Quantitative Impact of the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Practice Guideline Update on Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: A Systematic Analysis.

CONTEXT.­: The global impact of the new 2018 American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) practice guideline update on the overall HER2 status designation, compared with the prior 2013 iteration, is unknown. OBJECTIVES.­: To report the quantitative impact of the new guideline on HER2 status distribution. DESIGN.­: The analysis comprised a retrospective cohort of patients from the authors' institution, combined with other peer-reviewed publications that assessed the impact of the 2018 guideline in relation to the 2013 guideline. RESULTS.­: Our study revealed that the new guideline led to an average 9% reclassification rate for the overall HER2 status, with a net gain in overall HER2 negative designation. This is largely due to reclassification of the equivocal (Group 4) groups. Unexpectedly, infrequent but consistent discordance between Group 1/5 and fluorescence in situ hybridization results are observed across studies (1.8%; 73 of 3965 cases where fluorescence in situ hybridization and immunohistochemistry are both reported). CONCLUSIONS.­: Early clinical recognition of these resultant changes, including emerging issues of tumor heterogeneity, and potential discordance between immunohistochemistry to fluorescence in situ hybridization, is important for accurate clinical assessment of individual HER2 test results.

Clinicopathological and Prognostic Significance of Programmed Death Ligand 1 Expression in Korean Patients With Triple-negative Breast Carcinoma.

BACKGROUND/AIM: The clinicopathological and prognostic significances of programmed death ligand 1 (PD-L1) expression in triple-negative breast carcinoma (TNBC) are still unclear. We investigated whether PD-L1 expression is associated with clinicopathological characteristics and outcomes of TNBC patients. MATERIALS AND METHODS: We performed immunostaining for PD-L1 (SP142) in 83 TNBCs. Staining proportion of ≥1% was regarded as positive PD-L1 expression. RESULTS: Positive intratumoral (IT) PD-L1 expression (19/83; 22.9%) was inversely associated with lymphovascular invasion (LVI) and distant metastasis, and was significantly associated with better disease-free survival for TNBC patients. Positive stromal PD-L1 expression (44/83; 53.0%) also correlated inversely with LVI. CONCLUSION: Positive IT PD-L1 expression was associated with favorable outcomes in TNBC. In addition, positive IT and stromal PD-L1 were inversely associated with LVI and distant metastasis of TNBC.

CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer.

Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24- are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24-/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-ßR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance.

Systematic assessment of HER2/neu in gynecologic neoplasms, an institutional experience.

BACKGROUND: HER2/neu overexpression and/or amplification has been widely studied in a number of solid tumors, primarily in the breast. In gynecologic neoplasms, determination of HER2/neu status has not been well studied as a predictive biomarker in anti-HER2/neu treatment. METHODS: We systematically evaluated the HER2/neu reactions by immunohistochemistry and fluorescent in situ hybridization in malignant gynecologic neoplasms as experienced in our institution. RESULTS: The HER2/neu overexpression or amplification occurred in 8 % of the cancers of the gynecological organs in our series. Majority of the HER2/neu overexpression and/or amplification occurred in clear cell (27 %) and serous (11 %) carcinomas. HER2/neu positivity was also seen in undifferentiated as well as in mixed clear cell and serous carcinomas. Discordant IHC and FISH results (positive by FISH but not IHC) was seen in 2 cases. Majority of the HER2/neu overexpression and/or amplification occurs in the endometrium rather than the ovary. Heterogeneity of the HER2/neu by IHC staining was in < 2 % of the tumors in our series. CONCLUSIONS: We recommend the HER2/neu studies on Müllerian carcinomas of clear cell, serous, and undifferentiated types, particularly when they arise in the endometrium. Since there are some discordant IHC/FISH results, we also propose performing the HER2/neu testing by FISH when the IHC score is less than 3 + .

Upgrade rates of high-risk breast lesions diagnosed on core needle biopsy: a single-institution experience and literature review.

Optimal management of high-risk breast lesions detected by mammogram yielding atypical ductal hyperplasia, flat epithelial atypia, atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar without atypia on core needle biopsy is controversial. This is a single-institution retrospective review of 5750 core needle biopsy cases seen over 14.5 years, including 249 (4.3%), 72 (1.3%), 50 (0.9%), 37 (0.6%), and 54 (0.9%) cases of atypical ductal hyperplasia, flat epithelial atypia, atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar without atypia, respectively. Patient age, radiologic characteristics, needle gauge, and excision diagnoses were recorded. Of 462 high-risk cases analyzed, 333 (72%) underwent excision. Upgrade rate to ductal carcinoma in situ, pleomorphic carcinoma in situ, or invasive mammary carcinoma was 18% for atypical ductal hyperplasia, 11% for flat epithelial atypia, 9% for atypical lobular hyperplasia, 28% for lobular carcinoma in situ, and 16% for radial scar. Carcinoma diagnosed on excision was more likely to be in situ than invasive, and if invasive, more likely to be low grade than high grade. Overall, cases that were benign (vs high risk or carcinoma) on excision were less likely to have residual calcifications after biopsy (17% vs 27%, P=0.013), and more likely to have a smaller mass size (<1 cm) (82% vs 50%, P=0.001). On subgroup analysis, atypical ductal hyperplasia cases that were benign (vs high risk or carcinoma) on excision were more likely to have smaller mass size (<1 cm) (P=0.025). Lobular neoplasia diagnosed incidentally (vs targeted) on core needle biopsy was less likely to upgrade on excision (5% vs 39%, P=0.002). A comprehensive literature review was performed, identifying 116 studies reporting high-risk lesion upgrade rates, and our upgrade rates were similar to those of more recent larger studies. Careful radiological-pathological correlation is needed to identify high-risk lesion subgroups that may not need excision.

Phyllodes tumours of the breast: a consensus review.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

Sentinel Lymph Node in Breast Cancer: Review Article from a Pathologist's Point of View.

Breast cancer staging, in particular N-stage changed most significantly due to the advanced technique of sentinel lymph node biopsy two decades ago. Pathologists have more thoroughly examined and scrutinized sentinel lymph node and found increased number of small volume metastases. While pathologists use the strict criteria from the Tumor Lymph Node Metastasis (TNM) Classification, studies have shown poor reproducibility in the application of American Joint Committee on Cancer and International Union Against Cancer/TNM guidelines for sentinel lymph node classification in breast cancer. In this review article, a brief history of TNM with a focus on N-stage is described, followed by innate problems with the guidelines, and why pathologists may have difficulties in assessing lymph node metastases uniformly. Finally, clinical significance of isolated tumor cells, micrometastasis, and macrometastasis is described by reviewing historical retrospective data and significant prospective clinical trials.

The Effect of Young Age in Hormone Receptor Positive Breast Cancer.

BACKGROUND: Studies have shown that young breast cancer patients have more advanced disease and worse survival compared to older patients. Our objective was to study disease characteristics and survival in the subset of young women with hormone receptor positive (HR+) and HER2 negative (HER2-) cancer. METHODS: We retrospectively analyzed HR+/HER2- breast cancer patients who underwent surgery at our institution between 2002 and 2010. We compared clinical characteristics, pathology, treatment, and recurrence-free survival between younger (≤40 years) and older (>40 years) patients. RESULTS: Of 669 HR+/HER2- breast cancer cases, 54 (8.1%) patients were 40 years or younger. Younger patients had more luminal B subtype, high grade, poor differentiation, and increased lymphovascular invasion. Younger women were treated more often with mastectomy and adjuvant chemotherapy. Although the unadjusted recurrence-free survival at median 55-month follow-up was lower in younger women, adjusting for stage, there was no significant difference (90.7% versus 89.3%, p = 0.74) between groups. CONCLUSION: Younger patients with HR+/HER2- breast cancer had more advanced disease and more aggressive treatment than older patients. The unfavorable pathologic features suggest a biologically different tumor in young women. After adjusting for these factors, younger patients have a recurrence-free survival similar to older patients.

"Score the Core" Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers.

A quality initiative of postoperative radiographic imaging performed on mastectomy specimens to reduce histology cost and pathology report turnaround time.

Breast pathology relies on gross dissection for accurate diagnostic work, but challenges can necessitate submission of high tissue volumes resulting in excess labor, laboratory costs, and delays. To address these issues, a quality initiative was created through implementation of the Faxitron PathVision specimen radiography system as part of the breast gross dissection protocol; this report documents its impact on workflow and clinical care. Retrospective data from 459 patients who underwent simple or modified radical mastectomy at our institution between May 2012 and December 2014 were collected. Comparison was made between the mastectomy specimen control group before radiography use (233 patients, 340 breasts) and Faxitron group that underwent postoperative radiography (226 patients, 338 breasts). We observed a statistically significant decrease in mean number of blocks between control and Faxitron groups (47.0 vs 39.7 blocks; P<.0001), for calculated cost savings of US $146 per mastectomy. A statistically significant decrease in pathology report turnaround time was also observed (4.2 vs 3.8days; P=.038). Postoperative mastectomy specimen radiography has increased workflow efficiency and decreased histology costs and pathology report turnaround time. These findings may underestimate actual benefits and highlight the importance of quality improvement projects in anatomical pathology.

Predictors for contralateral prophylactic mastectomy in breast cancer patients.

BACKGROUND: In recent years, radical breast cancer surgery has been largely replaced by breast conservation treatment, due to early diagnosis and more effective adjuvant treatment. While breast conservation is mostly preferred, the trend of bilateral mastectomy has risen in the United States. The aim of this study is to determine factors influencing patients' choice for having contralateral prophylactic mastectomy (CPM). METHODS: This is a retrospective study of 373 patients diagnosed with primary invasive breast cancer who were treated by bilateral or unilateral mastectomy (BM or UM) at the Revlon/UCLA Breast Center between Jan. 2002 and Dec. 2010. In the BM group, only those with unilateral breast cancer who chose CPM were included in the analysis. RESULTS: When compared with the UM group, the following factors were found to be associated with BM: younger age, pre-menopausal, a family history of breast/ovarian cancer, BRCA mutation, more breast biopsies, history of breast augmentation, having MRI study within 6 months before the surgery, more likely to have reconstruction and sentinel lymph node biopsy (SLNB) and fewer had neoadjuvant/adjuvant chemotherapy/radiation. When patients with bilateral breast cancer were excluded, multivariate logistic regression analysis indicated younger patients with negative nodes, SLNB as the only nodal surgery and positive family history were significant factors predicting CPM and immediate reconstruction using tissue expanders or implants. CONCLUSION: Younger age, lower TN stage, requiring only SLNB and high risk family history predict contralateral prophylactic mastectomy. Tissue expander/implant-based reconstructions were more frequently chosen by patients with BM.

Cytokeratin 7 negative invasive breast carcinoma: clinicopathological and immunohistochemical analysis of 14 cases with clinical follow-up.

Cytokeratin 7 (CK 7) negative breast tumours are reported to occur rarely. We studied 14 CK 7 negative cases of primary invasive ductal carcinoma (IDC) detected during sentinel lymph node metastases work-up and immunohistochemistry panel in the work-up of metastatic carcinoma of unknown origin. Axillary lymph node metastases were present in seven patients (50%). Oestrogen receptor (ER) was strongly positive in all cases: progesterone receptor in 78%, Her-2/neu in 7% and high proliferation index with Ki-67 >20% was seen in 71% of the cases. Metastatic and/or recurrence were found in 8 of 14 patients (57%) with the mean clinical follow-up of 55 months. Metastatic sites include multiple bones, brain, spinal cord, liver, pancreas, ovary, lung, lymph node other than ipsilateral axillary and skin. 12 of 14 patients received adjuvant chemotherapy. All 14 patients received hormonal therapy and radiation therapy. Morphologically, IDC with neuroendocrine features was noted in 57%. Synaptophysin stain was positive in 57% and chromogranin was positive in 21% of the cases. In conclusion, these CK 7 negative breast carcinomas were ER positive, mostly Her-2/neu negative, had high Ki-67 and frequently showed neuroendocrine differentiation. More than half of these cases had a poor outcome.

Is axillary lymph node dissection necessary after sentinel lymph node biopsy in patients with mastectomy and pathological N1 breast cancer?

BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial reported that axillary lymph node dissection (ALND) did not change the recurrence and overall survival (OS) rates in patients with lumpectomy and one to two positive nodes detected by sentinel lymph node biopsy (SLNB). The aim of this study was to determine whether patients with mastectomy and pathological N1 disease found by SLNB could forego ALND. MATERIALS AND METHODS: This is a retrospective study of 214 patients diagnosed with primary invasive breast cancer who were treated by mastectomy and lymph node staging surgery (SLNB or ALND) at the Revlon/UCLA Breast Center between January 2002 and December 2010. Patients with pathological N1 disease were separated by their first nodal surgery into SLNB (subgroups: observation, radiation, and additional ALND with or without radiation) and ALND groups (subgroups: ALND with or without radiation). RESULTS: After a median follow-up of 43.6 months, the OS and systemic relapse-free survival (RFS) rate of the radiation group and additional ALND group were significantly better than the observation group (p = 0.031 and 0.046, respectively). Human epidermal growth factor receptor 2 (HER2) expression was found to predict OS and patients' age, histological grade and HER2 expression predicted systemic recurrence. Compared with the SLNB group, pain (p = 0.021) and lymphedema (p = 0.043) occurred more frequently in the ALND group. CONCLUSION: Radiation was as effective as ALND in patients with mastectomy and N1 disease for OS and RFS rates, yet radiation after SLNB had fewer side effects than ALND. SLNB followed by radiation could replace ALND in patients with mastectomy and pathological N1 breast cancer identified by SLNB.

Comparative evaluation of ProEx C and ImmunoCyt/uCyt assays in atypical urine cytology.

CONTEXT: Detection of urothelial carcinoma by urine cytology can be challenging. Recently, ProEx C has been studied as a marker to improve detection of urothelial carcinoma. ProEx C is an assay targeting expression of topoisomerase II-α and the minichromosome maintenance protein-2 and is used to assist in diagnoses of gynecologic specimens. OBJECTIVE: To evaluate the utility of ProEx C and uCyt in atypical urine cytology. DESIGN: Sixty-eight specimens with a diagnosis of atypical urine cytology, concurrent uCyt testing, and surgical biopsy follow-up were included. Slides were restained with ProEx C. ProEx C was recorded as positive when nuclear staining was seen in at least one morphologically atypical urothelial cell. The uCyt was scored as positive if at least one morphologically atypical urothelial cell showed positive fluorescence staining. Thirteen cases (19%) had benign histologic diagnoses, 18 (26%) had low-grade papillary urothelial carcinoma, and 37 (54%) had high-grade urothelial carcinoma. RESULTS: The overall sensitivity was 85% for ProEx C, 85% for uCyt, and 93% for the combination of the 2 assays. The overall specificity was 69% for ProEx C, 31% for uCyt, and 23% for the combination of the 2 tests. In predicting high-grade urothelial carcinoma, sensitivity was 92% for ProEx C, 86% for uCyt, and 92% for both tests. In predicting low-grade papillary urothelial carcinoma, sensitivity was best with the combination of the 2 tests at 94%. CONCLUSION: ProEx C has superior specificity to uCyt. The combination of the 2 tests yielded high sensitivity not only for high-grade urothelial carcinoma but also for low-grade papillary urothelial carcinoma.

The impact of atypia/follicular lesion of undetermined significance and repeat fine-needle aspiration: 5 years before and after implementation of the Bethesda System.

BACKGROUND: Limited studies have examined the impact of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) and specifically the category of atypia or follicular lesion of undetermined significance (AUS/FLUS). We studied their effects on reporting rates, subsequent management, and surgical outcome over a 10-year period, 5 years before and after implementation of the BSRTC. METHODS: A retrospective review of thyroid fine-needle aspiration (FNA) reports from 2003 to 2012 was performed. Diagnoses made before BSRTC were reclassified into the most appropriate category. Repeat FNA results for all AUS/FLUS cases were recorded. Surgical follow-up results were matched by side and size of the targeted nodule. Incidental microcarcinomas were not considered "malignant" on excision. Malignancy rates were calculated based on excision and by all aspirated specimens. RESULTS: Initial AUS/FLUS cases increased from 3% to 7% (P = .001) with implementation of the BSRTC. The nondiagnostic rate decreased from 19% to 10% (P = .026). Differences in malignancy rates before and after implementation of the BSRTC were not significant for all diagnostic categories. More repeat FNAs and fewer surgical excisions were performed after an initial AUS/FLUS diagnosis. Repeat FNA reclassified 56% of AUS/FLUS cases into a definitive category. The malignancy risks for AUS/FLUS plus benign and AUS/FLUS plus AUS/FLUS repeat FNAs were elevated compared with single benign and AUS/FLUS diagnoses. CONCLUSIONS: AUS/FLUS cases are increasing with the implementation of the BSRTC. Given the potential increase in repeat FNAs as a result, it may be important to alert the clinician regarding the elevated malignancy risk of a benign or AUS/FLUS diagnosis associated with a prior AUS/FLUS finding.

A pregnant dilemma: primary hyperparathyroidism due to parathyromatosis in pregnancy.

OBJECTIVE: To describe an exceedingly rare case of parathyromatosis in pregnancy and the limited medical treatment options available for such cases that are refractory to surgery. METHODS: Case presentation and description of clinical course with brief review of the literature. RESULTS: A 21-year-old woman with a history of 3.5 gland parathyroidectomy presented with severe hyperemesis during her first trimester of pregnancy and was found to have primary hyperparathyroidism attributable to parathyromatosis. We describe the diagnostic and management dilemmas associated with this case, which included localization of the culprit lesions, a technically challenging surgical resection and subsequent medical management with cinacalcet when symptomatic hypercalcemia recurred during the third trimester. To our knowledge, this is only the third report of the successful use of cinacalcet during pregnancy, and the first case report of parathyromatosis presenting during pregnancy. CONCLUSION: Cinacalcet was used safely and effectively during the third trimester of pregnancy to treat symptomatic hypercalcemia due to parathyromatosis.

Utility of ProEx C in the histologic evaluation of the neoplastic and nonneoplastic urothelial lesions.

ProEx C is an antibody cocktail targeting the expression of topoisomerase IIα and minichromosome maintenance protein 2. ProEx C staining is being used mainly to assist in diagnoses of dysplasia in gynecological specimens. This study was designed to determine the utility of ProEx C in assessing the urothelial lesions. Sixty-four patient specimens were divided into 5 groups: group I, 22 benign; group II, 13 low-grade noninvasive papillary urothelial carcinoma; group III, 10 high-grade urothelial carcinoma in situ (flat lesion); and group IV, 19 high-grade noninvasive papillary and invasive urothelial carcinomas. ProEx C reactions were scored in basal, parabasal, intermediate, and superficial cell layers. A sample was recorded as positive when nuclear staining was seen in the cells of the intermediate and/or superficial layers. Of 22 cases in group I, 21 were negative for ProEx C with a specificity of 95%. Of 13 cases in group II, 11 had positive results with sensitivity of 85%. All cases in groups III and IV had positive staining pattern with ProEx C with a sensitivity of 100%. In this study, ProEx C stain had an overall 95% sensitivity and specificity with positive and negative predictive values of 98% and 91%, respectively, for detection of urothelial carcinoma. We conclude that ProEx C is effective in differentiating carcinoma in situ and benign urothelial lesions. It also resolves issues in low- versus high-grade papillary urothelial carcinomas. To our knowledge, this is the first publication on the diagnostic application of ProEx C in histopathology of the urothelial lesions.