[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.

[Hemophagocytic lymphohistiocytosis associated with a lymphohistiocytic pattern anaplastic large cell lymphoma: a case report]. / Syndrome d'activation macrophagique révélant un lymphome anaplasique à grandes cellules de variante lymphohistiocytaire : à propos d'un cas.

We report the case of a 16-year-old girl with an anaplastic large cell lymphoma of lymphohistiocytic pattern revealed by a hemophagocytic syndrome. Histologically, the lymphomatous population was concealed by clusters of histiocytes. Immunohistochemical study allowed the diagnosis. The combination of these two entities is rarely described and may be a source of delay in diagnosis of a life-threatening condition.

[Second expert review on lymphoma: assessment of a one year activity in a general hospital]. / Expertise systématique des lymphomes diagnostiqués au cours d'une année d'activité d'un centre hospitalier : évaluation.

A standardized second histological review for lymphomas was established by the French National Cancer Institute in 2010. The objective of our study was to assess the clinical impact of this process between a general hospital (reader 1) and an expert (reader 2). This prospective study was conducted between April 1st 2010 and April 1st 2011. Fifty-four cases of lymphoma were subjected to an expert review following the "LYMPHOPATH" recommendations and diagnoses of readers 1 and 2 were compared according to the WHO 2008 classification of lymphomas. We distinguished serious discrepancies (lymphoma versus other malignancy) from subtyping disagreement with or without impact on therapeutic strategy. We also determined the delays between the initial reception of the sample and reader 1's (period A) and reader 2's (period B) reports, respectively. Any additional analysis performed by second reader was also reported. Our study revealed one case of subtyping discordance (1.85%). The mean delays were 7 days for period A and 20 days for period B, respectively. Additional immunohistochemical techniques were requested by reader 2 in 11 cases (20.4%). These data provide evidence to suggest that in our department, a second review targeted on difficult diagnoses, rare lymphomas or when further analyses are required would be more relevant than a standardized second review.

[Tumor-to-tumor metastasis: report of three cases]. / Métastases d'une tumeur dans une autre tumeur : à propos de trois cas.

Tumor-to-tumor metastasis is a very rare event. We report three cases of tumor metastasizing in another tumor: a clear cell renal cell carcinoma in a vesicular thyroid adenoma, a lung carcinoma in a meningioma and a neuroendocrine lung carcinoma in a clear cell renal cell carcinoma. According to the literature, clear cell renal cell carcinoma is the most common tumor recipient of metastasis while lung carcinoma is the most common donor tumor. Several physiopathological mechanisms can explain this phenomenon, but many of them are still unknown.

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.

[Request of second opinion for difficult diagnosis in surgical pathology. Assessment of a one year activity in a general hospital]. / Evaluation des demandes d'avis à un expert pour lésions de diagnostic difficile en anatomie et cytologie pathologiques. Analyse d'une année d'activité dans un service hospitalier.

OBJECTIVE: The objective of this study was to evaluate our practices concerning difficult lesions sent for second opinion to an expert. MATERIAL AND METHODS: We analyzed retrospectively all the requests for second opinion carried out over one year in our laboratory. The following data were indexed: organ, pathology (tumoral or not), type of sampling, the time, additional techniques carried out by the expert and comparison of the initial diagnosis with that of the expert. A provisional report was systematically performed before sending the observation to the expert. RESULTS: Among the 54 cases, 40 lesions were tumoral and 31 malignant. The type of pathology which were more often sent for opinion were lymphomas (18.5%) and soft tissue tumors (11%). The average time between reception of the sampling in our laboratory and the answer of the expert was 32.8 days. In 40.7% of the cases, additional techniques like immunohistochemistry (19 cases) or molecular biology (7 cases) were carried out by the expert and concerned especially lymphomas or soft tissue pathology. The comparison of the initial diagnosis with that of the expert showed no change in 53.7% of cases, 13% of divergence from benign-malignant (6 cases) or malignant-benign (1 case) type, 16.7% of changes of classification without modification of the benignity or the malignity, and 16.7% of difficult interpretation. CONCLUSION: This study seems to be a good means of evaluating our professional practices related to difficult lesions and confirms the importance of deep-freezing tumors, holding multidisciplinary meetings and participating in specialized working groups.

[Histologic changes after stereotactic 11-Gauge directional vacuum assisted breast biopsy for mammary calcification: experience in 31 surgical specimens]. / Cicatrice et lésions de déplacement: étude anatomo-pathologique de 31 pièces opératoires après macrobiopsies à l'aiguille de 11 Gauge pour des foyers de microcalcifications du sein.

II Gauge directional large core vacuum assisted biopsy has been used recently in the etiological diagnosis of microcalcifications. The objective of our work was to summarize the histological modifications resulting from vacuum biopsies observed on 31 surgical specimens issuing from a series of 109 biopsies performed over a 15-month period for malignant and borderline lesions. Histological modifications attributable to vacuum biopsies, scar tissue and displacements, were searched for in all cases. Scar tissue was seen as granulations, inflammation and hemorrhagic tissue associated or not with fat necrosis and/or foreign body giant-cell reaction. Displacements were seen as movements of injured tissue generally in the vicinity of scar tissue or vascular channels. Scar tissue was identified in all cases, presenting as star-shaped tissue measuring 12.8 mm on the average. Five displacements of either benign or malignant epithelia or of lymphovascular channels were observed (16% of the specimens). Scar tissue seen on surgical specimens indicates the location of the mammotome cut and confirms correctly directed surgery. It is particularly important to identify scar tissue because the lesions are nonpalpable and difficult to localize, or may have been totally removed at the initial biopsy. Displacements can be mistaken for infiltrating carcinoma or lymphatic invasion and must be carefully localized. They seem to be less frequent after vacuum biopsy.

[Keratoacanthoma: two cases with intravascular spread]. / Kératoacanthome: deux cas avec emboles vasculaires.

We report two patients with keratoacanthoma, simple in one and multiple in the other, displaying typical histological features except for intravascular spread. Although this spread points to malignancy, it did not allow to rule out the diagnosis of keratoacanthoma. These aggressive histological features, as well as perineural invasion, are not linked to malignant clinical course, according to the literature. Intravascular spread suggests that keratoancanthoma could be considered as a peculiar form of well differentiated squamous cell carcinoma. Comparison between clinical and pathological observations should lead to more specific diagnosis.

Immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells.

Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle. We previously reported that antigen specific CD4(+) T cell are immunologically ignorant to endogenous Ova in this model but can be stimulated upon immunization. In contrast, Ova-specific CD8(+) T cells were suspected to be either unresponsive to Ova challenge or functionally defective. We now extend our investigations on the mechanisms governing CD8(+) tolerance in SM-Ova mice. We show herein that Ova-specific CD8(+) T cells are not detected upon challenge with strongly immunogenic Ova vaccines even after depletion of regulatory T cells. Ova-specific CD8(+) T cells from OT-I mice adoptively transferred to SM-Ova mice started to proliferate in vivo, acquired CD69 and PD-1 but subsequently down-regulated Bcl-2 and disappeared from the periphery, suggesting a mechanism of peripheral deletion. Peripheral deletion of endogenous Ova-specific cells was formally demonstrated in chimeric SM-Ova mice engrafted with bone marrow cells containing T cell precursors from OT-I TCR-transgenic mice. Thus, the present findings demonstrate that immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8(+) T cells.

Improved Immunological Tolerance Following Combination Therapy with CTLA-4/Ig and AAV-Mediated PD-L1/2 Muscle Gene Transfer.

Initially thought as being non-immunogenic, recombinant AAVs have emerged as efficient vector candidates for treating monogenic diseases. It is now clear however that they induce potent immune responses against transgene products which can lead to destruction of transduced cells. Therefore, developing strategies to circumvent these immune responses and facilitate long-term expression of transgenic therapeutic proteins is a main challenge in gene therapy. We evaluated herein a strategy to inhibit the undesirable immune activation that follows muscle gene transfer by administration of CTLA-4/Ig to block the costimulatory signals required early during immune priming and by using gene transfer of PD-1 ligands to inhibit T cell functions at the tissue sites. We provide the proof of principle that this combination immunoregulatory therapy targeting two non-redundant checkpoints of the immune response, i.e., priming and effector functions, can improve persistence of transduced cells in experimental settings where cytotoxic T cells escape initial blockade. Therefore, CTLA-4/Ig plus PD-L1/2 combination therapy represents a candidate approach to circumvent the bottleneck of immune responses directed toward transgene products.