to the AJCC 8th staging system.

Results: A total of 611 and 31,941 TNBCs were identified in two cohorts, with a median follow-up of 53.5 and 27 months respectively. PS upstaged 46.1% of patients in SYSUCC-PWH cohort, and 62.4% in SEER cohort. No significant difference was observed in C index between AS and PS models for disease-specific survival (DSS), progression-free survival (PFS) or overall survival (OS) in either cohort. χ2 statistic and Hazard Ratio for PFS, DSS and OS showed better discrimination between IA and IB, IIB and IIIA, IIIA and IIIB in AS model than PS model. Besides, patients with IIIC unchanged stage showed worse PFS compared to those with AS IIIA or IIIB upstaged to PS IIIC in both cohorts(p = 0.049, p < 0.001).

Conclusions: Our findings demonstrated that prognostic staging system did not provide better discriminatory ability in predicting TNBCs prognosis than anatomic staging system.
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http://dx.doi.org/10.1186/s12885-019-6494-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945658PMC
January 2020

ASO Author Reflections: Resolving the Challenges in the Management of Mammary Phyllodes Tumor.

Ann Surg Oncol 2019 12 11;26(Suppl 3):774-775. Epub 2019 Oct 11.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.

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http://dx.doi.org/10.1245/s10434-019-07930-7DOI Listing
December 2019

Predicting Outcome in Mammary Phyllodes Tumors: Relevance of Clinicopathological Features.

Ann Surg Oncol 2019 Sep 20;26(9):2747-2758. Epub 2019 May 20.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.

Background: Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms. Most behave in a benign fashion but they also have the potential to recur locally or to metastasize.

Methods: In the current study involving 290 PTs (181 benign, 76 borderline, and 33 malignant) from three hospitals over an 11-year period, we assessed the relationship between histologic parameters (including histologic features affecting grade and surgical margin status), postoperative adjuvant treatment, and local recurrences and distant metastases.

Results: An involved surgical margin was the only factor associated with increased risk of local recurrences (hazard ratio [HR] 4.673, p = 0.003), but not for distant metastases. For local recurrences, a wider margin did not confer additional benefits. None of the histologic factors were predictive for local recurrences. In contrast, distant metastases were correlated with histologic parameters, particularly an infiltrative border (HR 10.935, p = 0.012) and the presence of necrosis (HR 15.311, p = 0.007). In this series, all local recurrences were found in patients without radiotherapy, regardless of surgical margin status.

Conclusion: A negative surgical margin is mandatory for the effective local control of PT recurrence, and a minimal margin clearance may be sufficient. For distant metastases, the inherent characteristics of PTs are important, thus it may be prudent to evaluate additional histologic features, including necrosis, for patients' prognostication.
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http://dx.doi.org/10.1245/s10434-019-07445-1DOI Listing
September 2019

Molecular Classification of Breast Cancer.

Adv Anat Pathol 2020 Jan;27(1):27-35

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.

Cancer classification aims to provide an accurate diagnosis of the disease and prediction of tumor behavior to facilitate oncologic decision making. Traditional breast cancer classification, mainly based on clinicopathologic features and assessment of routine biomarkers, may not capture the varied clinical courses of individual breast cancers. The underlying biology in cancer development and progression is complicated. Recent findings from high-throughput technologies added important information with regard to the underlying genetic alterations and the biological events in breast cancer. The information provides insights into new treatment strategies and patient stratifications that impact on the management of breast cancer patients. This review provides an overview of recent data on high throughput analysis of breast cancers, and it analyzes the relationship of these findings with traditional breast cancer classification and their clinical potentials.
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http://dx.doi.org/10.1097/PAP.0000000000000232DOI Listing
January 2020

Diagnostic upgrade of atypical ductal hyperplasia of the breast based on evaluation of histopathological features and calcification on core needle biopsy.

Histopathology 2019 Sep 16;75(3):320-328. Epub 2019 Jul 16.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Aims: Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher-grade lesions were found in the excision in a substantial proportion of ADH on CNB, factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision.

Methods And Results: One hundred and forty-three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co-existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty-eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P = 0.026), a higher number of ADH foci (P = 0.004), the presence of solid pattern (P = 0.037) and older age (P = 0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P = 0.025), co-existing columnar cell lesions (CCL) (P = 0.001) and the presence of calcifications (P = 0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR = 2.810, P = 0.013) was an independent positive predictor, while co-existing CCL (HR = 0.391, P = 0.013) was an independent negative predictor for upgrade.

Conclusions: Patients with ADH in CNB showing the presence of co-existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation-only management.
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http://dx.doi.org/10.1111/his.13881DOI Listing
September 2019

Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer.

EBioMedicine 2018 Dec 20;38:89-99. Epub 2018 Nov 20.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong. Electronic address:

Background: Amyloid precursor protein (APP), best known for its association with Alzheimer disease, has recently been implicated in breast cancer progression. However, the precise mechanism involved remains unclear. Here, we investigated the role of APP proteolytic cleavage in breast cancer functions.

Methods: The presence of APP proteolytic cleavage products was examined in breast cancer cell lines. The functional roles of APP in breast cancer were studied in vitro and tumor xenograft model using siRNA. The effects of full length APP and the α-secretase cleaved ectodomain fragment, soluble APPα (sAPPα) were further investigated for their overexpression in breast cancers. The α-secretase involved was identified. The α-secretase expression together with APP was examined in clinical breast cancers.

Results: We showed that APP underwent proteolytic cleavage in breast cancer cells to generate sAPPα. The sAPPα and full length protein mediated breast cancer migration and proliferation, but in different functional extent. This proteolytic cleavage was mediated by ADAM10. Downregulation of APP and ADAM10 brought about similar functional effects. Overexpression of sAPPα reversed the effects of ADAM10 downregulation. Interestingly, in patients with non-luminal breast cancers, APP and ADAM10 expression correlated with each other and their co-expression was associated with the worst outcome.

Conclusions: These results demonstrated the contributory role of APP cleavage on its oncogenic roles in breast cancer. ADAM10 was the key α-secretase. APP and ADAM10 co-expression was associated with worse survival in non-luminal breast cancers. Targeting of APP or its processing by ADAM10 might be a promising treatment option in these cancers.
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http://dx.doi.org/10.1016/j.ebiom.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306343PMC
December 2018

Expression of biomarkers in the AKT pathway correlates with malignancy and recurrence in phyllodes tumours of the breast.

Histopathology 2019 Mar 15;74(4):567-577. Epub 2019 Jan 15.

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Aims: Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms with the potential to recur and metastasise. Apart from histological grading, the expression of biological markers and its relationship with tumour behaviour have been topics of interest. The phosphatidylinositol 3-kinase (PI3K)-AKT pathway regulates diverse biological functions, and is one of the most frequently deregulated pathways in cancers. Little is known of PI3K-AKT pathway alteration in PT. We aim to investigate the alterations in different component of AKT pathway in PTs.

Methods And Results: This study investigated the expression of four biological markers involved in this pathway (PTEN, INPP4B, PI3KCA and pAKT) in 134 PTs by the use of immunohistochemistry. According to an immunoscore incorporating staining intensity and proportion, low epithelial INPP4B expression (P = 0.045) was associated with recurrence. A trend of association was found for low epithelial PTEN expression with recurrence (P = 0.090). Interestingly, low epithelial INPP4B expression was also associated recurred tumours (P = 0.043). Stromal PI3KCA expression (P = 0.016) and pAKT expression (P = 0.006) were found to be correlated with increased histological grade, but an opposite trend was seen for stromal INPP4B expression (P = 0.018). In addition, epithelial and stromal PTEN expression, PI3KCA expression and pAKT expression showed strong correlations with each other (P ≤ 0.001).

Conclusions: These findings indicate that alterations in AKT pathway activation may correlate with malignant transformation and recurrence in PT. Low epithelial INPP4B/PTEN expression is associated with shorter recurrence-free survival. These observations suggest that the pathway may play a crucial role in the biological behaviour and progression of PT, and assessing the expression of this pathway may be of value in diagnosis, grading, prognostication, and management.
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http://dx.doi.org/10.1111/his.13782DOI Listing
March 2019

Core needle biopsy as an alternative to whole section in IHC4 score assessment for breast cancer prognostication.

J Clin Pathol 2018 Dec 18;71(12):1084-1089. Epub 2018 Sep 18.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

Aims: IHC4 score, based on expression of four routine markers (oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker, Ki67), is a recently developed, cost-effective prognostic tool in breast cancer. Possibly, the score may be useful also in advanced diseases where only core needle biopsy (CNB) is available and neoadjuvant therapy. However, its studies on CNB are scant. This study examined whether IHC4 score assessment on CNB is comparable to that from whole section (WS).

Methods: Immunohistochemical (IHC) analysis was performed for ER, PR, HER2 and Ki67 on 108 paired CNB and WS to evaluate IHC4 score (with follow-up range 1-230 months and 5 relapse/death). Concordance between the two was examined. Factors that affected the concordance were analysed. Additionally, IHC4 score was compared with Nottingham Prognostic Index (NPI).

Results: There was moderate concordance between IHC4 score on CNB and WS (all cases: κ=0.699, p<0.001; ER+ cases: κ=0.595, p<0.001). Among the IHC4 components, concordance for HER2 was the poorest (κ=0.178, p<0.001 in all cases; ER+ cases: κ=0.082, p<0.097). Significant factors affecting concordance between CNB and WS included number of cores, total core length and percentage of tumour cells in cores (p≤0.030), indicating the importance of sufficient sampling. Interestingly, the concordance was also affected by patients' age (p=0.039). There was poor agreement between IHC4 score and NPI (κ≤0.160).

Conclusion: Our results suggested that IHC4 score can be used on adequately sampled CNB. Its poor agreement with NPI highlights the independence of the two factors.
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http://dx.doi.org/10.1136/jclinpath-2018-205228DOI Listing
December 2018

The Clinical Value of PELP1 for Breast Cancer: A Comparison with Multiple Cancers and Analysis in Breast Cancer Subtypes.

Cancer Res Treat 2019 Apr 23;51(2):706-717. Epub 2018 Aug 23.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.

Purpose: Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a novel nuclear receptor (NR) co-regulator, is highly expressed in breast cancer. We investigated its expression in breast cancer subtypes, in comparison with other breast markers as well as cancers from different sites. Its prognostic relevance with different subtypes and other NR expression was also examined in breast cancers.

Methods: Immunohistochemical analysis was performed on totally 1,944 cancers from six different organs.

Results: PELP1 expression rate was the highest in breast cancers (70.5%) among different cancers. Compared to GATA3, mammaglobin and gross cystic disease fluid protein 15, PELP1 was less sensitive than GATA3 for luminal cancers, but was the most sensitive for non-luminal cancers. PELP1 has low expression rate (<20%) in colorectal cancers, gastric cancers and renal cell carcinomas, but higher in lung cancers (49.1%) and ovarian cancers (42.3%). In breast cancer, PELP1 expression was an independent adverse prognostic factor for non-luminal cancers (disease-free survival [DFS]: hazard ratio [HR], 1.403; p=0.012 and breast cancer specific survival [BCSS]: HR, 1.443; p=0.015). Interestingly, its expression affected the prognostication of androgen receptor (AR). ARposPELP1lo luminal cancer showed the best DFS (log-rank=8.563, p=0.036) while ARnegPELP1hi non-luminal cancers showed the worst DFS (log-rank=9.536, p=0.023).

Conclusion: PELP1 is a sensitive marker for breast cancer, particularly non-luminal cases. However, its considerable expression in lung and ovarian cancers may limit its utility in differential diagnosis in some scenarios. PELP1 expression was associated with poor outcome in non-luminal cancers and modified the prognostic effects of AR, suggesting the potential significance of NR co-regulator in prognostication.
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http://dx.doi.org/10.4143/crt.2018.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473277PMC
April 2019

Amyloid Precursor Protein Is Associated with Aggressive Behavior in Nonluminal Breast Cancers.

Oncologist 2018 11 14;23(11):1273-1281. Epub 2018 Aug 14.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong

Background: β-amyloid precursor protein (APP), a potential target for Alzheimer's disease treatment, has recently been shown to take part in carcinogenesis. Increased APP promotes migration, survival, and proliferation in breast cancer cell lines. We examined the clinical value of APP in breast cancers. A comprehensive examination of clinicopathological features related to APP expression in a large cohort of breast cancers and the corresponding metastatic lymph nodes was performed. APP expression and its prognostic impact in different breast cancer subtypes were examined.

Results: APP was highly expressed in nonluminal breast cancers and correlated with features associated with nonluminal breast cancers (including higher grade, the presence of necrosis, and higher proliferative index, growth factor receptor, and basal marker expression). Multivariate Cox hazard analysis demonstrated that APP was an independent adverse prognostic factor of disease-free survival (DFS; hazard ratio [HR], 2.090; = .013; 95% confidence interval [CI], 1.165-3.748) and breast cancer-specific survival (BCSS; HR, 2.631; = .002; 95% CI, 1.408-4.915) in the nonluminal group. The independent prognostic impact was also seen in triple negative breast cancers. Interestingly, a higher expression of APP was found in nodal metastasis compared with primary tumor. Such APP upregulation was correlated with further distal metastasis and poorer outcome (DFS: log-rank, 12.848; < .001; BCSS: log-rank, 13.947; < .001).

Conclusion: Our findings provided evidence of oncogenic roles of APP in clinical breast cancers. Patients with positive APP expression, particularly those with APP upregulation in lymph node metastases, may require vigilant monitoring of their disease and more aggressive therapy.

Implications For Practice: β-amyloid precursor protein (APP), a potential target for Alzheimer's disease, has recently been implicated in oncogenesis. Here, evidence of its roles in clinical breast cancers is provided. Positive APP expression was found to be an independent prognostic factor in nonluminal cancers, particularly triple negative breast cancers (TNBCs). Interestingly, a higher APP in nodal metastases was associated with distal metastases. TNBCs are heterogeneous and currently have no available target therapy. APP could have therapeutic potential and be used to define the more aggressive cases in TNBCs. Current prognostic analysis is based on primary tumor. The present data suggest that investigation of nodal metastases could provide additional prognostic value.
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http://dx.doi.org/10.1634/theoncologist.2018-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291326PMC
November 2018

CD147 expression is associated with poor overall survival in chemotherapy treated triple-negative breast cancer.

J Clin Pathol 2018 Nov 11;71(11):1007-1014. Epub 2018 Aug 11.

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China

Aims: In breast cancer models, the functional roles of CD147 in proliferation, invasion and treatment resistance have been widely reported. However, there are only a few studies examining the clinicopathological correlation and prognostic relevance of CD147 in breast cancer, especially in relation to breast cancer molecular subtypes.

Methods: In this study, we analysed CD147 expression in a large cohort of breast cancers, correlating with clinicopathological features and the expression of a comprehensive panel of biomarkers in triple-negative breast cancer (TNBC) and non-TNBC subsets. Its relationship with patients' survival was also analysed.

Results: CD147 was expressed in 11.9%(140/1174) of all cases and in 23.8% (40/168) of TNBC. The expression was associated with tumour histological subtypes (p=0.01) and most commonly seen in carcinoma with medullary features (26.0%). CD147 expression correlated with high tumour grade, presence of necrosis and basal-like breast cancer (BLBC) subtype, high Ki67 and expression of some other basal markers and stem-like markers. CD147 expression was also associated with poor overall survival in chemotherapy treated patients with TNBC.

Conclusions: CD147 is a putative marker in identifying TNBC or BLBC, and may be useful as a prognosis indicator for patients with TNBC or BLBC post chemotherapy.
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http://dx.doi.org/10.1136/jclinpath-2018-205342DOI Listing
November 2018

Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast.

Sci Rep 2018 03 1;8(1):3881. Epub 2018 Mar 1.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

Phyllodes tumor (PT) of the breast is a rare but clinically important fibroepithelial tumor with potential risks of recurrence and metastasis. Recent studies identified recurrent TERT promoter mutations in PTs. However, the clinical significance of this alteration has not been fully examined. Two hundred and seven PTs from two intuitions were included. All cases were subjected to immunohistochemical analysis for TERT expression. Analysis of TERT promoter mutations was further performed by Sanger sequencing targeting the hotspot mutation region on cases from one of the involved institutions. The expression of TERT was correlated with clinicopathologic features, mutation status and recurrence. There was an association of TERT expression and its promoter mutation. Both stromal TERT expression and its promoter mutation correlated with PT grading and older patient age. Recurrence free survival (RFS) of PT patients with high stromal TERT expression was shorter if the excision margin was positive. Our findings suggested a possible pathogenic role of TERT alteration in PT malignancy. Currently there is no consensus for re-excision for PT patients with positive surgical margin, particularly for low grade cases. Stromal TERT expression could be potentially useful to guide management patients with benign PTs.
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http://dx.doi.org/10.1038/s41598-018-22232-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832760PMC
March 2018

GATA-3 is superior to GCDFP-15 and mammaglobin to identify primary and metastatic breast cancer.

Breast Cancer Res Treat 2018 May 16;169(1):25-32. Epub 2018 Jan 16.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong.

Purpose: Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression in primary cancers from sites with frequent breast metastases remains unclear.

Methods: To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers [gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB)].

Results: GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers [59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes]. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.

Conclusions: GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.
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http://dx.doi.org/10.1007/s10549-017-4645-2DOI Listing
May 2018

Mammary phyllodes tumour: a 15-year multicentre clinical review.

J Clin Pathol 2018 Jun 16;71(6):493-497. Epub 2017 Nov 16.

Department of Surgery, Division of Breast Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.

Aims: Phyllodes tumour (PT) is an uncommon fibroepithelial tumour of the breast. It has a spectrum of aggressiveness in biological behaviour with chance of local recurrence and, occasionally, metastasis.

Methods: A 15-year retrospective review from a multicentre database in Hong Kong was performed.

Results: Clinical and pathological records of 465 patients with 469 PTs between 1998 and 2014 were reviewed. Median age of occurrence was 44 years (range 12-86 years). 281 (59.9%) PTs were benign, 124 (26.4%) were borderline and 64 (13.6%) were malignant. About half of all PTs (239, 51.5%) were between 2 and 5 cm while another 186 (40.1%) were >5 cm in size. Most PT (84.6%) were radiologically benign. Breast-conserving surgery (BCS) was feasible in 384 (82%) patients, whereas 84 (18%) patients had mastectomy. Multivariate analysis found that positive surgical margin (P<0.001) and BCS (P<0.001) were the only significant risk factors for local recurrence, while large tumour size (P=0.008) and malignant PT histotype (P<0.001) were the only significant risk factors for metastasis. Long-term prognosis of benign and borderline PT was excellent. After median follow-up interval of 85 months (range 12-180 months), the disease-specific survival of benign, borderline and malignant PT were 99.6%, 100% and 90.6%, respectively.

Conclusions: Local recurrence of PTs occurs irrespective of the tumour grade. Surgical margin is the only amendable factor to reduce the chance of recurrence.
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http://dx.doi.org/10.1136/jclinpath-2017-204827DOI Listing
June 2018

Robust and accurate digital measurement for HER2 amplification in HER2 equivocal breast cancer diagnosis.

Sci Rep 2017 07 28;7(1):6752. Epub 2017 Jul 28.

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Currently, there are no recommended alternative assays for HER2 cases deemed equivocal by immunohistochemistry and fluorescent in situ hybridization. Digital PCR (ddPCR), a highly accurate method to determine DNA copy number, could be a robust alternative for clinical HER2 diagnostics. HER2 and CEP17 copy numbers were quantified using two ddPCR platforms (QX200 and RainDrop) in 102 samples of invasive breast cancers. Compared to routine assays, ddPCR gave a sensitivity and specificity of 82.8% and 97.3% respectively, with a kappa value of 0.833 (p < 0.001). Moreover, the method proved to be robust as the results from two platforms was highly correlated (R = 0.91; Concordance rate = 97%; κ = 0.923, P < 0.001). Its performance was further tested on 114 HER2 equivocal cases in an independent validation cohort. 75% (21/28) of cases with HER2 amplification and 95% (82/86) of HER2 non-amplified case were classified as positive and negative by ddPCR respectively (κ = 0.709, P < 0.001). Notably, in the HER2 amplified cases, a lower percentage of HER2 positive cells could be related to the discordant results. Altogether, ddPCR is a robust alternative for clinical HER2 diagnostics. However, intratumoral heterogeneity of HER2 status still pose a challenge for HER2 analysis by ddPCR.
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http://dx.doi.org/10.1038/s41598-017-07176-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533703PMC
July 2017