Time to Treatment Initiation for Breast Cancer During the 2020 COVID-19 Pandemic.

PURPOSE: The COVID-19 pandemic has posed significant pressures on healthcare systems, raising concern that related care delays will result in excess cancer-related deaths. Because data regarding the impact on patients with breast cancer are urgently needed, we aimed to provide a preliminary estimate of the impact of COVID-19 on time to treatment initiation (TTI) for patients newly diagnosed with breast cancer cared for at a large academic center. METHODS: We conducted a retrospective study of patients with newly diagnosed early-stage breast cancer between January 1, 2020, and May 15, 2020, a time period during which care was affected by COVID-19, and an unaffected cohort diagnosed between January 1, 2018 and May 15, 2018. Outcomes included patient volume, TTI, and initial treatment modality. Adjusted TTI was compared using multivariable linear regression. RESULTS: Three hundred sixty-six patients were included. There was an 18.8% decrease in patient volume in 2020 (n = 164) versus 2018 (n = 202). There was no association between time of diagnosis (pre-COVID-19 or during COVID-19) and adjusted TTI (P = .926). There were fewer in situ diagnoses in the 2020 cohort (P = .040). There was increased use of preoperative systemic therapy in 2020 (43.9% overall, 20.7% chemotherapy, and 23.2% hormonal therapy) versus 2018 (16.4% overall, 12.4% chemotherapy, and 4.0% hormonal therapy) (P < .001). CONCLUSION: TTI was maintained among patients diagnosed and treated for breast cancer during the COVID-19 pandemic at a single large academic center. There was a decrease in patient volume, specifically in patients with in situ disease and a shift in initial therapy toward the use of preoperative hormonal therapy.

Iatrogenic issues in breast pathology.

Modern breast imaging techniques include digital mammography, 3-dimensional tomography, high-resolution ultrasound, and magnetic resonance imaging. Each of these has enabled the diagnosis of ever smaller, largely non-palpable lesions, not all of which require surgery. As these techniques evolved, so too did methods of accurately targeting and sampling the lesions, necessitating methods to mark the areas should surgical localization be needed. These methods have introduced heretofore unseen histologic changes to both breast tissue and lymph nodes, especially sentinel lymph nodes. These changes are the topic of this review.

Microglandular Adenosis: A Possible Non-Obligate Precursor to Breast Carcinoma With Potential to Either Luminal-Type or Basal-Type Differentiation.

Microglandular adenosis (MGA) of the breast is exceedingly rare, with only a few case reports and series published to date. Previous studies have elegantly demonstrated the progression of benign MGA to atypical MGA to MGA-in situ carcinoma to invasive carcinoma and therefore suggest MGA as a possible non-obligate precursor lesion to a subset of breast carcinomas. Immunohistochemically, MGA is negative for estrogen receptor (ER), progesterone receptor (PR), and HER2-neu oncoprotein expression, and carcinomas arising in the setting of MGA are often reported to be triple negative. In this article, we present a unique case of an ER+/PR+/HER2- invasive carcinoma associated with MGA and atypical MGA. Our case highlights the diagnostic pitfall of MGA and suggests that MGA is a heterogeneous group of lesions with potential for either luminal-type or basal-type differentiation during progression to breast carcinoma.

Adenomyoepitheliomas of the Breast Frequently Harbor Recurrent Hotspot Mutations in PIK3-AKT Pathway-related Genes and a Subset Show Genetic Similarity to Salivary Gland Epithelial-Myoepithelial Carcinoma.

Adenomyoepitheliomas (AME) of the breast and epithelial-myoepithelial carcinomas (EMCs) of salivary gland are morphologically similar tumors defined by the presence of a biphasic population of ductal epithelial elements mixed with myoepithelial cells. We sought to explore the molecular profile of AMEs and determine whether they might also share the PLAG1, HMGA2, and HRAS alterations seen in EMCs. Tumor tissue from 19 AMEs was sequenced and analyzed using Ion AmpliSeq Cancer Hotspot Panel v2 covering ∼2800 COSMIC mutations across 50 cancer-related genes. Cases were additionally screened by FISH for PLAG1 and HMGA2 rearrangements. Of 19 AMEs (12 benign; 7 malignant), 2 cases failed the DNA extraction. Of the remaining 17 cases, 14 had at least one nonsynonymous mutation identified. The most common mutations were in PIK3CA (6/17) and AKT1 (5/17), which were mutually exclusive. Two tumors demonstrated mutations in APC, while 1 demonstrated an STK11 mutation. Mutations in ATM, EGFR, FGFR3 or GNAS were identified in 4 cases with concurrent AKT1 mutations. HRAS mutation co-occurring with PIK3CA mutation was noted in 1 case of ER-negative malignant AME. While 2 cases harbored alterations in HMGA2, none was positive for PLAG1 rearrangement. Our findings confirm that breast AMEs are genetically heterogeneous exhibiting recurrent mutually exclusive mutations of PIK3CA and AKT1 in a majority of cases. HRAS mutations co-occur with PIK3CA mutations in ER-negative AMEs and may possibly be linked to clinically aggressive behavior. We identified hotspot mutations in additional genes (APC, STK11, ATM, EGFR, FGFR3, and GNAS). We report the presence of HMGA2 alterations in 2/16 AMEs, supporting their relationship with EMC of salivary glands in at least a subset of cases. PIK3CA, AKT1 and HRAS may serve as potential actionable therapeutic targets in clinically aggressive AMEs.

Evaluation of Biomarkers in Multiple Ipsilateral Synchronous Invasive Breast Carcinomas.

CONTEXT.­: The College of American Pathologists guidelines recommend testing additional tumor foci in multifocal invasive breast carcinomas for the biomarkers estrogen receptor (ER), progesterone receptor, and HER2 only if the carcinomas show different morphologies or grades. OBJECTIVE.­: To assess clinical significance of testing for biomarkers in additional tumor foci in multifocal invasive breast tumors. DESIGN.­: Retrospective analysis of 118 patients diagnosed with ipsilateral synchronous multifocal breast carcinomas from January 2015 through March 2016 at Mount Sinai Hospital (New York, New York). RESULTS.­: Eighty-six cases were tested for at least 1 of the 3 biomarkers in additional tumor foci. Fifteen cases (17%) showed discordant staining between the 2 foci for at least one biomarker. Of the 7 of 67 ER-discordant cases (10%), 4 (57%) showed major variation from negative to positive expression, including 3 cases in which a smaller tumor focus was strongly positive for ER whereas the index tumor was negative. Similarly, within the 7 of 67 progesterone receptor-discordant cases (10%), 4 (57%) showed major variation from negative to positive, and in 3 cases with major discordance, the index tumor was negative for progesterone receptor, whereas a smaller focus was positive. A difference in HER2 expression was noted in 5 of 86 cases (6%). In only 5 of the 15 patients (33%) with discordant results, biomarker testing on additional foci would have been offered per the College of American Pathologists recommendations because of differences in histology or grading. Of the remaining 10 patients, 7 (70%) with positive results on smaller foci would have been deprived of appropriate adjuvant systemic treatment if the smaller focus had not been tested. CONCLUSIONS.­: We propose that negative values expressed in the primary tumor be repeated routinely on additional ipsilateral synchronous tumors.

MYB rearrangement and immunohistochemical expression in adenomyoepithelioma of the breast: a comparison with adenoid cystic carcinoma.

AIMS: Adenomyoepithelioma (AME) and adenoid cystic carcinoma (ACC) of the breast have been noted to occur simultaneously, raising the possibility that AME may represent a related or precursor lesion to ACC. ACC frequently harbours genetic rearrangement of the MYB gene. We sought to clarify the relationship between AME and ACC by comparing their rates of MYB expression by IHC and MYB rearrangement by FISH. METHODS AND RESULTS: IHC and FISH for MYB rearrangement were performed on paraffin-embedded sections of 11 breast ACCs, 11 non-breast ACCs and 11 breast-AMEs. Using FISH, five of eight (63%) interpretable breast ACCs demonstrated MYB gene rearrangement. Nine of 11 (81%) breast ACCs demonstrated MYB expression (range = 20-95%). Of the three FISH-negative breast ACCs, two were solid variant and demonstrated strong MYB expression by IHC. Of the 10 interpretable non-breast ACCs, six showed MYB rearrangement, all of which were conventional type. Nine of these 11 (81%) cases showed MYB immunoexpression (range = 10-90%), including three solid-variant cases which were negative by FISH. No MYB rearrangements were detected by FISH in 10 interpretable AMEs. However, three of 11 cases (27%) showed weak to moderate MYB expression by IHC (range = 10-40%). CONCLUSIONS: Our results indicate that AMEs do not harbour MYB gene rearrangement. IHC for MYB may be helpful in diagnosing FISH-negative cases of ACC, particularly the diagnostically more difficult solid variants. However, weak to moderate MYB expression in a subset of AMEs highlights not only a potential diagnostic pitfall, but also shared pathophysiology with ACC worth investigating further at the genomic level.

Mucinous Cystadenocarcinoma of the Breast: Report of 2 Cases Including One With Long-Term Local Recurrence.

Primary mucinous cystadenocarcinoma (MCA) of breast is an exceedingly rare tumor with histologic resemblance to MCA arising in ovary, pancreas, and gastrointestinal tract. In this article, we present 2 additional cases of MCA of breast, one highlighting the diagnostic challenges of a rare entity that may potentially lead to unnecessary chemotherapy and the second case presenting with recurrence after 8 years of primary surgical excision defying the indolent behavior reported in the literature. To our knowledge, this is the first reported instance of such behavior.

Observation versus excision of lobular neoplasia on core needle biopsy of the breast.

PURPOSE: Controversy surrounds management of lobular neoplasia (LN), [atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS)], diagnosed on core needle biopsy (CNB). Retrospective series of pure ALH and LCIS reported "upgrade" rate to DCIS or invasive cancer in 0-40%. Few reports document radiologic/pathologic correlation to exclude cases of discordance that are the likely source of most upgrades, and there is minimal data on outcomes with follow-up imaging and clinical surveillance. METHODS: Cases of LN alone on CNB (2001-2014) were reviewed. CNB yielding LN with other pathologic findings for which surgery was indicated were excluded. All patients had either surgical excision or clinical follow-up with breast imaging. All cases included were subject to radiologic-pathologic correlation after biopsy. RESULTS: 178 cases were identified out of 62213 (0.3%). 115 (65%) patients underwent surgery, and 54 (30%) patients had surveillance for > 12 months (mean = 55 months). Of the patients who underwent surgical excision, 13/115 (11%) were malignant. Eight of these 13 found malignancy at excision when CNB results were considered discordant (5 DCIS, and 3 invasive lobular carcinoma), with the remainder, 5/115 (4%), having a true pathologic upgrade: 3 DCIS, and 2 microinvasive lobular carcinoma. Among 54 patients not having excision, 12/54 (22%) underwent subsequent CNB with only 1 carcinoma found at the initial biopsy site. CONCLUSIONS: Surgical excision of LN yields a low upgrade rate when careful consideration is given to radiologic/pathologic correlation to exclude cases of discordance. Observation with interval breast imaging is a reasonable alternative for most cases.

Iatrogenically false positive sentinel lymph nodes in breast cancer: Methods of recognition and evaluation.

With the introduction of sentinel lymph node (SLN) biopsy as a standard procedure for staging clinically node negative breast cancer patients, meticulous pathologic evaluation of SLNs by serial sections and/or immunohistochemistry for cytokeratins has become commonplace in order to detect small volume metastases (isolated tumor cells and micrometastases). This practice has also brought to the fore the concept of iatrogenically false positive sentinel nodes secondary to epithelial displacement produced largely by preoperative needling procedures. While this concept is well described in the clinical and pathologic literature, it is, in our experience, still under-recognized, with such lymph nodes frequently incorrectly diagnosed as harboring true metastases, possibly resulting in unwarranted further surgery and/or chemotherapy. This review discusses the concept of displaced epithelium in the histologic evaluation of breast surgical specimens and provides a stepwise approach to the correct identification of iatrogenically transported displaced epithelial cells in sentinel lymph nodes.

The Impact of 2013 Updated ASCO/CAP HER2 Guidelines on the Diagnosis and Management of Invasive Breast Cancer: A Single-Center Study of 1739 Cases.

BACKGROUND: The purpose of this study was to determine the impact of revised ASCO/CAP 2013 HER2 guidelines on the clinical practice of pathologists and oncologists. MATERIALS AND METHODS: Retrospective analysis of 1739 patients with invasive breast carcinoma who underwent reflex HER2 (fluorescence in situ hybridization [FISH]) testing, using both 2007 and 2013 guidelines (2007-2014). RESULTS: Using 2013 guidelines, 255 (15%; 95% confidence interval [CI], 13%-16%) cases were classified as HER2+ as opposed to 186 (11%; 95% CI, 9%-12%) by 2007 guidelines (odds ratio [OR] 1.4; 95% CI, 1.2-1.8; P = .0005). Sixty-nine cases equivocal by 2007 guidelines (12% of all equivocal cases) were converted to HER2+ by 2013 guidelines. Sixty-two of these 69 cases shifted from HER2 equivocal to positive due to change in FISH ratio cutoff from 2.2 to 2.0. Six cases had FISH ratio < 2.0 but immunohistochemistry (IHC) score 3+ in 10% to 30% of tumor cells. One case had FISH ratio of 2.0 and IHC score 3+ in 10% to 30% of tumor cells. FISH and IHC test results were discordant in 5% (95% CI, 4%-6%) of cases using 2013 guidelines. No increase in HER2 FISH equivocal cases was observed. Reflex FISH testing of all IHC 1+ cases at our institution additionally detected 58 patients (5%; 95% CI, 4%-6%) with HER2 amplification. CONCLUSIONS: The 2013 guidelines increase the detection of HER2+ cases, without introducing significant difference in discordance rate of the IHC and FISH assays. Inclusion of HER2 copy number criterion does not increase the number of FISH equivocal cases in our cohort. We recommend IHC 1+ cases should be offered reflex FISH testing because failure to test them will miss a small number (5%) of potentially treatable cases.

Correlation of Oncotype DX Recurrence Score with Histomorphology and Immunohistochemistry in over 500 Patients.

Oncotype Dx is used to determine the recurrence risk (RR) in patients with estrogen receptor positive (ER+) and lymph node negative (LN-) breast cancer. The RR is divided into low (0-17), intermediate (18-30), and high (31) to predict chemotherapy benefit. Our goal was to determine the association between histomorphology, immunohistochemistry, and RR. We retrospectively identified 536 patients with ER+ and LN- breast cancers that underwent Oncotype testing from 2006 to 2013. Tumor size ranged from 0.2 cm to 6.5 cm (mean = 1.3 cm) and was uniform in all 3 categories. The carcinomas were as follows: ductal = 63.2%, lobular = 11.1%, and mixed = 35.7%. The RR correlated with the Nottingham grade. Increasing RR was inversely related to PR positivity but directly to Her2 positivity. Of the morphologic parameters, a tubular(lobular) morphology correlated only with low-intermediate scores and anaplastic type with intermediate-high scores. Other morphologies like micropapillary and mucinous were uniformly distributed in each category. Carcinomas with comedo intraductal carcinoma were more likely associated with high RR. Forty-four patients with either isolated tumor cells or micrometastases were evenly distributed amongst the 3 RR. While there was only 1 ER discrepancy between our immunohistochemistry (3+ 80%) and Oncotype, up to 8% of PR+ cases (mean = 15%, median = 5%) and 2% of HER2+ cases were undervalued by Oncotype.

Novel Hormone Receptors Present in Apocrine Cystadenoma of the Eyelid.

A 53-year-old woman presented with an apocrine cystadenoma of the right upper eyelid. Histologic examination revealed proliferating epithelial cells with apocrine snouts and occasional mitotic figures. Immunohistochemical analysis revealed a Ki-67 index of 15% and positive staining for synaptophysin, chromogranin, estrogen receptor, progesterone receptor, gross cystic disease fluid protein (GCDFP)-15, and mammoglobin. The complement of positive immunomarkers in this case reinforces the importance of total excision and careful histologic assessment.

Changes in Pathological Complete Response Rates after Neoadjuvant Chemotherapy for Breast Carcinoma over Five Years.

Historically, neoadjuvant chemotherapy (NACT) was extrapolated from adjuvant regimens. Dual HER2 blockade and the introduction of carboplatin for triple negative breast cancers (TNBC) emerged by December 2013 and have improved pathological complete response (pCR) rates. The objective of this study was to assess the pCR rates before and after the introduction of these new neoadjuvant regimens. Materials and Methods. Stage I-III breast cancer patients who received NACT were analyzed for rates of pCR by clinical characteristics (i.e., age, BMI, axillary lymphadenopathy, and histologic subtype), by time period (1 = 3/2010-11/2013, 2 = 12/2013-3/2015), and by type of chemotherapy (e.g., anthracycline/taxane only, carboplatin-containing, and HER2 blockade). Results. 113 patients received NACT. Overall pCR rate was 26.5 percent (n = 30). The pCR rate increased from 14% to 43.1% (p = 0.001) from time period 1 to time period 2 and were associated with HER2 positivity (p = 0.003), receiving treatment during time period 2 (p = 0.001) and using an anthracycline/taxane plus additional agent type of regimen (p = 0.004). Conclusions. Our study revealed a significant difference in rates of pCR over five years. Window of opportunity trials and other trials that utilize pCR analysis should be encouraged.

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.

The clinical significance of internal mammary lymph node (IMLN) biopsy during autologous reconstruction in breast cancer patients.

The clinical significance of IMLN metastases in breast cancer is controversial. Although IMLN status is an integral part of current AJCC staging of breast cancer, the elective sampling of IMLN is not part of routine surgery for breast cancer. The purpose of this study was to determine the incidence of IMLN metastases, associated risk factors if any, and its impact on further management and outcome. We retrospectively studied 470 cases that underwent autologous reconstruction surgery between 2002 and 2014. Of 470 cases, 157 breast cancer cases had histology-confirmed IMLN removal during the reconstruction. Only 9 patients (6 %) showed IMLN metastases as compared to 45 (34 %) that showed axillary nodal metastases (p < 0.01). Interestingly, 4 patients had metastases limited to IMLN without any metastases to axillary nodes. IMLN metastasis was significantly associated with age <40 years, lymphovascular invasion, and negative PR status. IMLN metastasis resulted in upstaging of 2 patients from stage I to III, and 1 from stage II to III. Five patients received additional chest wall radiation to target the positive IMLNs. Nine of 157 (6 %) patients with IMLN removal during reconstruction had loco-regional recurrence/metastasis as compared to 20 of 293 (7 %) patients without IMLN removal (p > 0.05) (follow-up, 1-134 months). The overall rate of IMLN metastases (6 %) is much lower than the rate of axillary node metastases. Selective biopsy of IMLNs in patients with breast cancer, especially if younger than 40 years, and with lymphovascular invasion and negative PR status, may guide adjuvant treatment.

A unique presentation of occult primary breast cancer with a review of the literature.

We are reporting a case of a 34-year-old woman with occult primary breast cancer discovered after initially presenting with neurological symptoms. She was successfully treated with neoadjuvant chemotherapy followed by definitive axillary lymph node dissection and ipsilateral whole breast radiotherapy. The case presented is unique due to the rarity of occult primary breast cancer, especially in light of her initial confounding neurological signs and symptoms, which highlights the importance of careful staging.

Are cytokeratin-positive cells in sentinel lymph nodes of patients with invasive breast carcinomas up to 5 mm usually insignificant?

AIMS: It is known that sentinel lymph nodes (SLN) may be falsely positive due to displaced epithelial cells, particularly in cases with an underlying intraductal papilloma. Given the low metastatic rate in pT1a carcinomas, we aimed to investigate the effect of this phenomenon on staging. METHODS AND RESULTS: Using morphology and immunohistochemistry, we classified the epithelial cells in the SLN in 39 cases of pT1a carcinoma as positive for carcinoma in six, negative in 26 and undetermined in seven. Comparative morphology and immunohistochemistry (using oestrogen receptor, ER) showed complete concordance between the primary carcinoma and SLN in the positive cases, and discordance in the negative cases. The primary tumours in the negative cases were ER-positive except one, in contrast to the SLN cytokeratin-positive (CK(+) ) cells, which were ER-negative. The exception was a case with a Her2-positive primary, in which the SLN CK(+) cells did not stain for Her2. In these cases considered SLN-negative, either displacement (19 cases) or an intraductal papilloma (20 cases) was identified. Two cases showed displacement of benign and malignant cells in the biopsy. Seven cases were indeterminate due to the small number of SLN CK(+) cells, precluding comparison with the primary. CONCLUSION: Given the low rate of metastases in pT1a carcinomas, the significance of SLN CK(+) cells should be resolved by comparative morphology and immunohistochemistry to prevent erroneous upstaging.

Evolution of sentinel lymph node biopsy in breast cancer, in and out of vogue?

Sentinel lymph node biopsy (SLNB) was introduced 2 decades ago and thereafter validated for routine surgical management of breast cancer, including cases treated with neoadjuvant chemotherapy. As the number of lymph nodes for staging has decreased, pathologists have scrutinized SLN with a combination of standard hematoxylin and eosin, levels, immunohistochemistry (IHC), and molecular methods. An epidemic of small-volume metastases thereby arose, leading to modifications in the American Joint Committee on Cancer staging to accommodate findings such as isolated tumor cells (ITC) and micrometastases. With the goal of determining the significance of these findings, retrospective followed by prospective trials were performed, showing mixed results. The ACOSOG Z10 and NSABP B-32 trials both independently showed that ITC and micrometastases were not significant and thus discouraged the use of levels and IHC for detecting them. However, the Surveillance Epidemiology and End Results database showed that patients with micrometastases had an overall decreased survival. In addition, the MIRROR (Micrometastases and ITC: Relevant and Robust or Rubbish?) trial, showed that patients with ITC and micrometastases treated with adjuvant therapy had lower hazard ratios compared with untreated patients. Subsequently, the ACOSOG Z0011 trial randomized patients with up to 2 positive SLN to axillary lymph node dissection (ALND) or not, all treated with radiation and chemotherapy, showing no difference in survival or recurrence rates between the 2 groups and causing a shift from ALND. As the rate of ALND has declined, the necessity of performing levels, IHC, frozen section, and molecular studies on SLN needs to be revisited.

Breast pathology review: does it make a difference?

BACKGROUND: Breast pathology is a challenging field, and previous work has shown discrepancies in diagnoses, even among experts. We set out to determine whether mandatory pathology review changes the diagnosis or surgical management of breast disease. METHODS: Cases were referred for pathology review after patients presented for surgical opinion to the Dubin Breast Center at Mount Sinai Medical Center over the course of 2 years. Surgical pathologists with expertise in breast disease reviewed slides submitted from the primary institution and rendered a second opinion diagnosis. Comparison of these reports was performed for evaluation of major changes in diagnosis and definitive surgical management. RESULTS: A total of 306 patients with 430 biopsy specimens were reviewed. Change in diagnosis was documented in 72 (17 %) of 430 cases and change in surgical management in 41 (10 %). A change in diagnosis was more likely to occur in patients originally diagnosed with benign rather than malignant disease (31 vs. 7 %, p < 0.001). Twelve (7 %) of 169 specimens initially diagnosed as benign were reclassified as malignant. A malignant diagnosis was changed to benign in 4 (2 %) of 261 cases. Change in diagnosis was less common in specimens originating from commercial laboratories than community hospitals or university hospitals (8, 19, 21 %, p = 0.023). Change in management was not dependent on initial institution. Type of biopsy specimen (surgical or core) did not influence diagnostic or management changes. CONCLUSIONS: We recommend considering breast pathology review based on the individual clinical scenario, regardless of initial pathologic diagnosis or originating institution.