MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming.

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.

Granulomatous mastitis: etiology, imaging, pathology, treatment, and clinical findings.

PURPOSE: To outline the demographics, clinical presentation, imaging features, and treatment modalities observed among a series of patients diagnosed with biopsy-proven granulomatous mastitis (GM). METHOD: Following approval by institutional review board, retrospective chart review was performed on patients with biopsy-proven granulomatous mastitis at our institution in the period from January 2013 until October 2017. RESULTS: A total of 90 patients were identified: 87 women and 3 men. The mean age was 35 years, mostly women in their reproductive age. In our study, patients with GM were more likely to be Hispanic compared to the general population. Sixty-three percent of patients were within 5 years of previous pregnancy. Painful palpable mass-like lesion was the most common physical finding. Breast ultrasound (US) was performed in all patients, and most commonly showed a hypoechoic irregular-shaped mass. Mammography (MG) showed asymmetry or irregular mass as the main finding. Definitive diagnosis was obtained by imaging-guided core needle biopsies in 94.4%. Conservative management was preferred, and only one patient underwent surgery. CONCLUSION: Although clinical and radiological findings of patients with GM may mimic those of breast carcinoma, our study showed that women of childbearing age, especially among Hispanic ethnicity with a recent history of pregnancy or high prolactin level and newly tender mass-like lesion, in addition to new focal asymmetry on mammogram and heterogeneous hypoechoic irregular-shaped mass on ultrasound exam, should raise concern for GM. Non-invasive approach and clinical follow-up were the preferred treatment method.

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.

Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses.

Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8(+) tumor cells. The proinflammatory mediators TNF, IL-1ß, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1-CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.

Benign mucocele-like lesions of the breast: revisited.

Mucocele-like lesions of the breast are ruptured ducts that discharge their contents into the stroma. They constitute a spectrum from benign to atypical to malignant. The current management of these lesions diagnosed on core biopsy is excision. The goal of our study was to evaluate the necessity of this practice for benign mucocele-like lesions. Retrospective review of the pathology database from 1 January 2000 to 1 June 2008 identified 61 cases, with follow-up information available in 50 cases. Clinical, radiological, and pathological information was correlated. Core biopsies were reviewed to confirm the diagnosis and verify previous biopsy site. In all, 45 patients underwent surgery, whereas 5 patients were followed for >1 year and remained stable. Patient's ages ranged from 44 to 76 years. Most benign mucoceles were diagnosed stereotactically while targeting calcifications (93.3%); rarely, the lesion was a sonographically detected mass. Most excisions had no residual mucocele (37/45=82%). In seven cases (15.6%), atypical duct hyperplasia was present, three with residual mucocele. In one case, the residual mucocele showed a continuum from florid to atypical duct hyperplasia at the core biopsy site. The other six cases showed atypical duct hyperplasia adjacent to but not directly at the core biopsy site. The sizes of the benign mucoceles ranged from incipient to 0.6 cm, all containing calcifications except one, which was incidental. Radiological-pathological correlation was concordant in all cases except one with suspicious calcification, which was ductal carcinoma in situ on excision. In this series, the largest of its kind, the upstage rate of benign mucoceles diagnosed on core biopsy was 17.8%. With the exception of the ductal carcinoma in situ case, no radiological or morphological features were predictive of atypia. Thus, because of associated atypical duct hyperplasia, sampling reasons, and intralesional heterogeneity, we continue to recommend excision of benign mucocele-like lesions diagnosed on core biopsy.

Lobular neoplasia on core needle biopsy does not require excision.

BACKGROUND: Lobular neoplasia (LN), encompassing atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), is often an incidental finding on core needle biopsies (CNBs) performed in instances of radiologic densities and/or calcifications. Because LN is generally considered a risk factor for breast carcinoma, the utility of subsequent excision is controversial. METHODS: The authors' database yielded 98 cases of LCIS and/or ALH. Cases containing LN accompanied by a second lesion mandating excision (eg, radial scar, atypical ductal hyperplasia [ADH]) and those failing to meet strict diagnostic criteria for LN (eg, atypical cells, mitoses, single-cell necrosis) were excluded. Radiographic calcifications were correlated with their histologic counterparts in terms of size, number, and pattern. RESULTS: Ninety-one biopsies were performed for calcifications and 7 were performed for mass lesions. The ages of the patients ranged from 35 to 82 years. Fifty-three patients were followed radiologically without excision, 42 of whom had available clinicoradiologic information. The 45 patients who underwent excision were without disease at follow-up periods ranging from 1 to 8 years. Of these 45 patients, 42 (93%) had biopsy results demonstrating only LN. The remaining 3 patients had biopsies with the following findings: ADH in 1 biopsy, residual LCIS and a separate minute focus of infiltrating lobular carcinoma (clearly an incidental finding) in the second biopsy, and ductal carcinoma in situ admixed with LCIS in the third biopsy (a retrospective examination performed by 2 blinded breast pathologists revealed foci of atypical cells and mitoses). CONCLUSIONS: Excision of LN is unnecessary provided that: 1) careful radiographic-pathologic correlation is performed; and 2) strict histologic criteria are adhered to when making the diagnosis. Close radiologic and clinical follow-up is adequate.

Axillary sentinel lymph nodes can be falsely positive due to iatrogenic displacement and transport of benign epithelial cells in patients with breast carcinoma.

PURPOSE: Immunohistochemical (IHC) staining for cytokeratins (CK) is common practice in evaluating sentinel lymph nodes (SLNs) in patients with breast carcinoma. IHC positivity typically indicates metastasis. SLN procedures are increasingly common in patients with pure intraductal carcinoma (DCIS). Iatrogenic epithelial cell displacement and benign transport of breast epithelial cells into axillary lymph nodes are recently described phenomena. We report 25 cases in which these factors probably resulted in benign epithelial cells in axillary SLNs (ie, false positivity). METHODS: We reviewed 25 cases of CK-positive SLNs in which the epithelial cells had histologic and IHC characteristics different from their respective patients' underlying breast carcinomas. RESULTS: In all cases, the cytologic features of the epithelial cells in the SLNs were benign, and 22 matched those of corresponding intraductal papillomas that were involved by or were separate from the DCIS in the original cores or surgical biopsies. Fifteen cases were pure DCIS; most invasive tumors were smaller than 1.0 cm. In six carcinomas (DCIS) showing strong Her-2/neu staining, the corresponding epithelial cells in the SLNs were negative. In 13 tumors that were strongly and uniformly positive for estrogen receptor (ER), the cytokeratin-positive cells in the SLNs were negative for ER. Nineteen cases showed benign epithelial cell displacement at the biopsy site. CONCLUSION: Epithelial cells in SLNs may result from transport of displaced cells, usually originating in intraductal papillomas. Positive immunohistochemical results in SLNs should be interpreted with extreme caution to avoid automatically concluding that such cells represent metastasis. Sentinel lymph nodes in breast carcinoma can be falsely positive.

Endocervical glandular involvement is associated with high-grade SIL.

OBJECTIVE: To examine whether endocervical glandular involvement (EGI) by squamous intraepithelial lesions (SIL) is associated with the grade of the squamous lesion and to assess the usefulness of such association for diagnostic purposes. METHODS: Histologic sections from two hundred successive cases of cervical SIL were reviewed retrospectively from the archives of the Department of Pathology of a tertiary care medical center. RESULTS: Nine of 93 (9.7%) low-grade lesions and 41 of 107 (38.3%) high-grade lesions showed glandular involvement (P = 0.001, Chi-squared test). The relative risk of having EGI in high-grade lesions as compared to low-grade lesions was 3.95. CONCLUSION: EGI is seen approximately four times more frequently in high-grade SIL than in low-grade SIL. Therefore, in cases that are difficult to grade, the presence of EGI is in favor of the lesion being a high-grade SIL.