Une lésion labiale inhabituelle.

A 75 years old patient presented with a papular easily bleeding lesion of the lower lip that had been growing for two months. He was known for alcoholic cirrhosis complicated with hepatocellular carcinoma treated since one year. A working diagnostic hypothesis of benign vascular lesion was proposed. Microscopic examination showed a neoplastic dermal proliferation that had been fully excised, made of lobules segregated by thin fibrous septae. The neoplastic architecture was trabecular and delineating spaces forming pseudo-rosettes. Tumour cells were monomorphic, cuboidal or cylindric with abundant eosinophilic and granulous cytoplasm and centered by a lone nucleus that often contained a prominent nucleolus. Some spaces were filled with a brownish-greenish pigmented material. Immunohistochemical study showed that tumour cells were positive with the hepatocyte paraffin 1 antibody as well as cytokeratin 8 antibody. Chromogranin A and synaptophysin stainings were negative. Thus we concluded to a lip metastasis from the previously known hepatocellular carcinoma. Skin metastasis arise in around 3% of cases of hepatocellular carcinoma. They account for less than 1% of all cutaneous metastasis. Overall appearance of cutaneous metastasis of hepatocellular carcinoma is associated with a poor prognosis and an aggravated risk of metastasis to other locations and organs and a median overall survival of less than 5 months. Since incidence of hepatocellular carcinoma is rising pathologists might face more frequently in years to come to cutaneous metastasis whose varied clinical presentations make a diagnostic challenge.

[The first data challenge of the french society of pathology: An international competition in 2020, a research tool in A.I. for the future?] / Le premier data challenge organisé par la Société Française de Pathologie : une compétition internationale en 2020, un outil de recherche en intelligence artificielle pour l'avenir ?

The french society of pathology (SFP) organized in 2020 its first data challenge with the help of Health Data Hub (HDH). The organisation of this event first consisted in recruiting almost 5000 slides of uterus cervical biopsies obtained in 20 pathology centers. After having made sure that patients did not refuse to include their slides in the project, the slides were anonymised, digitized and annotated by expert pathologists, and were finally uploaded on a data challenge platform for competitors all around the world. Competitors teams had to develop algorithms that could distinguish among four diagnostic classes in epithelial lesions of uterine cervix. Among many submissions by competitors, the best algorithms obtained an overall score close to 95%. The best 3 teams shared 25k€ prizes during a special session organised during the national congress of the SFP. The final part of the competition lasted only 6 weeks and the goal of SFP and HDH is now to allow for the collection to be published in open access. This final step will allow data scientists and pathologists to further develop artificial intelligence algorithms in this medical area.

[An unusual digestive complication under anti-PD-1 (pembrolizumab)]. / Une complication digestive rare sous anti-PD-1 (pembrolizumab).

The most commonly reported pattern of anti-PD-1 induced colitis is an active colitis characterized by neutrophilic inflammation and prominent apoptosis. On the other hand, reports of collagenous colitis (which is a microscopic colitis) are exceptional. In this report, we describe an unusual case of anti-PD1-associated collagenous colitis in a 76-year-old man, treated with pembrolizumab for a stage IV cutaneous melanoma. Fourteen months after the start of pembrolizumab, the patient developed a grade 3 diarrhea (up to 9 stools per day) associated with profound hypokalemia. No bacterial, viral or parasitological infectious agents were found from stool analysis. The rectosigmoidoscopy showed colonic diffuse congestion with no ulceration. Systematic biopsies were performed during endoscopy. Histologically, the fragments analyzed revealed a moderately thickened subepithelial collagen layer (20-30µm thick) associated with a mild mixed inflammatory infiltrate within the lamina propria. There were no granuloma lesions, ulcerations or viral inclusion bodies. The patient was initially successfully treated with corticosteroids (prednisone) and temporary interruption of pembrolizumab. However, during corticosteroids tapering, a relapse was observed. The treatment was switched to budesonide, leading to a complete and definitive resolution of diarrhea. To date, budesonide has been stopped and pembrolizumab has not been restarted. Currently, there is a bone progression treated by radiotherapy alone. In case of a more important progression, a systemic treatment will be secondarily discussed.

[Large bowel ganglioneuromatosis associated with neurofibromatosis type 1]. / Ganglioneuromatose du tube digestif dans le cadre d'une neurofibromatose de type 1.

Gastrointestinal tract ganglioneuromatosis is a rare condition, which is isolated or included in a syndromique disease. Multiple endocrine neoplasia type 2 is the most frequently associated syndrome. Association with type 1 neurofibromatosis has also been established, but much rarely. We report the case of large bowel ganglioneuromatosis found incidentally in a patient with type 1 neurofibromatosis.

[A misleading breast metastasis of medullary thyroid carcinoma]. / Métastase mammaire d'un carcinome médullaire thyroïdien : un challenge diagnostique.

Recognition of mammary metastases by pathologists is fundamental because their prognosis and treatment are different from those of primary mammary carcinomas. We report the case of a 54-year-old woman presenting on her mammography a left breast nodule known for 5 years, having discreetly increased in size. Breast ultrasound showed a regular 1.2cm hypoechogenic nodular formation. A microbiopsy was performed. On microscopic examination, we observed a tumor proliferation realizing nests within a small, richly vascularized stroma. The tumor cells had a moderately abundant, eosinophilic, granular cytoplasm and a rounded, slightly atypical nucleus. One mitosis was found for 10 fields at×400 magnification. Tumor cells did not express hormone receptors but chromogranin A, synaptophysin, TTF1 and thyrocalcitonin. The proliferation index established by the anti-Ki67 antibody was 5 %. The diagnosis was a secondary localization of a well-differentiated neuroendocrine tumor which immunohistochemical profile firstly suggests a thyroid origin. We later learned that the patient had a history of total thyroidectomy 13 years ago. It was a sporadic medullary carcinoma of the thyroid. Bone scintigraphy revealed a lacunar lesion of the posterior part of the right iliac wing suspicious of secondary location. This right iliac lesion was biopsied. It was also a localization of the medullary thyroid carcinoma. The final diagnosis is a metastatic medullary thyroid carcinoma, slowly progressive, the mammary metastasis having probably existed for 5 years.

[Large scale teaching in pathology]. / Pédagogie à grande échelle en ACP.

Medical education is currently facing great changes that affect all medical specialties, including anatomical pathology. Due to rapidly increasing medical knowledge and diagnostic complexity, we are living an era of teaching resources mutualization. We present different tools that allow large numbers of students to access courses, self-evaluations, and competencies assessments. MOOC platforms and e-learning platforms are central to these new online tools, which include the French National Platform of Medical Specialties, dedicated to the teaching of 50,000 medical residents in France. We also discuss "serious games" and the use of images and virtual slides in anatomical pathology teaching. These new modalities can deliver essential knowledge to large student populations, but they must be used in conjunction with adapted teacher-led courses focusing on competencies and professional skills in order to be fully effective.

Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy?

BACKGROUND: Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. METHODS: Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. RESULTS: 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn's colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). CONCLUSIONS: Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. TRIAL REGISTRATION NUMBER: IRB 001508, Paris 7 University.

Utility and Safety of Liver Biopsy in Patients with Undetermined Liver Blood Test Anomalies after Allogeneic Hematopoietic Stem Cell Transplantation: A Monocentric Retrospective Cohort Study.

Liver blood test anomalies are common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but their cause often remains difficult to identify. Our objective was to evaluate the safety and utility of liver biopsies in patients who underwent allo-HSCT. In a retrospective single-center cohort study, we reviewed all cases of patients who underwent liver biopsy between June 2005 and July 2017. During this period, 54 biopsies were performed in 45 patients, in which 38 patients underwent allo-HSCT for malignant and 7 for nonmalignant hematological disorders. Median time between allo-HSCT and liver biopsy was 213 days. Seven biopsies were percutaneous, and 47 were transjugular. No adverse event related to the biopsy procedure occurred; 94.5% biopsies (51 of 54) led to a histological diagnosis. Cholestatic graft-versus-host disease was histologically demonstrated in 16 biopsies (30%); hepatitis-like graft-versus-host disease in 9 biopsies (17%); nonalcoholic steatohepatitis in 6 biopsies (9%); regenerative nodular hyperplasia in 4 biopsies (5%); and drug-induced liver injury, sinusoidal obstruction syndrome, and viral hepatitis each in 3 biopsies (5%). Association between clinical, laboratory, imaging and pathological features was poor. Only 34% of physicians' prebiopsy hypotheses were confirmed by pathological findings. Patient management was influenced by liver biopsy results in 65% of cases, allowing us to identify a new diagnosis (n = 13), rule out a differential diagnosis (n = 14), or confirm the main hypothesis (n = 6). In conclusion, liver biopsy is a safe and useful technique to investigate liver blood test anomalies following allo-HSCT.

18FDG-PET/CT for predicting the outcome in ER+/HER2- breast cancer patients: comparison of clinicopathological parameters and PET image-derived indices including tumor texture analysis.

BACKGROUND: This study investigated the value of some clinicopathological parameters and 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) indices, including textural features, to predict event-free survival (EFS) in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced breast cancer (BC) patients. METHODS: FDG-PET/CT indices and clinicopathological parameters were assessed before neoadjuvant chemotherapy (NAC). After completion of chemotherapy, all patients had breast surgery with axillary lymph node dissection, followed by radiation therapy and endocrine therapy for 5 years. EFS was estimated using the Kaplan-Meier method. A Cox proportional hazard regression model was used for multivariate analysis. RESULTS: One hundred forty-three consecutive patients with stage II-III ER+/HER2- BC and without distant metastases at baseline PET were included. High standardized uptake values (SUVs), were associated with shorter EFS (HR = 3.51, P < 0.01 for SUVmax; HR = 2.76, P = 0.02 for SUVmean; and HR = 4.40 P < 0.01 for SUVpeak). Metabolically active tumor volume (MATV, HR = 3.47, P < 0.01) and total lesion glycolysis (TLG, HR = 3.10, P < 0.01) were also predictive of EFS. Homogeneity was not predictive (HR = 2.27, P = 0.07) and entropy had weak prediction (HR = 2.89, P = 0.02). Among clinicopathological parameters, EFS was shorter in progesterone receptor (PR)-negative tumor (vs. PR-positive tumor; HR = 3.25, P < 0.01); histology was predictive of EFS (lobular vs. ductal invasive carcinoma; HR = 3.74, P = 0.01) but not tumor grade (grade 3 vs. grade 1-2; HR = 1.64, P = 0.32). Pathological complete response after NAC was not correlated to the risk of relapse. Three parameters remained significantly associated with EFS in multivariate analysis. MATV (HR = 1.01, P < 0.01), progesterone receptor expression (HR = 2.90, P = 0.03) and tumor histology (HR = 3.80, P = 0.02). CONCLUSIONS: Baseline PET parameters measured before neoadjuvant treatment have prognostic values in ER+/HER2- locally advanced breast cancer patients. After multivariate analysis, metabolically active tumor volume remains significant while textural analysis of PET images is not of added value. Considering histopathological parameters, our study shows that patients with PR-negative or lobular invasive tumor have poorer prognosis than patients with PR-positive or ductal carcinoma, respectively.

[Primary epithelioid adrenal angiosarcoma mimicking undifferentiated carcinoma]. / Angiosarcome épithélioïde surrénalien primitif simulant un carcinome peu différencié.

The adrenal primary epithelioid angiosarcoma (ASE) is a rare malignant tumor which can be histologically confused with other neoplasms. We report one case in a 79-year-old man who underwent adrenal tumor surgery for a mass fortuitly discovered by imaging for examination of an inflammatory syndrome associated with anemia. The histological diagnosis was difficult because of the undifferentiated and epithelioid appearance of tumor cells, whose immunohistochemical epithelial markers positivity led to frequent confusion with a metastatic carcinoma. Careful research for vascular differentiation at histopathological study and expression of immunohistochimical endothelial markers, are crucial to confirm the diagnosis.

[Results of the Massive Open Online Course (MOOC) on cancer diagnosis and evaluation of its impact on the perception of the pathology specialty]. / Massive open online course (MOOC) sur le diagnostic des cancers : bilan et évaluation de l'impact sur la perception de l'anatomie et cytologie pathologiques.

The Massive Open Online Course (or MOOC) "Diagnostic Strategies Cancers", was hosted in autumn 2016 on the platform "France Université Numérique" and had two levels of learners: students in the field of health and biology and the general public. Of the 5285 learners in 81 different countries, 1237 (23%) were successfully certified. This MOOC was also integrated into the teaching program of medical students of Paris Diderot University and Paris 13 University. Using anonymous questionnaires before and after MOOC, it has been shown that pathology is less known than other medical specialties. Participation in this MOOC led to a marked improvement in participants' knowledge of the place and role of the pathologist in the diagnosis of cancers. Regarding the students who have followed the MOOC as part of their university course, their comments were very positive, but it is necessary to make substantial adjustments in the amounts and contents of the campus-based courses.

[Backstage of a massive open online course (MOOC) on cancer diagnosis]. / Les coulisses d'un Massive Open Online Course (MOOC) sur le diagnostic des cancers.

Massive open online course (or MOOC) is a new online and open access teaching approach aimed at unlimited participation and providing interactions among students and teaching staff. These academic courses, often still free, lead to the delivery of a certificate of attendance and could soon also deliver a diploma. The MOOC "Stratégies diagnostiques des cancers" will be hosted in autumn 2016 on the platform "France Université Numérique" and will have two levels of learners: students in the field of health and biology and the general public. This MOOC will also be integrated into the teaching program of medical students of Paris Diderot University and Paris 13 University. The educational objective of this MOOC is to convey to all participants an overview of the diagnostic steps of cancers and of the various medical specialties involved in this diagnosis. The second week of the MOOC, entitled "tumor samples, macroscopic and microscopic analysis", presents the pathology specialty with the technical treatment of tissue or cell samples and the basic elements of the tissue section analysis to get a diagnosis of benign or malignant tumor. After this MOOC, it is planned to assess the impact of this new modality of teaching the pathology specialty or pathology, especially by the general public.

[Ductal carcinoma in situ diagnosis: 3 French national guidelines]. / Diagnostic du carcinome canalaire in situ : 3 recommandations nationales françaises.

OBJECTIVE: Since the last guidelines published by the French National Cancer Institute (INCa) and the learning society "Société française de sénologie et de pathologie mammaire (SFSPM)" in 2009 about diagnosis and management of ductal carcinoma in situ, new data raised issues about overdiagnosis and its consequences, overtreatment. Therefore, an update was necessary, to provide healthcare professionals up-to-date guidelines and study therapeutic desescalation in particular. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by a multidisciplinary experts workgroup. The recommendations are thus based on the best available evidence and experts agreement. Prior to publication, the guidelines are also reviewed by more than 100 independent practitioners in cancer care delivery. RESULTS: This article presents French guidelines about MRI and vacuum assisted breast biopsy indications for DCIS diagnosis and the management of low-grade DCIS.

Individual xenograft as a personalized therapeutic resort for women with metastatic triple-negative breast carcinoma.

A localized left breast ductal invasive triple-negative breast carcinoma (TNBC) was diagnosed in a 44-year-old woman. After surgery, she was treated with chemotherapy and radiation therapy in accordance with national guidelines. At the end of treatment, she had local and metastatic relapse with multiple sub-diaphragmatic lymph nodes.

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

Distinct tumor protein p53 mutants in breast cancer subgroups.

Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.

SISH/CISH or qPCR as alternative techniques to FISH for determination of HER2 amplification status on breast tumors core needle biopsies: a multicenter experience based on 840 cases.

BACKGROUND: Until now, FISH has been the gold standard technique to identify HER2 amplification status in ambiguous cases of breast cancer. Alternative techniques have been developed to increase the capacities of investigating HER2 amplification status. The aims of this multicenter study in a large series of breast cancer patients were to prospectively compare the level of performance of CISH, SISH, and qPCR alternative techniques on paraffin-embedded core biopsies with "gold standard FISH" for evaluation of HER2 amplification status. METHODS: This study was performed on 840 cases scored by immunohistochemistry (IHC): 0=317 (38%), 1+=183 (22%), 2+=109 (13%), 3+=231 (27%). Each of the 15 French centers participating in the study analyzed 56 breast carcinoma cases diagnosed on fixed paraffin-embedded core biopsies. HER2 amplification status was determined by commercially available FISH used as the reference technique with determination of the HER2/CEN17 ratio or HER2 copy number status. The alternative techniques performed on the same cases were commercially available SISH or CISH and a common qPCR method especially designed for the study including a set of 10 primer pairs: 2 for HER2 (exons 8 and 26), 5 to evaluate chromosome 17 polysomy TAOK1, UTP6, MRM1, MKS1, SSTR2 and 3 for diploidy control TSN, LAP3 and ADAMTS16. RESULTS: The concordance between IHC and FISH was 96% to 95% based on the HER2/CEN17 ratio (n=766) or HER2 copy number (n=840), respectively. The concordance of the alternative techniques with FISH was excellent: 97% and 98% for SISH (498 and 587 cases), 98% and 75% for CISH (108 and 204 cases) and 95% and 93% (699 and 773 cases) for qPCR based on the HER2/CEN17 ratio or HER2 copy number, respectively. Similarly, sensitivity ranged from 99% to 95% for SISH, 100% to 99% for CISH and 89% to 80% for qPCR. The concordance with FISH (ratio) in the 2+ cases was 89% for SISH, 100% for CISH and 93% for qPCR. CONCLUSION: These alternative techniques showed an excellent concordance with FISH in core biopsies allowing their use in routine clinical practice. This newly designed qPCR on paraffin-embedded core biopsies deserves special attention, as it is reliable, easy to perform and less expensive than ISH tests.

[The inter-university learning website: a national university network for online teaching of pathology]. / Le portail pédagogique inter-universitaire en anatomie et cytologie pathologiques : un outil collaboratif national pour l'enseignement en ligne.

Building online teaching materials is a highly time and energy consuming task for teachers of a single university. With the help of the Collège des pathologistes, we initiated a French national university network for building mutualized online teaching pathology cases, tests and other pedagogic resources. Nineteen French universities are associated to this project, initially funded by UNF3S (http://www.unf3s.org/). One national e-learning Moodle platform (http://virtual-slides.univ-paris7.fr/moodle/) contains texts, medias and URL pointing toward decentralized virtual slides. The Moodle interface has been explained to the teachers since september 2011 using web-based conferences with screen-sharing. The following contents have been created: 20 clinical cases, several tests with multiple choices and short answer questions, and gross examination videos. A survey with 16 teachers and students showed a 94 % satisfaction rate, most of the 16 participants being favorable to the development of e-learning, in parallel with other courses in classroom. These tools will be further developed for the different study levels of pathology. In conclusion, these tools offer very interesting perspectives for pathology teaching. The organization of a national inter-university network is a useful way to create and share numerous and good-quality pedagogic resources.