The morphologic spectrum of lobular carcinoma in situ (LCIS) observations on clinical significance, management implications and diagnostic pitfalls of classic, florid and pleomorphic LCIS.

Lobular carcinoma in situ (LCIS) is a non-invasive proliferation of atypical dyscohesive epithelial cells characterized by loss or functional alteration of E-cadherin-mediated cell adhesion. The morphologic spectrum of LCIS encompasses classic (C-LCIS), florid (F-LCIS) and pleomorphic LCIS (P-LCIS), as recently defined by the World Health Organization (WHO) Expert Consensus Group. Atypical lobular hyperplasia (ALH) is also part of this spectrum.This article highlights the morphologic and immunohistochemical features of the three forms of LCIS and summarizes their management implications and prognosis, with emphasis on F-LCIS and P-LCIS.

Accuracy of the Breast Cancer Surveillance Consortium Model Among Women with LCIS.

PURPOSE: The Breast Cancer Surveillance Consortium (BCSC) model predicts risk of invasive breast cancer risk based on age, race, family history, breast density, and history of benign breast disease, including lobular carcinoma in situ (LCIS). However, validation studies for this model included few women with LCIS. We sought to evaluate the accuracy of the BCSC model among this cohort. METHODS: Women with LCIS diagnosed between 1983 and 2017 were identified from a prospectively maintained database. The BCSC score was calculated; those with prior breast cancer, unknown breast density, age < 35 years or > 74 years, or with history of chemoprevention use were excluded. The Kaplan-Meier method was used to estimate incidence rates. Time-dependent receiver operating characteristic (ROC) analysis was used to analyze the discriminative capacity of the model. RESULTS: 1302 women with LCIS were included. At a median follow-up of 7 years, 152 women (12%) developed invasive cancer (6 with bilateral disease). Cumulative incidences of invasive breast cancer were 7.1% (95% CI 5.6-8.7) and 13.3% (95% CI 10.9-15.6), respectively, and the median BCSC risk scores were 4.9 and 10.4, respectively, at 5 and 10 years. The median 10-year BCSC score was significantly lower than the 10-year Tyrer-Cuzick score (10.4 vs 20.8, p < 0.001). The ROC curve scores (AUC) for BCSC at 5 and 10 years were 0.59 (95% CI 0.52-0.66) and 0.58 (95% CI 0.52-0.64), respectively. CONCLUSION: The BCSC model has moderate accuracy in predicting invasive breast cancer risk among women with LCIS with fair discrimination for risk prediction between individuals.

Lobular Carcinoma In Situ during Preoperative Biopsy and the Rate of Upgrade.

PURPOSE: There is a potential risk that lobular carcinoma in situ (LCIS) on preoperative biopsy might be diagnosed as ductal carcinoma in situ (DCIS) or invasive carcinoma in the final pathology. This study aimed to evaluate the rate of upgrade of LCIS on preoperative biopsy to DCIS or invasive carcinoma. MATERIALS AND METHODS: Data of 55 patients with LCIS on preoperative biopsy were analyzed. All patients underwent surgery between 1991 and 2016 at Severance Hospital in Seoul, Korea. We analyzed the rate of upgrade of preoperative LCIS to DCIS or invasive cancer in the final pathology. The clinicopathologic features related to the upgrade were evaluated. RESULTS: The rate of upgrade of LCIS to DCIS or invasive carcinoma was 16.4% (9/55). In multivariate analysis, microcalcification and progesterone receptor expression were significantly associated with the upgrade of LCIS (p=0.023 and p=0.044, respectively). CONCLUSION: The current study showed a relatively high rate of upgrade of LCIS on preoperative biopsy to DCIS or invasive cancer. The presence of microcalcification and progesterone receptor expression may be potential predictors of upgradation of LCIS on preoperative biopsy. Surgical excision of the LCIS during preoperative biopsy could be a management option to identify the concealed malignancy.

Risk management recommendations and patient acceptance vary with high-risk breast lesions.

INTRODUCTION: Lobular carcinoma in situ (LCIS), atypical ductal and lobular hyperplasia (AH) increase breast cancer risk. We examined risk management recommendations (RMR) and acceptance in AH/LCIS. METHODS: All patients with AH/LCIS on core needle biopsy from 2013 to 2016 at our institution were identified; cancer patients were excluded. Univariate and multivariate analysis examined factors associated with management. RESULTS: 98 % of patients were evaluated by breast surgeons and 53 % underwent risk model calculation (RC). 77 % had new RMR. RMR of MRI screening (MRI), genetic counselling (GC) and medical oncology (MO) referral were 41 %, 18 %, 77 %, respectively. MRI screening was more likely recommended in those with strong family history (p = 0.01), and high RC (p < 0.001). Uptake of at least one RMR did not occur in 84 % of patients. Use of RC correlated with MO acceptance (p = 0.049). CONCLUSIONS: Diagnosis of atypia has the potential to change risk management for most, however only 16 % of patients accepted all RMR.

Classical Lobular Carcinoma In Situ Arising From an Intraductal Papilloma of the Breast: A Case Report.

Intraductal papilloma of the breast is a benign, mass-forming, proliferative lesion with a papillary architecture confined within a duct. Lobular neoplasia can rarely arise from an intraductal papilloma of the breast. In this article, we report the morphologic features of a rare case of classical LCIS (lobular carcinoma in situ) arising from an intraductal papilloma in a 76-year-old woman. The monomorphic dyscohesive cells were present between the myoepithelial and luminal epithelial layer in the periphery of the papilloma. These cells partially obliterated the spaces between the papillae forming solid sheets. The monomorphic dyscohesive cells showed lack of E-cadherin expression and uniform staining for estrogen receptor. We review the histologic differential diagnosis and stress the importance of correct classification to ensure optimal care for patients. We also propose a new criterion for the distinction of lobular neoplasia within a papilloma.

Upgrade at excisional biopsy after a core needle biopsy diagnosis of classic lobular carcinoma in situ.

BACKGROUND: Management of patients with classic lobular carcinoma in situ diagnosed on core needle biopsy remains controversial, in part because of clinicopathologic overlap with atypical lobular hyperplasia. Although atypical lobular hyperplasia on core needle biopsy is observed because of its low upgrade rate (~1%), consensus is lacking for lobular carcinoma in situ. Therefore, we evaluated lobular carcinoma in situ upgrade rates. METHODS: With institutional review board approval, we identified 90 patients (from October 2008 to December 2019) with lobular carcinoma in situ on core needle biopsy as their highest-risk lesion. We excluded patients with concurrent ipsilateral cancer. Variables associated with upgrade were assessed with logistic regression. RESULTS: Of the 90 patients, 81 (90%), median age 55 y, underwent surgical excision. Indications for diagnostic core needle biopsy included mammographic calcifications (48, 53.3%), mass/distortion (28, 31.1%), and non-mass enhancement (12, 13.3%). Final surgical pathology upgraded 11 of 81 patients (13.6%, 95% CI: 7.8%-22.7%) to cancer: invasive lobular (n = 7), invasive ductal (n = 1), and ductal carcinoma in situ/pleomorphic lobular carcinoma in situ (n = 3). Only 1 patient with invasive cancer was node-positive. Concurrent contralateral cancer (OR 4.41, 95% CI: 1.06-17.38, P = .04) and larger lesion size (OR 1.78 per 1 cm, 95% CI: 1.19-2.95, P = .005) predicted upgrade. CONCLUSION: Our data suggest that, unlike atypical lobular hyperplasia, lobular carcinoma in situ identified on core needle biopsy should be surgically excised. The high proportion of upgrades to early stage invasive lobular carcinoma underscores the value of this approach.

Lobular carcinoma in situ: diagnostic criteria and molecular correlates.

Lobular neoplasia (LN) is an atypical proliferation of small, dyscohesive epithelial cells within the terminal duct lobular unit (TDLU), with or without pagetoid extension and encompasses both lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LN is a non-obligate precursor of invasive breast carcinoma and the diagnosis of LN confers an increased risk of invasive carcinoma development, compared to the general population. Diagnostic challenges arise in the accurate classification of LCIS into classic, pleomorphic and florid subtypes, in distinguishing between LCIS and ductal carcinoma in situ (DCIS) and in the appropriate use and interpretation of E-cadherin immunohistochemistry. Due to the paucity of robust data on the natural history of LCIS, and hence its clinical significance, the management is often pragmatic rather than entirely evidence-based and requires a multidisciplinary approach. In this review, we discuss the clinicopathologic and molecular features of LCIS and address the key challenges that arise in the diagnosis and management of LCIS.

Case report of polymyalgia rheumatica in a male patient with three different neoplasms treated with pembrolizumab.

In this manuscript we aim to describe a particular case of a 63 years-old man who developed three different malignancies (one was a rare case of breast cancer) among nearly five years. In particular, for the diagnosis of melanoma, he was treated with pembrolizumab, a PD-1 inhibitor. After few months of treatment with pembrolizumab, the patient reported the onset of musculoskeletal symptoms such as inflammatory pain at the shoulders and morning stiffness, with raised CRP and ESR and imaging evidence of bursitis and tenosynovitis. A polymyalgia-like syndrome was diagnosed. Understanding if these manifestations are linked to the use of pembrolizumab or to a paraneoplastic syndrome, and how to manage the patient, was the real challenge.

[Histological lesions of risk of breast carcinoma. Survival guide for the general pathologist]. / Lesiones histológicas de riesgo de carcinoma de mama. Guía de supervivencia para el patólogo general.

Proliferative epithelial lesions are risk factors for breast cancer. They are a heterogeneous group of lesions in which the presence of atypia is related to varying degrees of risk. They should be considered in the differential diagnosis with benign lesions, in situ ductal carcinoma and infiltrating carcinoma. An accurate histopathological diagnosis is important in choosing the best therapeutic option, including vacuum assisted biopsy and surgery. We revise diagnostic criteria and the differential diagnosis of usual ductal hyperplasia, radial scar and complex sclerosing lesions, distinct types of adenosis, papillary lesions, atypical ductal hyperplasia, flat epithelial atypia and lobular neoplasia in situ. Furthermore, we summarize the degree of risk associated with the different conditions and management possibilities.

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma in situ, or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months (P = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL (P = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.

Raman Spectroscopy Reveals That Biochemical Composition of Breast Microcalcifications Correlates with Histopathologic Features.

Breast microcalcifications are a common mammographic finding. Microcalcifications are considered suspicious signs of breast cancer and a breast biopsy is required, however, cancer is diagnosed in only a few patients. Reducing unnecessary biopsies and rapid characterization of breast microcalcifications are unmet clinical needs. In this study, 473 microcalcifications detected on breast biopsy specimens from 56 patients were characterized entirely by Raman mapping and confirmed by X-ray scattering. Microcalcifications from malignant samples were generally more homogeneous, more crystalline, and characterized by a less substituted crystal lattice compared with benign samples. There were significant differences in Raman features corresponding to the phosphate and carbonate bands between the benign and malignant groups. In addition to the heterogeneous composition, the presence of whitlockite specifically emerged as marker of benignity in benign microcalcifications. The whole Raman signature of each microcalcification was then used to build a classification model that distinguishes microcalcifications according to their overall biochemical composition. After validation, microcalcifications found in benign and malignant samples were correctly recognized with 93.5% sensitivity and 80.6% specificity. Finally, microcalcifications identified in malignant biopsies, but located outside the lesion, reported malignant features in 65% of in situ and 98% of invasive cancer cases, respectively, suggesting that the local microenvironment influences microcalcification features. This study confirms that the composition and structural features of microcalcifications correlate with breast pathology and indicates new diagnostic potentialities based on microcalcifications assessment. SIGNIFICANCE: Raman spectroscopy could be a quick and accurate diagnostic tool to precisely characterize and distinguish benign from malignant breast microcalcifications detected on mammography.

Psychotropic Medication Use and Postmenopausal Breast Cancer Risk.

BACKGROUND: Prior studies evaluating psychotropic medications in relation to breast cancer risk are inconsistent and have not separately evaluated invasive and in situ disease. METHODS: We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of psychotropic medication use (any, typical antipsychotics, atypical antipsychotics, and lithium) with invasive and in situ breast cancer risk among Women's Health Initiative participants (N = 155,737). RESULTS: Prevalence of psychotropic medication use was low (n = 642; 0.4%). During an average 14.8 (SD, 6.5) years of follow-up, 10,067 invasive and 2,285 in situ breast tissues were diagnosed. Any psychotropic medication use was not associated with invasive breast cancer risk compared with nonusers (HR, 0.82; 95% CI, 0.57-1.18). In situ breast cancer risk was higher among "typical" antipsychotic medication users compared with nonusers (HR, 2.05; 95% CI, 0.97-4.30). CONCLUSIONS: These findings do not support an association of psychotropic medication use with invasive breast cancer risk. The possible elevation in in situ breast cancer risk associated with "typical" antipsychotics could not be explained by differences in screening mammography utilization and merits further study. IMPACT: Our findings contribute to knowledge of the safety profile of psychotropic medications and may be useful to clinicians and patients considering use of these medications.

The Tyrer-Cuzick Model Inaccurately Predicts Invasive Breast Cancer Risk in Women With LCIS.

BACKGROUND: The Tyrer-Cuzick model has been shown to overestimate risk in women with atypical hyperplasia, although its accuracy among women with lobular carcinoma in situ (LCIS) is unknown. We evaluated the accuracy of the Tyrer-Cuzick model for predicting invasive breast cancer (IBC) development among women with LCIS. METHODS: Women with LCIS participating in surveillance from 1987 to 2017 were identified from a prospectively maintained database. Tyrer-Cuzick score (version 7) was calculated near the time of LCIS diagnosis. Patients with prior or concurrent breast cancer, a BRCA mutation, receiving chemoprevention, or with pleomorphic LCIS were excluded. Invasive cancer-free probability was estimated using the Kaplan-Meier method. RESULTS: A total of 1192 women with a median follow-up of 6 years (interquartile range [IQR] 2.5-9.9) were included. Median age at LCIS diagnosis was 49 years (IQR 45-55), 88% were white; 37% were postmenopausal, 28% had ≥ 1 first-degree family member with breast cancer, and 13% had ≥ 2 second-degree family members with breast cancer. In total, 128 patients developed an IBC; median age at diagnosis was 54 years (IQR 49-61). Five- and 10-year cumulative incidences of invasive cancer were 8% (95% confidence interval [CI] 6-9%) and 14% (95% CI 12-17%), respectively. The median Tyrer-Cuzick 10-year risk score was 20.1 (IQR 17.4-24.3). Discrimination measured by the C-index was 0.493, confirming that the Tyrer-Cuzick model is not well calibrated in this patient population. CONCLUSIONS: The Tyrer-Cuzick model is not accurate and may overpredict IBC risk for women with LCIS, and therefore should not be used for breast cancer risk assessment in this high-risk population.

Membranous overexpression of S100A10 is associated with a high-grade cellular status of breast carcinoma.

S100A10 promotes tumor invasion in various cancers. Although genetic studies on S100A10 in breast carcinoma (BC) have been used for molecular biological classification, immunohistochemical studies are lacking. We aimed to identify the correlation between S100A10 expression in BC and various pathological parameters, including morphological features to determine histological grade (HG). Immunostained serial paraffin-embedded tissue sections from 176 cases of resected BC or normal mammary ducts (controls) were assessed for the membrane expression of S100A10. Of the 176 cases, 125 conventional infiltrating ductal carcinomas were chosen, comprising 67 (53.6%) S100A10-positive tumors, whereas normal mammary ducts were S100A10-negative. S100A10 immunoreactivity in ductal carcinoma in situ (n = 51) was similar to that of invasive carcinoma. The distinct membrane-immunopositivity was correlated with high HG, severe nuclear pleomorphism, frequent mitotic counts, high Ki-67 labeling index, HER2/neu overexpression, and low estrogen receptor status (P < 0.05), but not with tubular formation, pT categories, node metastasis, vessel permeation, and pStage. Membrane overexpression of S100A10 in BC correlates with the high-grade morphological and molecular status of the carcinoma cell rather than stromal invasion and architectural deviation. Evidence points to the use of S100A10 as a biomarker representing a high-grade cellular status of BC.

Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters.

OBJECTIVES: Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. RESULTS: Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

Overview of breast cancer.

Each year, more than 250,000 women in the United States are diagnosed with invasive breast cancer. Although overall mortality for breast cancer patients has declined, it is still the second most common cause of cancer death in women. This article provides an overview of nonmetastatic breast cancer in women, including general features, diagnostic considerations, and treatments for the most common breast cancer subtypes.

The Influence of Age on the Histopathology and Prognosis of Atypical Breast Lesions.

BACKGROUND: Although several prognostic variables and risk factors for breast cancer are age-related, the association between age and risk of cancer with breast atypia is controversial. This study aimed to compare the type of breast atypia and risk of underlying or subsequent breast cancer by age. METHODS: Adult women with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ) at a single institution from 2008 to 2017 were stratified by age at initial diagnosis: <50 y, 50-70 y, and >70 y. Regression modeling was used to estimate the association of age with risk of underlying carcinoma or subsequent cancer diagnosis. RESULTS: A total of 530 patients with atypia were identified: 31.1% < 50 y (n = 165), 58.1% 50-70 y (n = 308), and 10.8% > 70 y (n = 57). The proportion of women with atypical ductal hyperplasia steadily increased with age, compared with atypical lobular proliferations (P = 0.04). Of those with atypia on needle biopsy, the overall rate of underlying carcinoma was 17.5%. After adjustment, older age was associated with a greater risk of underlying carcinoma (odds ratio: 1.028, 95% confidence interval: 1.003-1.053; P = 0.03). Of those confirmed to have atypia on surgical excision, the overall rate of a subsequent cancer diagnosis was 15.7%. Age was not associated with a long-term risk for breast cancer (P = 0.48) or the time to a subsequent diagnosis of carcinoma (log-rank P = 0.41). CONCLUSIONS: Although atypia diagnosed on needle biopsy may be sufficient to warrant surgical excision, older women may be at a greater risk for an underlying carcinoma, albeit the long-term risk for malignancy associated with atypia does not appear to be affected by age.