Accurate diagnosis of lymphoma on whole-slide histopathology images using deep learning.

Histopathological diagnosis of lymphomas represents a challenge requiring either expertise or centralised review, and greatly depends on the technical process of tissue sections. Hence, we developed an innovative deep-learning framework, empowered with a certainty estimation level, designed for haematoxylin and eosin-stained slides analysis, with special focus on follicular lymphoma (FL) diagnosis. Whole-slide images of lymph nodes affected by FL or follicular hyperplasia were used for training, validating, and finally testing Bayesian neural networks (BNN). These BNN provide a diagnostic prediction coupled with an effective certainty estimation, and generate accurate diagnosis with an area under the curve reaching 0.99. Through its uncertainty estimation, our network is also able to detect unfamiliar data such as other small B cell lymphomas or technically heterogeneous cases from external centres. We demonstrate that machine-learning techniques are sensitive to the pre-processing of histopathology slides and require appropriate training to build universal tools to aid diagnosis.

Melanoma-expressed CD70 is involved in invasion and metastasis.

BACKGROUND: CD70 is a costimulatory molecule of the tumour necrosis factor family expressed in activated immune cells and some solid tumours. In lymphocytes CD70 triggers T cell-mediated cytotoxicity and mitogen-activated protein kinase phosphorylation. METHODS: We evaluated the expression of CD70 in biopsies and melanoma cell lines. Using melanoma cell lines positive or not for CD70, we analysed CD70 function on melanoma progression. RESULTS: We report CD70 expression in human melanoma cell lines and tumour cells from melanoma biopsies. This expression was observed in 95% of primary melanomas but only 37% of metastases. Both monomeric and trimeric forms of CD70 were detected in tumour cell membrane fractions, whereas cytoplasmic fractions contained almost exclusively monomeric CD70. In vitro and in vivo experiments demonstrated that CD70 expression inhibited melanoma cell migration, invasion and pulmonary metastasis implantation independently of the tumour immune microenvironment. Increasing the levels of the trimeric form of CD70 through monoclonal antibody binding led to an increase in CD70+ melanoma cell invasiveness through MAPK pathway activation, RhoE overexpression, ROCK1 and MYPT1 phosphorylation decrease, and stress fibres and focal adhesions disappearance. CONCLUSIONS: Our results describe a new non-immunological function of melanoma-expressed CD70, which involves melanoma invasiveness through MAPK pathway, RhoE and cytoskeletal modulation.

The Role of Sentinel Lymph Node Biopsy and Factors Associated with Invasion in Extensive DCIS of the Breast Treated by Mastectomy: The Cinnamome Prospective Multicenter Study.

BACKGROUND: When invasive components are discovered at mastectomy for vacuum-assisted biopsy (VAB)-diagnosed ductal carcinoma in situ (DCIS), the only option available is axillary lymph node dissection (ALND). The primary aim of this prospective multicenter trial was to determine the benefit of performing upfront sentinel lymph node (SLN) biopsy for these patients. The secondary aim was to determine DCIS factors associated with microinvasion or invasion. METHODS: The SLN procedure was performed during mastectomy, and for positive SLN an ALND was performed during the same intervention. A tissue microarray containing DCIS lesions from the mastectomy specimens was subsequently performed. RESULTS: From May 2008 to December 2010, 228 patients were enrolled from 14 French cancer centers, including 192 eligible patients with pure DCIS on VAB and successful SLN procedures. ALND was avoided for 51 [67 %; 95 % confidence interval (CI), 56-77 %] of all the patients who had microinvasive DCIS or DCIS associated with invasive carcinoma at mastectomy and a negative SLN. Of the 192 patients, 76 (39 %) with VAB-diagnosed DCIS were upgraded after mastectomy to micro (n = 20) or invasive disease (n = 56). The rate of positive SLN for patients with DCIS on VAB was 14 %. High nuclear grade of DCIS was associated with greater risk of microinvasion and invasion, and HER2-amplified DCIS was associated with greater risk of invasion. CONCLUSIONS: Underestimation of invasive components is high when DCIS is diagnosed by VAB in patients undergoing mastectomy. Upfront SLN for patients with VAB-diagnosed extensive DCIS avoids unnecessary ALND for two-thirds of patients with micro or invasive disease on mastectomy.

A large retrospective multicenter study of vaginal melanomas: implications for new management.

The outcome of patients presenting with vaginal melanoma has been assessed in a large multicentric retrospective study. The databases of 12 French institutions were searched for primary vaginal melanomas managed between 1990 and 2007. Among the 54 patients recorded, 46 were managed with a curative intent and included in the study. The clinical characteristics, treatments, and detection of c-KIT protein expression have been studied. The median age of the patients was 63.5 years (42-88). Twenty-eight patients were classified as International Federation of Gynecology and Obstetrics (FIGO) stage I, five as stage II, six as stage III, and one as stage IVA. c-KIT protein was overexpressed in 80% of the patients. Forty-two patients underwent surgical resection of the tumor, nine patients received local adjuvant treatment, and 10 received systemic adjuvant therapy. The median relapse-free survival was 10.9 months. c-KIT-negative status (P=0.01) and stage I (P=0.02) were associated with locoregional recurrence. The rate of metastasis was increased for advanced FIGO stages (P<0.01). The median overall survival (OS) was 28.4 months. The finding of lymph node metastasis adversely affected OS (P<0.01). Conservative surgery and radiotherapy were associated with a decrease in metastasis-free and OS (P<0.01) compared with surgery alone, this group of patients presenting with advanced FIGO stages (P=0.02). Despite the use of limited data, conservative surgery combined with a sentinel lymph node procedure, followed by adjuvant radiotherapy could be proposed to patients with early FIGO stage in the absence of validated management. c-KIT negativity by immunochemistry appears to be a poor prognosis marker in terms of locoregional recurrences but not for metastatic spread nor survival. Further assessment of the role of c-KIT expression in this disease is thus mandatory to select patients for targeted therapy.

Typical medullary breast carcinomas have a basal/myoepithelial phenotype.

Medullary breast cancer (MBC) is a rare, diagnostically difficult, pathological subtype. Despite being high grade, it has a good prognosis. MBC patients have an excess of BRCA1 germ-line mutation and reliable identification of MBC could help to identify patients at risk of carrying germline BRCA1 mutations or in whom chemotherapy could be avoided. The aim of this study was therefore to improve diagnosis by establishing an MBC protein expression profile using immunohistochemistry (IHC) on tissue-microarrays (TMA). Using a series of 779 breast carcinomas ('EC' set), diagnosed initially as MBC, a double-reading session was carried out by several pathologists on all of the histological material to establish the diagnosis as firmly as possible using a 'medullary score'. Only MBCs with high scores, i.e. typical MBC (TMBC) (n=44) and non-TMBC grade III with no or low scores (n=160), were included in the IHC study. To validate the results obtained on this first set, a control series of TMBC (n=17) and non-MBC grade III cases (n=140) ('IPC' set) was studied. The expression of 18 proteins was studied in the 61 TMBCs and 300 grade III cases from the two sets. The global intra-observer concordance of the first reading for the diagnosis of TMBC was 94%, with almost perfect kappa (kappa) of 0.815. TMBC was characterized by a high degree of basal/myoepithelial differentiation. In multivariate analysis with logistic regression, TMBC was defined by the association of P-cadherin (R=2.29), MIB1 > 50 (R=3.80), ERBB2 negativity (R=2.24) and p53 positivity (RR=1.45).

Bilateral breast metastases from ewing sarcoma of the femur.

We report a case of bilateral breast metastases from Ewing sarcoma of the femur. A 40-year-old woman presented with Ewing sarcoma of the left thigh, treated by complete surgical exeresis and chemotherapy. Secondary, a large tumor appeared in the left breast. Bone scintigraphy, chest, and abdominal computed tomographic scan were normal. A breast biopsy found a malignant tumor composed of small round cells consistent with the initial diagnosis. After the first cycle of chemotherapy, a tumor was discovered in the controlateral breast. After 5 cycles, residual tumors persisted in the 2 breasts. Tumor exeresis was performed and found bilateral breast metastases of Ewing sarcoma. Because of the early recurrence of the left breast tumor, segmentectomy of the right breast and left mastectomy were performed. The histopathological analysis confirmed Ewing sarcoma metastases in the left breast. Despite local radiotherapy, the clinical course was marked by lumbar bone metastasis, local chest evolution, and progression of the disease. Metastases to the breast by extramammary malignant neoplasms are unusual. Sarcoma is an extremely rare cause of breast metastases and our case is the first report of breast metastases from Ewing sarcoma.