Human epidermal growth factor receptor 2 (HER2) status in breast cancer: practice points and challenges.

Human epidermal growth factor receptor 2 (HER2)-enriched breast cancer benefits significantly from anti-HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti-HER2 regimens. Recently, the emerging eligibility of patients with HER2-low breast cancers for a novel HER2-targeted antibody-drug conjugate (T-DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0-1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation.

Survey of recurrent diagnostic challenges in breast phyllodes tumours.

BACKGROUND: Breast phyllodes tumours (PTs) are graded as benign, borderline, or malignant by analysis of multiple histological features. PT grading is often inconsistent, likely due to variation in the weighting of grading criteria by pathologists. DESIGN: The hierarchy of use of diagnostic criteria was identified using a 20-question survey. RESULTS: In all, 213 pathologists from 29 countries responded. 54% reported 10-50 PT cases per year. Criteria considered key to PT diagnosis were: increased stromal cellularity (84.3%), stromal overgrowth (76.6%), increased stromal mitoses (67.8%), stromal atypia (61.5%), stromal fronding (59.0%), periductal stromal condensation (58.0%), irregular tumour borders (46.3%), and/or lesional heterogeneity (33.7%). The importance of grading parameters were: mitotic activity (55.5%), stromal overgrowth (54.0%), stromal atypia (51.9%), increased stromal cellularity (41.7%), and nature of the tumour border (38.9%). 49% would diagnose malignant PT without a full array of adverse features. 89% used the term "cellular fibroepithelial lesion (FEL)" for difficult cases; 45% would diagnose an FEL with stromal fronding (but lacking other PT features) as fibroadenoma (FA), 35% FEL, and 17% PT. 59% deemed clinico-radiological findings diagnostically significant; 68% considered age (≥40 years) important in determining if an FEL was a FA or PT. In FELs from young patients, increased stromal cellularity (83%), fronding (52%), and mitoses (41%) were more common. 34% regarded differentiating cellular FA from PT as a specific challenge; 54% had issues assigning a borderline PT grade. CONCLUSION: Criteria for grading PT lie on a spectrum, leading to interpretive variability. The survey highlights the criteria most used by pathologists, which do not completely align with WHO recommendations.

Artificial intelligence modelling in differentiating core biopsies of fibroadenoma from phyllodes tumor.

Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice.

Morphologic and genetic heterogeneity in breast fibroepithelial lesions-a comprehensive mapping study.

Breast fibroepithelial lesions (FELs) encompass the common fibroadenoma (FA) and relatively rare phyllodes tumour (PT); the latter entity is usually classified as benign, borderline or malignant. Intratumoural heterogeneity is frequently present in these tumours, making accurate histologic evaluation challenging. Despite their rarity, PTs are an important clinical problem due to their propensity for recurrence and, in the case of malignant PT, metastasis. Surgical excision is the mainstay of management. Recent work has uncovered myriad genetic alterations in breast FELs. In this study, exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including FAs, PTs of all grades, and a case of metaplastic spindle cell carcinoma arising in PT, in order to elucidate their intratumoural genetic repertoire. Gene mutations identified encompassed cell signalling, tumour suppressor, DNA repair and cell cycle regulating pathways. Mutations common to multiple tumour regions generally showed higher variant allele frequency. Frequent mutations included MED12, TP53, RARA and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumour progression. In summary, histological heterogeneity correlated with genetic changes in breast FELs.

Isolated invasive ductal carcinoma of the nipple-areolar complex: A rare occurrence yet to be reported in current literature.

Invasive ductal carcinoma of the nipple-areolar complex is exceedingly rare. Patients who present with bloody nipple discharge with or without the presence of Paget's disease constitute one-third of all symptomatic in situ patients. Only rarely does an invasive cancer cause nipple discharge in the absence of a clinical mass. Even more obscure is the case of the invasive cancer involving solely the nipple-areolar complex. Sir James Paget first described 'an eczematous change in the skin of the nipple preceding an underlying mammary cancer' in 1874, which is now known as Paget's disease, considered to be ductal carcinoma in situ of the nipple-areolar region. There are two competing theories as to the pathogenesis of Paget's disease of the breast-one suggests that Pagetoid cells are keratinocytes that have undergone malignant transformation. According to this theory, Paget's disease of the breast represents an in situ carcinoma of the skin-and that overlying skin changes and underlying malignancy are discontinuous. The second theory suggests that cells migrate along basement membranes and enter the epidermis and dermis of the nipple-areola complex. Pagetoid cells and underlying carcinomas demonstrate similar immunohistochemical staining patterns.

Tumor size and Fuhrman grade further enhance the prognostic impact of perinephric fat invasion and renal vein extension in T3a staging of renal cell carcinoma.

OBJECTIVE: To evaluate the prognostic values of perinephric fat invasion and renal vein invasion in pT3a renal cell carcinoma, as stand-alone factors and in combination with tumor size and Fuhrman grade. METHODS: Survival data of pT1 and pT2 renal cell carcinomas were analyzed alongside pT3a tumors of similar size bands (pT1 vs pT3a <7 cm, pT2 vs pT3a >7 cm). Patients with adjuvant therapy, positive surgical margins, metastasis or pT3b-pT4 tumors were excluded. RESULTS: No significant baseline demographic differences existed between the groups. Patients with renal vein invasion had larger tumors (median, 7.2 ± 3.0 cm vs 5.5 ± 3.6 cm, P = 0.039), and were more symptomatic (90.0% vs 61.7%, P = 0.028) compared with patients with perinephric fat invasion alone. Patients with perinephric fat invasion alone appeared to have better disease-free survival compared with those with renal vein invasion (P = 0.009). Having both perinephric fat invasion and renal vein invasion did not result in a poorer disease-free survival. pT3a (perinephric fat invasion) tumors <4 cm and 4-7 cm have significantly worse disease-free survival compared with pT1a and pT1b tumors (P < 0.001). Similarly, pT3a (perinephric fat invasion) tumors measuring ≥7 show a trend of poorer disease-free survival compared with pT2a and pT2b tumors (P = 0.267). Disease-free survival correlated with Fuhrman grading for patients with perinephric fat invasion (P = 0.008). In multivariate analysis, the survival curve of pT3a perinephric fat invasion group closely approximates that of pT2 group, whereas survival of the renal vein invasion group was significantly worse than the pT2 and perinephric fat invasion groups (P = 0.001). CONCLUSION: pT3a tumors with perinephric fat invasion appear to have better prognosis than those with renal vein invasion. Further stratification of pT3a renal cell carcinomas with regard to tumor size and Fuhrman grade further enhances the prognostic value in this group.

Special Histologic Type and Rare Breast Tumors - Diagnostic Review and Clinico-Pathological Implications.

Breast cancer is the most common malignant tumor in females. While most carcinomas are categorized as invasive carcinoma, no special type (NST), a diverse group of tumors with distinct pathologic and clinical features is also recognized, ranging in incidence from relatively more common to rare. So-called "special histologic type" tumors display more than 90% of a specific, distinctive histologic pattern, while a spectrum of tumors more often encountered in the salivary gland may also arise in the breast. Metaplastic carcinomas can present diagnostic challenges. Some uncommon tumors harbor pathognomonic genetic alterations. This article provides an overview of the key diagnostic points and differential diagnoses for this group of disparate lesions, as well as the salient clinical characteristics of each entity.

Multiparametric MRI reporting using Prostate Imaging Reporting and Data System version 2.0 (PI-RADSv2) retains clinical efficacy in a predominantly post-biopsy patient population.

OBJECTIVE: To evaluate the efficacy of multiparametric magnetic resonance imaging (mp-MRI) using Prostate Imaging Reporting and Data System version 2.0 (PI-RADSv2) definitions in detecting organ-confined prostate cancer. METHODS: All patients who underwent radical prostatectomy between January 1, 2014 and December 30, 2014 were identified. All underwent mp-MRI within 180 days before surgery. Those with prior pelvic irradiation or androgen deprivation therapy were excluded. Fully embedded, whole-mount histopathology was centrally reviewed and correlated with imaging for tumour location, Gleason score (GS) and stage. RESULTS: There were 39 patients included, of which 35 (90%) had mp-MRI done post-biopsy. A total of 93 cancer foci were identified on whole-mount pathology, of which mp-MRI detected 63 (68%). Of those detected by mp-MRI, 14 were PI-RADS 3 (n = 6 for GS 6, n = 8 for GS 7, no GS ≥ 8) and 49 were PI-RADS 4-5 (n = 7 for GS 6, n = 33 for GS 7, and n = 9 for GS ≥ 8). There were 30 (32%) cancer foci missed by mp-MRI (n = 15 for GS 6, n = 13 for GS 7 and n = 2 for GS ≥ 8). A lesion classified as PI-RADS 4-5 predicted a higher grade cancer on pathology as compared to PI-RADS 3 (for GS 7 lesions, odds ratio [OR] = 3.53, 95% CI: 0.93-13.45, p = 0.064). The mp-MRI size detection limit was 20 mm2 and 100 mm2 for 50% and 75% probability of cancer, respectively. In associating with radiological and pathologic stage, the weighted Kappa value was 0.69 (p < 0.0001). The sensitivity and positive predictive values for this study were 68% (95% CI: 57%-77%) and 78% (95% CI: 67%-86%), respectively. CONCLUSION: In this predominantly post-biopsy cohort, mp-MRI using PI-RADSv2 reporting has a reasonably high diagnostic accuracy in detecting clinically significant prostate cancer.

A Diagnostic Approach to Fibroepithelial Breast Lesions.

Fibroepithelial breast lesions encompass a heterogeneous group of neoplasms that range from benign to malignant, each exhibiting differing degrees of stromal proliferation in relation to the epithelial compartment. Fibroadenomas are common benign neoplasms that may be treated conservatively. Phyllodes tumors are relatively rare lesions, and classified as benign, borderline, or malignant based on histologic evaluation of various parameters. The diagnostic interpretation of "gray-zone" fibroepithelial lesions often imposes formidable demands on a pathologist's skills. This article offers practical recommendations for the diagnostic workup of these lesions, including the appropriate utilization of ancillary investigations and the approach to core needle biopsies.

Clinicopathologic Characteristics of Solid Papillary Carcinoma of the Breast.

Solid papillary carcinoma (SPC) of the breast is defined as a "distinctive form of papillary carcinoma characterized by closely apposed expansive, cellular nodules." This uncommon tumor frequently demonstrates neuroendocrine differentiation. SPCs are staged as in situ tumors, except those that exhibit jagged borders within desmoplastic stroma, or if accompanied by conventional invasive carcinoma, which is separately graded and staged. In this study, we review the immunomorphologic characteristics of SPCs diagnosed at our institution, with a view toward elucidating points of distinction from other mammary carcinomas that manifest neuroendocrine differentiation. A total of 250 cases of in situ and invasive carcinomas with immunohistochemically documented neuroendocrine differentiation, spanning 12 years, were retrieved from the records of the Department of Pathology, Singapore General Hospital. Morphologic review identified 108 (43.2%) cases of SPC (in situ and/or invasive) among this group of tumors. Tumors with SPC components were significantly associated with estrogen receptor, progesterone receptor, and chromogranin A expression, spindled tumor morphology, and older patient age (above median age). In addition, invasive carcinomas with SPC components were more likely to be of smaller size (≤20 mm), low grade (grade 1), and to occur in older patients (above median age), compared with cases of invasive carcinoma lacking an SPC component. In situ SPCs were significantly associated with mucin production and demonstrated improved disease-free survival over cases of conventional ductal carcinoma in situ with neuroendocrine differentiation. Presence of an SPC pattern is associated with favorable clinicopathologic characteristics, with in situ SPCs demonstrating improved disease-free survival, emphasizing the importance of accurately diagnosing this uncommon tumor.