The differential diagnosis of cystic axillary masses is broad and includes intranodal lesions. Cystic metastatic tumor deposits are rare, and have been reported in a few tumor types, most commonly in ...the head and neck region, but rarely described with metastatic mammary carcinoma. We report a case of a 61-year-old female who presented with a large right axillary mass. Imaging studies revealed a cystic axillary mass and ipsilateral breast mass. She was managed with breast conservation surgery and axillary dissection for invasive ductal carcinoma, no special type, Nottingham grade 2 (21 mm). One of nine lymph nodes contained a cystic nodal deposit (52 mm), which resembled a benign inclusion cyst. Oncotype DX recurrence score for the primary tumor was low (8), conferring a low risk of disease recurrence despite the large size of the nodal metastatic deposit. A cystic pattern of metastatic mammary carcinoma is rare and important to recognize for accurate staging and management decisions.
Aims
Cystic neutrophilic granulomatous mastitis (CNGM) is an uncommon but increasingly recognised cause of mastitis, often associated with Corynebacterium ssp. infection. We studied the ...histopathological and clinical features of CNGM in a Canadian setting, and the work‐up required to identify pathogenic microorganisms.
Methods and results
A retrospective search for breast specimens with abscess, acute, chronic and/or granulomatous inflammation from 1998 to 2018 was performed. Haematoxylin and eosin slides were reviewed for typical histological features of CNGM. Histochemically stained slides for microorganisms were also reviewed. Repeat Gram stains were performed if initially negative. Electronic medical records were ed for microbiology results and relevant clinical data. Twelve cases were identified. All were female, aged 25–57 years, mainly Caucasian, with one Venezuelan and two of Chinese ethnicity. Most were parous (10 of 12); five of 12 had an endocrinopathy. Bacteria were identified in one or more specimens from eight of 12 patients; additional Gram stains revealed organisms in four of 12 cases. Of four bacterial cultures, one grew Corynebacterium kroppenstedtii. 16S polymerase chain reaction for three samples was negative. Two patients had multiple breast biopsies, showing early palisaded granulomas followed by classic features of CNGM. The patients had various management approaches, including surgery and antimicrobials.
Conclusions
CNGM may present as palisaded granulomatous inflammation, without the expected ‘cystic’ pattern, suggesting that there is an evolution of histomorphology with this infection. Most patients with CNGM are parous, and there may be an association with endocrinopathies. Application of multiple Gram stains increases the yield of microorganism identification. Recognition of CNGM in breast biopsies and collaborative communications are essential to direct appropriate therapy.
Mammary adenoid cystic carcinoma (ACC) is a rare subtype of breast cancer with a favorable prognosis. Here we report on predictors of outcome based on a detailed morphologic review and analysis of ...108 mammary ACC. Sixty-four tumors (59.2%) were pure conventional ACC, 23 (21.3%) were pure basaloid ACC. Follow-up was available for 87 patients (median: 51 mo). Eighteen patients (20.7%) developed recurrence: 7 (8%) had local recurrence and 14 (16%) had distant metastasis. Two patients died of disease, 1 died of an unrelated cause, 14 were alive with disease (including 8 in palliative care), and 70 (80.5%) were alive with no evidence of disease. Of 90 patients with known lymph node (LN) status 9 (10%) had nodal involvement (all with basaloid ACC). Distant metastases in patients with predominantly basaloid ACC compared with pure conventional ACC were more common (40% vs. 7.7%) and occurred earlier (22 vs. 84 mo). The following factors were found to be predictive of recurrence-free survival: positive margin, Nottingham grade, neovascularization, basaloid component, perineural invasion, lymphovascular invasion, >30% solid growth, necrosis and LN involvement; the first 3 remained statistically significant on multivariate analysis. Factors predictive of distant disease-free survival were neovascularization, Nottingham grade, lymphovascular invasion, solid component >50%, LN involvement, basaloid component >50%, tumor necrosis, perineural invasion, and final margin. Only neovascularization remained statistically significant on multivariate analysis. Basaloid ACC is an aggressive variant of mammary ACC with more frequent nodal involvement and higher incidence of distant spread. LN staging should be performed for all mammary basaloid ACC.
Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different ...PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.
Aims
The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 ...in‐situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours.
Methods and results
A total of 904 dual‐probe HER2/chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty‐five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2‐negative to ‐equivocal, 15 cases (1.7%) were reclassified as HER2‐positive and four cases from HER2‐equivocal to ‐negative. A subset of primary breast cancers, reported initially as HER2‐negative but ‐equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2‐negative and ‐positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement.
Conclusions
The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting.
In 2018, the American Society of Clinical Oncology/College of American Pathologists revised the criteria for HER2 immunohistochemistry (IHC) equivocal (2+) classification in their updated guideline. ...We reviewed invasive breast cancer specimens originally classified as equivocal (2+) under the 2018 guideline that underwent HER2 fluorescence in situ hybridization (FISH) testing from August 2018 to August 2019 at our Canadian reference hospital to investigate cases with ambiguous staining patterns between the 1+ and 2+ definitions. Demographics, pathologic features, and pre-analytic conditions were recorded. The H&E and corresponding HER2 IHC slides were reviewed to confirm tumor type and grade, and classify as HER2 indeterminate, 0, 1+, 2+, or “Intermediate” (staining features between the 1+ and 2+ classifications). FISH testing was performed on 289 cases and 273 met inclusion criteria. The FISH-amplified rate was 12.1%. Upon IHC review, 44.7% (122/273) of cases were reclassified as Intermediate. These cases had incomplete staining with moderate intensity (43/122, 35.3%) and/or <10% complete weak or moderate staining (102/122, 83.6%). Intermediate cases had a significantly lower frequency of amplified FISH results than 2+ cases (
p
< 0.0001), with only four (3.3%) FISH positive and two (1.6%) FISH heterogeneous. Our study highlights the ambiguity in the current guideline for classifying some HER2 IHC patterns. As the rate of gene amplification in these cases was low (4.9%), we recommend adhering to the 2018 HER2 2+ criteria for reflex FISH testing. However, cases with <10% moderate complete staining and certain heterogeneous patterns warrant special consideration. Further descriptive clarification of 1+ criteria is needed.
Objectives
To develop a breast cancer risk model to identify women at mammographic screening who are at higher risk of breast cancer within the general screening population.
Methods
This ...retrospective nested case-control study used data from a population-based breast screening program (2009–2015). All women aged 40–75 diagnosed with screen-detected or interval breast cancer (
n
= 1882) were frequency-matched 3:1 on age and screen-year with women without screen-detected breast cancer (
n
= 5888). Image-derived risk factors from the screening mammogram (percent mammographic density PMD, breast volume, age) were combined with core biopsy history, first-degree family history, and other clinical risk factors in risk models. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). Classifiers assigning women to low- versus high-risk deciles were derived from risk models. Agreement between classifiers was assessed using a weighted kappa.
Results
The AUC was 0.597 for a risk model including only image-derived risk factors. The successive addition of core biopsy and family history significantly improved performance (AUC = 0.660,
p
< 0.001 and AUC = 0.664,
p
= 0.04, respectively). Adding the three remaining risk factors did not further improve performance (AUC = 0.665,
p
= 0.45). There was almost perfect agreement (kappa = 0.97) between risk assessments based on a classifier derived from image-derived risk factors, core biopsy, and family history compared with those derived from a model including all available risk factors.
Conclusions
Women in the general screening population can be risk-stratified at time of screen using a simple model based on age, PMD, breast volume, and biopsy and family history.
Key Points
• A breast cancer risk model based on three image-derived risk factors as well as core biopsy and first-degree family history can provide current risk estimates at time of screen.
• Risk estimates generated from a combination of image-derived risk factors, core biopsy history, and first-degree family history may be more valid than risk estimates that rely on extensive self-reported risk factors.
• A simple breast cancer risk model can avoid extensive clinical risk factor data collection.
New therapies are being developed for breast cancer, and in this process, some “old” biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker’s ...intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs’ clinical utility.
Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs.
Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%.
Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.
Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that ...are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.
•HER2 is negative in most metastases that have a HER2 negative primary tumor.•A selective approach to HER2 ISH testing in metastases may be appropriate.•HER2 discordance in metastases may be predicted by morphologic or IHC differences.
Immunohistochemistry is used on cell blocks constructed from cytopathology samples fixed in methanol-based fixatives, such as CytoLyt (Cytyc Corp), and on surgical pathology tissues exposed to ...decalcifying agents, often without technical validation. We evaluated a panel of commonly utilized antibodies in normal tissues exposed to differing preanalytic conditions as follows: CytoLyt fixation, formalin fixation followed by exposure to decalcifying agents (Leica Decalcifier I-10% formic acid or Leica Decalcifier II-5% hydrochloric acid), or standard formalin fixation. Altered expression was observed with several antibodies compared with standard formalin fixation. Specifically, there was absent or near absent expression of thyroid transcription factor 1 (TTF-1), D2-40, and CD20 in CytoLyt-fixed tissues, whereas reduced expression was observed for p63, estrogen receptor, S100 protein, CD3, calretinin, chromogranin, and synaptophysin. Absent or near absent expression of TTF-1 was also observed with exposure to hydrochloric acid, whereas reduced expression was observed for CK5/6, CK7, p63, estrogen receptor, leukocyte common antigen, CD3, CD20, and synaptophysin. Exposure to formic acid had less impact with reduced expression observed for only 3 antibodies (CK8/18, CK7, and TTF-1). The results of this study demonstrate the need to validate immunohistochemical protocols on control tissue treated in the same manner as test tissue, including CytoLyt fixation and exposure of tissue to decalcifying agents.
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