Jeffrey Catalano

Non-mammary metastases to the breast and axilla: a study of 85 cases

Non-mammary metastases to the breast and axilla are rare occurrences. However, they are important diagnostic considerations as their treatment and prognosis differ significantly from primary breast cancer. Between 1990 and 2010, we identified a total of 85 patients, 72 women and 13 men, with non-mammary malignancies involving the breast, axilla, or both. The tumor types consisted of carcinoma (58%), melanoma (22%) and sarcoma (20%). Ovary was the most common site of origin for carcinoma, and metastatic high-grade ovarian serous carcinoma was most frequently misdiagnosed as a primary breast carcinoma. Melanoma was the single most common non-carcinomatous tumor type to involve the breast and/or axilla, and uterine leiomyosarcoma was the most common type of sarcoma. Most patients (77%) had other metastases at the time of diagnosis of the tumor, but in 11% the breast or axillary lesion was the first presentation. Without a clinical history, non-mammary metastases were difficult to diagnose because the majority of cases presented with a solitary nodule and lacked pathognomonic pathologic features. There were, however, certain recurrent histological findings identified, such as the often relatively well-circumscribed growth pattern of the metastatic lesion surrounded by a fibrous pseudocapsule, and the absence of an in situ carcinoma. Overall, these patients had poor survival; 96% of patients with follow-up available are dead of disease, with a median survival of 15 months after the diagnosis of the breast or axillary lesion. This finding emphasizes the need to accurately identify these tumors as metastases in order to avoid unnecessary procedures and treatments in these patients.

Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival.

Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients’ race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.

Radiation field design and regional control in sentinel lymph node‐positive breast cancer patients with omission of axillary dissection

Randomized data suggest that axillary clearance is not necessary in select, clinically lymph node‐negative women with positive sentinel lymph node (SLN) biopsies (SLNBs) who undergo breast‐conserving surgery or receive whole‐breast radiotherapy and systemic therapy. The additional value of axillary radiotherapy in these patients is unknown.

Is There a Role for Oncotype Dx Testing in Invasive Lobular Carcinoma

Oncotype Dx Breast Cancer Assay is a 21‐gene assay used in estrogen receptor (ER)‐positive breast cancer to predict benefit from chemotherapy (CT). Tumors are placed into one of three risk categories based on their recurrence score (RS). This paper explores the impact of tumor histopathologic features and Oncotype Dx RS on the treatment plan for invasive lobular carcinoma (ILC). Invasive lobular carcinoma cases submitted for Oncotype Dx testing were identified from a clinical data base. The histopathologic and immunohistochemical features and RS subcategory of each tumor, and treatment regimen and medical oncologic assessments of each patient were reviewed. A total of 135 cases of ILC had RS testing, which represented 15% of all ILC diagnosed at the institution over the time period. 80% of ILC was of the classical subtype and all tumors were ER positive and human epidermal growth factor receptor 2 (HER‐2) negative by immunohistochemistry. Sixty three percent of cases were low risk (LR), 35.5% were intermediate risk (IR) and 1.5% were high risk (HR). Both HR cases were pleomorphic ILC. Sixty eight percent of classical ILC had a LR score, while 70% of pleomorphic ILC had an IR score. Patients in the IR category were significantly more likely to undergo CT than patients in the LR category (54% versus 18%; p < 0.0001). In the LR category, those undergoing CT were significantly younger and more likely to have positive lymph nodes (p < 0.05). Qualitative analysis of medical oncologic assessments showed that RS played a role in decision‐making on CT in 74% of cases overall. At our institution, Oncotype Dx RS currently plays a role in the management of a proportion of ILC and impacts on treatment decisions.

Fibroepithelial Lesions in the Breast of Adolescent Females: A Clinicopathological Study of 54 Cases

Fibroepithelial lesions (FELs) are the most frequent breast tumors in adolescent females. The pubertal hormonal surge could impact the growth and microscopic appearance of FELs in this age group. In this study, we evaluate the morphology and clinical behavior of FELs in adolescents. We searched the 1992–2012 pathology data base for FELs in females 18 years old or younger (F ≤18 years). Seven FELs from 1975 to 1983 were also included. Three pathologists reviewed all available material. Patient (pt) characteristics and follow‐up information were obtained from electronic medical records. Forty‐eight F ≤18 years had 54 FELs with available slides. Thirty (67%) pts were Caucasian, 12 (27%) African‐American, two (4%) Hispanic, one (2%) Asian; three were of unknown race/ethnicity. Median age at diagnosis was 16 years. Median age at menarche was 12 years; most (96%) FELs occurred after menarche (median interval 48 months). All patients underwent lumpectomy; one required subsequent mastectomy. The FELs were 34 fibroadenomas (FAs) (11 usual, 23 juvenile), and 20 phyllodes tumors (PTs) (16 benign, one borderline and three malignant). Eight (35%) juvenile FAs showed slight intratumoral heterogeneity. The mean mitotic rate was 1.3 mitoses/10 high‐power fields (HPFs) (range, 0–6) in usual FAs, 1.8/10 HPFs in juvenile FAs, 3.1/10 HPFs in benign PTs, 10/10 HPFs in the borderline PT and 17/10 HPFs in malignant PTs. The mean follow‐up for 29 pts with 33 FELs was 44 months. Two (10%) PTs recurred locally (a benign PT at 18 months, and a borderline PT at 11 months). Both recurrent PTs had microscopic margins <1 mm. Mitotic activity in FAs from adolescents can be substantial and this finding should be interpreted cautiously. Awareness of the morphologic features of FELs in adolescents is important to avoid overdiagnosis of PTs, which can lead to additional unnecessary and potentially disfiguring surgery.

Atypical Ductal Hyperplasia Bordering on Ductal Carcinoma In Situ Interobserver Variability and Outcomes in 105 Cases

Background. The clinical implications of the diagnosis of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are very different. Yet there are “borderline” breast lesions that have characteristics of both ADH and DCIS. We examined interobserver diagnostic variability for such lesions and correlated pathologic features of the lesions with clinical outcomes. Methods. We identified all cases of borderline ADH/DCIS lesions treated at our center from 1997 to 2010. Five specialized breast pathologists blinded to clinical outcomes independently reviewed all available slides from each case and were instructed to classify each as benign, ADH, or DCIS. A majority diagnosis (MajDx) was defined as a diagnosis agreed upon by ≥3 pathologists. Results. A total of 105 women with borderline ADH/DCIS and slides available for review were identified. The MajDx was ADH in 84 (80%), and DCIS in 18 (17%). There were split diagnoses in 3 (3%). MajDx of DCIS correlated significantly with lesion size and nuclear grade. There was diagnostic agreement by all 5 pathologists in 30% of cases, 4 pathologists in 42%, and 3 pathologists in 25%. At a median follow-up of 37 months, 4 (3.8%) patients developed subsequent ipsilateral breast carcinoma (2 invasive, 2 DCIS); all 4 cases had MajDx of ADH. Conclusions. Borderline ADH/DCIS represents an entity for which reproducible categorization as ADH or DCIS cannot be achieved. Furthermore, histologic features of borderline lesions resulting in MajDx of ADH vs. DCIS are not prognostic for risk of subsequent breast carcinoma.

DNA mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors.

Recent studies have suggested that breast cancer is part of the tumor spectrum in Lynch syndrome (LS). However, the frequency and significance of DNA mismatch repair (MMR) deficiency in breast carcinoma in general is unclear. Some triple-negative breast carcinomas (TNBCs) have morphologic features similar to those described in LS-associated colorectal carcinomas; therefore, we hypothesized that TNBCs might be more likely to have MMR deficiency. In this study, we tested our hypothesis in a series of 226 TNBCs along with a control series of 90 non–triple-negative tumors, utilizing DNA MMR protein immunohistochemistry followed by PCR microsatellite instability testing and MLH1 promoter methylation testing. By immunohistochemistry, we identified 4 triple-negative carcinomas (4/226, 1.8%) showing loss of MMR proteins (3 lost MLH1 and PMS2, and 1 lost MSH2 and MSH6); whereas none of the 90 non–triple-negative carcinomas showed loss of protein. Further testing of the 3 MLH1/PMS2 protein-deficient carcinomas identified 1 tumor showing high-frequency microsatellite instability and MLH1 promoter hypermethylation. All 4 MMR protein-deficient carcinomas were ductal type with high histologic and nuclear grades. Prominent lymphocytic infiltration was noted in 2 tumors. The clinical characteristics and survival outcome varied widely among the 4 patients. In conclusion, our results suggest that DNA MMR deficiency is rare in breast carcinoma, and as such, testing of breast carcinoma for the detection of LS may best be restricted to high-risk individuals only. Our data also suggest that not all MMR protein-deficient breast tumors show microsatellite instability, and MLH1 promoter methylation is the molecular basis for at least a subset of microsatellite instable breast tumors. Although MMR-deficient breast carcinomas share certain morphologic features with the more typical types of LS-associated tumors, better characterization, and a better understanding of their clinical behavior await further analysis with a larger sample size.

Focal Extravasated Mucin in Breast Core Needle Biopsies: Is Surgical Excision Always Necessary?

Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin‐producing carcinoma. In the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22‐year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals [CI], 4%–33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%–48%) versus none (0/10; 0%; 95% CI, 0%–31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant.

Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER‐2 overexpression status for the period 2000–2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000–2003] to 8.7% [2008–2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER‐2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER‐2‐positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12‐year period 2000–2011 and no increase in the proportion of young patients presenting with metastatic disease.

Abstract P1-02-09: Positive predictive value (PPV) of the diagnosis of atypia in breast core biopsies: An audit of MSKCC breast pathology service

Percutaneous needle core biopsy is the standard of care in the assessment of suspicious breast lesions. The diagnostic term “Atypia” is used in breast biopsy reporting when histologic appearances are suspicious but not diagnostic of malignancy. Multiple histopathological appearances are encompassed by the umbrella term “atypia”, including atypical ductal hyperplasia (ADH), columnar cell change with atypia (CCCWA), which is also known as flat epithelial atypia (FEA), and a miscellaneous group of diagnoses, known as atypia NOS. A pathologic diagnosis of “atypia” in breast core biopsies usually leads to a recommendation to surgically excise the lesion. Many studies have correlated the diagnosis of “atypia” in core biopsies with the subsequent finding of carcinoma in the surgical excisions, and the percentage of carcinoma found represents the positive predictive value (PPV) of the diagnosis. To date, there is no agreed target PPV for the diagnosis of breast atypia on biopsy, but the most studies have demonstrated a PPV of 20- 40%. Individual “atypia” diagnoses such as CCCWA have an even lower PPV of 10-15%. One method of performance review is an audit of the average breast-atypia PPV within individual pathology departments, which then can be monitored and studied over time, to detect trends and “diagnostic drift” at an early stage. In addition, assessment of the individual PPV of each breast pathologist allows for analysis of the consistency of the diagnostic practice of each individual with their colleagues. Surprisingly, there have been no major studies assessing the intradepartmental range of PPVs for breast atypia diagnoses to date. In contrast, the American College of Radiology has designed the BIRADS classification system in order to audit and monitor the PPV of breast imaging in diagnosing malignancy. We undertook to measure the departmental PPV for malignancy following a biopsy diagnosis of breast atypia, and performed an anonymized subanalysis in order to establish the range of PPVs of atypia diagnoses between the sub-specialized breast pathologists within the department. This study established that the baseline PPV in our department is comparable to previously reported studies at 24%, while the range of PPV for an atypia diagnosis between pathologists is between 22.8 and 25% for 5 of 6 pathologists, with one pathologist demonstrating a higher PPV of 36.8%. ADH was the most common diagnosis of the atypia subtypes, and the PPV for ADH alone was 29.9%. 15% of ADH diagnoses were described as “ADH bordering on low grade DCIS”; within this subgroup the PPV was 48.5%. The PPV for a diagnosis of CCCWA alone was 10%. This study demonstrates that the PPV for breast atypia in a major tertiary cancer center is approximately 24%. We have demonstrated very reproducible use of this diagnostic term within the department. We plan to use the findings of this study to identify subgroups of patients with a sufficiently low PPV to justify a decision not to proceed to surgical intervention. We aim to develop an algorithm for use in the clinical setting in order to direct further patient management. The ultimate aim of this research is to reduce the number of patients undergoing unnecessary surgical interventions. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-09.