Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis.

In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis (n = 105), cerebellar degeneration (n = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis (n = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma (n = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice. Overall, Kelch-like protein 11 antibodies were detected in 11 patients [11/11, 100% were male; their median (range) age was 44 (35-79) years], 9 of them from the antibody-negative paraneoplastic neurological syndrome cohort, 1 from the antibody-positive (Ma2-Ab) cohort and 1 additional prospectively detected patient. All patients manifested a cerebellar syndrome, either isolated (4/11, 36%) or part of a multi-system neurological disorder (7/11, 64%). Additional core syndromes were limbic encephalitis (5/11, 45%) and myelitis (2/11, 18%). Severe weight loss (7/11, 64%) and hearing loss/tinnitus (5/11, 45%) were common. Rarer neurologic manifestations included hypersomnia and seizures (2/11, 18%). Two patients presented phenotypes resembling primary neurodegenerative disorders (progressive supranuclear palsy and flail arm syndrome, respectively). An associated cancer was found in 9/11 (82%) patients; it was most commonly (7/9, 78%) a spontaneously regressed ('burned-out') testicular germ cell tumour. A newly designed clinical score (MATCH score: male, ataxia, testicular cancer, hearing alterations) with a cut-off ≥4 successfully identified patients with Kelch-like protein 11 antibodies (sensitivity 78%, specificity 99%). Pathological findings (three testicular tumours, three lymph node metastases of testicular tumours, one brain biopsy) showed the presence of a T-cell inflammation with resulting anti-tumour immunity in the testis and one chronic, exhausted immune response-demonstrated by immune checkpoint expression-in the metastases and the brain. In conclusion, these findings suggest that Kelch-like protein 11 antibody paraneoplastic neurological syndrome is a homogeneous clinical syndrome and its detection can be facilitated using the MATCH score. The pathogenesis is probably T-cell mediated, but the stages of inflammation are different in the testis, metastases and the brain.

[2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France]. / Mise à jour 2021 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers infiltrants du sein en France.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

[Uterine malignant perivascular epithelioid cell tumor (PEComa): Two case reports]. / Tumeur des cellules épithélioïdes périvasculaires (PECome) maligne de l'utérus : deux observations.

Tumors of the perivascular epithelioid cells (PEComa) of the uterus are rare mesenchymal tumors that are characterized by the expression of both melanocyte and smooth muscle markers. It is often difficult to distinguish PEComas from other uterine tumors: endometrial stromal sarcoma, smooth muscle tumors including epithelioid tumors, melanoma and clear cell sarcoma. We report two cases of malignant PEComas of the uterus, treated in two different hospitals, found in women over 60, presenting a clinical picture of metrorrhagia in a context of myomatous uterus. In the first case, the histological examination of the hysterectomy specimen found a diffuse proliferation of epithelioid cells expressing HMB45. In the second case, the question of the differential diagnosis of the PEComa with a uterine epithelioid leiomyosarcoma arose, in front of the weak or even absent expression of the melanocytic immunohistochemical markers (melanA negative and focal HMB 45). The opinion requested from a network of experts (RRePS) had made it possible to validate the diagnosis of PEComa, notably by carrying out a complement of immunohistochemistry (expression of cathepsin K) by the tumor cells. In spite of its rarity, the diagnosis of PEComa should be considered before this type of epithelioid or clear cell uterine tumor because of the possibility of treatment by targeted therapies such as the mTOR (mammalian target of rapamycin) inhibitors.

[Bullous dermatitis with multinucleated keratinocytes in dermatitis artefacta: A case report]. / Dermatose bulleuse avec kératinocytes multinucléés révélant une dermatose factice : à propos d'un cas et revue de la littérature.

We report the case of a 13-year-old young lady with a one year reccuring bullous dermatitis history for which the diagnostic hypothesis of dermatitis arterfacta was made. This hypothesis was made by the pathologist, without it being suggested by the dermatologist, after observing singular histological lesions coresponding to a cutaneous blister associated with epidermic necrosis with multinucleated keratinocytes. When dermatitis artefacta is suspected, a biopsy is usually conducted to rule out differential diagnosis such as auto-immmune dermatitis when there is a blister. Confession from patients is rarely obtained. Therefore, having positive histogical clues for dermatitis artefacta would be of a great use to help making the diagnosis in difficult cases.

[GEFPICS' guidelines for management of breast cancer tissue samples in the neoadjuvant setting]. / Recommandations du GEFPICS pour la prise en charge des prélèvements dans le cadre du traitement néoadjuvant du cancer du sein.

Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).

[Microcystic serous cystadenoma: An uncommon neoplasm of pancreas. Report of two cases]. / Cystadénome séreux microkystique : une tumeur rare du pancréas. À propos de deux observations.

Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.

Histopathological Diagnosis of Prosthetic Joint Infection: Does a Threshold of 23 Neutrophils Do Better than Classification of the Periprosthetic Membrane in a Prospective Multicenter Study?

No gold standard exists for histopathological diagnosis of a prosthetic joint infection (PJI). The historical criterion considers the presence of neutrophil infiltration upon examination of periprosthetic tissue. Morawietz et al. proposed a classification of periprosthetic membranes (Morawietz et al., Clin Pathol 59:591-597, 2006, https://doi.org/10.1136/jcp.2005.027458) and a more recently described classification with a new cutoff value of 23 neutrophils in 10 high-power fields (Morawietz et al., Histopathology 54:847-853, 2009. https://doi.org/10.1111/j.1365-2559.2009.03313.x). We performed a multicenter prospective study, which compared both methods for the diagnosis of PJI. All suspicions of PJI (n = 264) between December 2010 and March 2012 in seven centers were prospectively included. Five perioperative specimens were collected per patient for cultures, and one was collected for histology. Diagnosis of PJI was made according to the Infectious Diseases Society of America (IDSA) guidelines. Histopathological analysis classified the patients according to the threshold of 23 neutrophils and according to the classification of Morawietz. Performances of both methods were compared by using clinical and/or bacteriological criteria as the gold standard. Among 264 patients with suspected PJI, a diagnosis of infection was confirmed in 215 and unconfirmed in 49 patients. Histopathological analysis was available for 150 confirmed PJI and 40 unconfirmed PJI cases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 78.7%, 90.0%, 96.7%, 52.9%, and 81.1%, respectively, for the Morawietz classification, and 82.0%, 90.0%, 96.9%, 57.1%, and 83.7%, respectively, for the 23-neutrophil threshold. The new algorithm using a threshold of 23 neutrophils can be proposed as a new gold standard for the histopathological diagnosis of PJI.

All pure flat atypical atypia lesions of the breast diagnosed using percutaneous vacuum-assisted breast biopsy do not need surgical excision.

BACKGROUND: The purposes of this study were to evaluate the outcome of women with pure flat atypical atypia (FEA) diagnosed at vacuum-assisted breast biopsy (VABB) targeting microcalcifications and to determine whether clinical, radiological and pathologic parameters are able to predict which lesions will be upgraded to malignancy. MATERIALS: 2414 cases of consecutive VABB for microcalcifications using VA 8-, 10- or 11-Gauge stereotactically guided core biopsy performed between January 2005 and December 2011 from two french breast cancer centers were evaluated. Data of women with VABB-diagnosed pure FEA who underwent either excisional surgery or mammographic follow-up were analyzed. Cases with mass lesions or ipsilateral cancers were excluded. Two pathologists (FA,PM) reviewed the results of procedures performed. Clinical, radiological, as well as histological criteria have been studied in order to determine the correlation between these factors and carcinoma underestimation. RESULTS AND CONCLUSION: This study included 70 cases of pure FEA. Twenty women underwent surgical excision and 50 had clinical and mammographic surveillance only. In three women FEA was upgraded to breast cancer on excision. Clinical and mammographic follow-up for a mean of 56 months ±â€¯27 in the group without excision showed two cancers in the same breast (Intermediate grade DCIS, and invasive ductal carcinoma 84 and 48 months respectively after VABB). Three factors were significantly predictive of underestimation or occurence of cancer for pure FEA when the radiologic lesions are calcifications: age≥ 57 years, radiologic size >10 mm and number of FEA foci ≥4.

Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as "combined" or "conventional." Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC.

Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria.

BACKGROUND: Merkel cell carcinoma (MCC) can present as a cutaneous tumor or a lymph node metastasis without a primary tumor. MCC presenting without a primary tumor (MCCWOPT) can be misinterpreted on histologic examination as lymph node metastasis (LNM) from another neuroendocrine carcinoma (LNMNEC). However, this distinction is crucial for therapeutic management. OBJECTIVE: To determine the discriminative criteria for the differential diagnosis of MCCWOPT, LNM from cutaneous MCC, and LNMNECs. METHODS: Clinical, morphologic, and immunohistochemical data (expression of cytokeratins AE1, AE3, 7, 19, and 20; chromogranin A, synaptophysin, thyroid transcription factor-1 [TTF-1]), as well as the presence of Merkel cell polyomavirus (by immunohistochemistry and PCR) were compared in patients with MCCWOPT (n = 17), LNM from a cutaneous MCC (n = 11), and LNMNEC (n = 20; 8 lung, 7 thyroid, 3 digestive tract, 2 other). RESULTS: MCC (including MCCWOPT and LNM from a cutaneous MCC) differed from LNMNEC by 7 discriminative criteria: 1) elderly age, 2) location of the tumor, 3) extent of the disease, 4) cytokeratin expression, 5) TTF-1 expression, 6) histologic type, and 7) Merkel cell polyomavirus detection, summarized under the acronym ELECTHIP. All MCC patients had ≥5 of the ELECTHIP criteria, whereas all patients with LNMNEC (except 1) had <3 criteria. LIMITATIONS: The discriminant ability of the ELECTHIP criteria should be validated in a second independent set. CONCLUSION: MCCWOPT can be distinguished from other LNMNEC by the ELECTHIP criteria.

[Gastro-intestinal neuroectodermal tumor (GNET): A case report of a small intestine tumor with hepatic metastases]. / Tumeur neuroectodermique gastro-intestinale (GNET) : à propos d'un cas de tumeur du grêle avec métastases hépatiques.

The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

[Colonic ulcers associated with taking Kayexalate(®) (sodium polystyrene sulfonate): about two cases]. / Ulcérations coliques associées à la prise de Kayexalate(®) (polystyrène sulfonate de sodium) : à propos de deux observations.

We report two cases of patients with chronic renal failure showing rectal bleeding due to digestive ulcers, associated with Kayexalate(®) alone. Kayexalate(®) crystals correspond to a typical histological picture and it is important to know how to identify them in order to discuss a possible pathogenicity.

[Pre-analytical stage for biomarker assessment in breast cancer: 2014 update of the GEFPICS' guidelines in France]. / Recommandations du GEFPICS concernant la phase pré-analytique pour l'évaluation de HER2 et des récepteurs hormonaux dans le cancer du sein : mise à jour 2014.

Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.